Spotlight: Subacute Endocarditis: The Great Masquerader

October 11, 2017

By  Helen Ma, MD

Peer Reviewed

Our new Spotlight series uses case vignettes to explore diagnosis, pathophysiology, and management of a wide variety of diseases seen in the outpatient and inpatient settings.  Articles in the Spotlight section contain clinical pearls that will be highlighted in the case discussion.  While the occasional zebra may appear, the goal of the series is to provide clinically relevant information, and each case has been selected specifically for the relevance of its learning points rather than its rarity. 

Learning objectives

1. To describe the reasons why s. viridans has a predilection toward heart valves.

2. Does antibiotic prophylaxis prior to dental procedures decrease incidence of infectious bacterial endocarditis?

Case summary

A 65-year-old man with hypertension, hypothyroidism and no known history of valvular heart disease presented to his primary care doctor with one month of generalized weakness and unintentional weight loss. The patient felt unwell, with neck and shoulder pain. He reported fever to 102 degrees Fahrenheit and cough at home. The patient had a dental procedure one month prior to admission. His blood work revealed white blood cells of 13.6mg/dL, hemoglobin of 13mg/dL, iron 27 ug/dl, TIBC 306 ug/dL with ferritin >800 ug/L and ESR 101mm/hr consistent with a systemic inflammatory state. A PET scan showed increased uptake in his spine involving multiple vertebral bodies. Blood cultures were positive for Streptococcus mitis, a species of the viridans group streptococcus and he presented to the hospital.

Physical exam at presentation to our hospital was notable for an elderly man who was alert and oriented. Vital signs were significant for an elevated temperature (100.2 F, BP 99/58, HR 89, RR 16, O2 98% RA). On cardiovascular exam, jugular venous distention was not present, and the patient was noted to have a regular rate and rhythm with normal S1/S2 but a harsh 2/4 short diastolic murmur. There were decreased breath sounds at the lung bases without bilateral lower extremity edema. A transthoracic echocardiogram revealed severe aortic insufficiency due to a 1.5cm aortic vegetation. He was treated with IV penicillin and gentamicin for two weeks followed by one month of ceftriaxone. He underwent aortic valve replacement given the risk of embolization with improvement in symptoms. The cause of his endocarditis was thought to be secondary to the dental procedure months before diagnosis; teeth #14 and #19 were found to have extensive carious lesions requiring extraction prior to surgery.


Why does Streptococcus viridans have a predilection toward heart valves in bacteremia?

In population studies, viridans group Streptococcus is among the most common cause of endocarditis. Both host and bacterial factors contribute to the pathogenesis of endocarditis. Host conditions include predisposing native valvular conditions, such as rheumatic heart disease, bicuspid aortic valves, prosthetic valves, intravenous drug use, intracardiac defibrillators, hemodialysis and advanced age[1,2].

Various factors make viridans streptococcus species well suited to causing endocarditis once it is in the bloodstream. First, viridans group streptococci can evade host immune surveillance by excreting a fibronectin binding protein to escape phagocytosis [3].  Second, viridans group streptococci have a fimbrial adhesion protein (FimA), which is a lipoprotein receptor antigen that serves as a major adhesin, allowing it to firmly adhere to heart valves, especially damaged valves, as in the conditions listed above predisposing these high-risk patients to clot formation [5].  As septic clusters flow through the bloodstream, they have a predilection to attach onto injured cardiac valves, already laden with platelet clots and unprotected by immune defenses, in which bacteria can colonize to form vegetations [4,5].  Viridans endocarditis can be difficult to treat as it is frequently associated with biofilm formation [4]. This limits antibiotic activity against the bacteria.  The persistent nature of biofilms also induces inflammation and contributes to chronic bacteremia and thromboembolic events.  Platelet-fibrin clots contribute to oral streptococci colonization as well as vegetation formation because of the platelet-bacteria-biofilm interaction seen in rat models and in human imaging [4,6].

Though our patient did not have known valvular disease, he may have had an undetected predisposing condition that led to the large vegetation on his aortic valve. Unlike severe heart failure or failure to respond to therapy, there is no definitive data for surgery in the prevention of stroke. Our patient did have improvement in fatigue and has been doing well after bioprosthetic heart valve replacement.

Does antibiotic prophylaxis prior to dental procedures decrease incidence of infectious bacterial endocarditis?

The most recent American Heart Association guidelines regarding antibiotic prophylaxis prior to dental procedures recommend limiting this to high-risk patients, such as those with prosthetic cardiac valves, previous infective endocarditis, congenital heart disease, and cardiac transplant recipients (table 1) [5].

Cardiac predisposition Absolute risk
None, general population 1 in 14 million dental procedures
Mitral valve prolapse 1 per 1.1 million dental procedures
Congenital heart disease 1 per 475 000 dental procedures
Rheumatic heart disease 1 per 142 000 dental procedures
Prosthetic cardiac valve 1 per 114 000 dental procedures
Previous infectious endocarditis 1 per 95 000 dental procedures

Table 1: Absolute risk of endocarditis in various conditions [5].

The consensus is that antibiotic prophylaxis leads to resistance as well as adverse reactions and that these costs outweigh any benefit. A study by the Mayo Clinic evaluating outcomes after reducing antibiotic prophylaxis revealed that the incidence of infective endocarditis caused by viridans group streptococci had not increased [7]. In addition, experimental rat models show that virulent strains of oral streptococci are refractory to antibiotic prophylaxis possibly because platelets absorb penicillin, reducing its bactericidal activity and allowing septic vegetations to form [4]. Though prophylaxis does not show a benefit in any group, in patients who are at high-risk there may be a theoretical justification for using antibiotics to prevent endocarditis; nonetheless it will be important to weigh the risks and benefits when prescribing.


Subacute endocarditis should be in the differential when patients present with weight loss, fever and chronic inflammation, especially when the work-up is inconsistent with the leading diagnosis. Host and bacterial factors contribute to the formation of vegetations, and damaged heart valves are especially susceptible.

Dr. Helen Ma, residency at NYU Langone Health

Peer reviewed by Stuart Dickerman, MD, Cardiologist, NYU Langone Health

Image courtesy of Wikimedia Commons


[1] Tleyjeh IM, Steckelberg JM. Changing epidemiology of infective endocarditis. CurrInfect Dis Rep. 2006 Jun;8(4):265-70.

[2] Correa de Sa DD, Tleyjeh IM, Anavekar NS, Schultz JC, Thomas JM, Lahr BD, Bachuwar A, Pazdernik M, SteckelbergJM, Wilson WR, Baddour LM. Epidemiological trends of infective endocarditis: a population-based study in Olmsted County, Minnesota. Mayo Clin Proc. 2010 May;85(5):422-6. doi: 10.4065/mcp.2009.0585.

[3] Jung CJ, Zheng QH, Shieh YH, Lin CS, Chia JS. Streptococcus mutans autolysin AtlA is a fibronectin-binding protein and contributes to bacterial survival in the bloodstream and virulence for infective endocarditis. Mol Microbiol. 2009;74:888-902.

[4] Jung CJ, Yeh CY, Hsu RB, Lee CM, Shun CT, Chia JS. Endocarditis pathogen promotes vegetation formation by inducing intravascular neutrophil extracellular traps through activated platelets. Circulation. 2015 Feb 10;131(6):571-81.

[5] Wilson W, Taubert KA, Gewitz M, Lockhart PB, Baddour LM, Levison M, Bolger A, Cabell CH, Takahashi M, Baltimore RS, Newburger JW, Strom BL, Tani LY, Gerber M, Bonow RO, Pallasch T, Shulman ST, Rowley AH, Burns JC, Ferrieri P, Gardner T, Goff D, Durack DT; American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology; Council on Cardiovascular Surgery and Anesthesia; Quality of Care and Outcomes Research Interdisciplinary Working Group; American Dental Association. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. J Am Dent Assoc. 2007 Jun;138(6):739-45, 747-60.

[6] Jung CJ, Yeh CY, Shun CT, Hsu RB, Cheng HW, Lin CS, Chia JS. Platelets enhance biofilm formation and resistance of endocarditis-inducing streptococci on the injured heart valve. J Infect Dis. 2012 Apr 1;205(7):1066-75.

[7] DeSimone DC, Tleyjeh IM, Correa de Sa DD, Anavekar NS, Lahr BD, Sohail MR, Steckelberg JM, Wilson WR, BaddourLM; Mayo Cardiovascular Infections Study Group. Incidence of Infective Endocarditis Due to Viridans Group Streptococci Before and After the 2007 American Heart Association’s Prevention Guidelines: An Extended Evaluation of the Olmsted County, Minnesota, Population and Nationwide Inpatient Sample. Mayo Clin Proc. 2015 Jul;90(7):874-81.






Stem cells for heart failure: What is the evidence?

September 27, 2017

StemcellheartrepairBy Maxine Wallis Stachel, MD

Peer Reviewed

The Scale of the Problem

Despite decades of rigorous data collection, drug research, patient education and evidence-based practice, ischemic heart disease (IHD) and congestive heart failure (CHF) remain among the most deadly diagnoses in America. The standardization of medical therapy and surgical revascularization have reduced morbidity and mortality, but these measures have not kept pace with the burden and cost of disease, which continue to expand as the population ages and more patients survive acute myocardial infarction. IHD and CHF are heterogeneous and multifactorial, but their common course is marked by dysfunctional cell signaling and the death of cardiomyocytes, leading to hibernating or scarred cardiac tissue and decreased pump function.

Vasodilators and diuretics both reduce symptoms of disease by helping to off-load the over-stressed heart, preventing further adverse remodeling. In theory, stem cells—with their limitless capability to replace lost cardiomyocytes or summon new blood vessels—might help reverse the dysfunction already present.

These cells might be harvested from the patient or a suitable donor; isolated, cultured or otherwise enhanced ex vivo; and then delivered back to the patient via intracardiac infusion or intramyocardial injection, perhaps during CABG or PCI.

Indeed, a number of clinical studies have investigated this premise, with variable but intriguing results. The studies discussed here are limited to bone-marrow derived stem cells and cardiac progenitor cells, those stem cell populations that have been most heavily researched and appear most promising for the development of a cell-based therapy. While embryonic and induced pluripotent stem cells have been investigated in animal models, their use is associated with many risks including tumorigenicity that will likely limit their application in the clinic. Similarly, skeletal myoblasts have been associated with arrhythmogenesis that will probably hinder widespread use. 

Bone-Marrow Derived Stem Cells for HF

Bone marrow-derived stem cells are isolated from marrow aspirates or peripheral blood (usually after mobilization with G-CSF), and are thought to work by either engrafting into the injured myocardium directly or through paracrine signaling. BMSCs are a mix of undifferentiated cell types, and have been shown to differentiate in vitro into both vascular endothelial cells and cardiomyocytes.[1]  The factors secreted by BMSCs have not been definitively characterized, but are believed to work by recruiting new blood vessels, inhibiting fibrosis and/or stimulating myogenesis.

A 2014 Cochrane review[2] of 23 randomized clinical trials evaluating BMSCs for chronic IHD found that, in aggregate, the delivery of BMSCs to patients resulted in an unclear effect on clinical outcomes (mortality and rehospitalization), but improved surrogate indicators (e.g,  LVEF and New York Heart Association (NYHA) class) over short- and long-term follow-up. Many trials included in the analysis did suggest improvement in clinical endpoints with BMSC treatment (mortality RR 0.28, p = 0.02; heart failure-related rehospitalization, RR 0.6, p = 0.04), but the Cochrane reviewers designated the evidence as “low quality,” due to the low number of deaths and hospital readmissions across these small studies (most had fewer than 50 participants). The trials were better-powered to report surrogate endpoints, with LVEF improved overall by 4.22% in studies less than 1 year in duration, and 2.62% in longer-term studies. NYHA Class improved by 0.63 in studies less than 1 year, and by 0.91 in longer-term studies. These data must also be interpreted with caution, however, as the studies were not always sufficiently blinded to remove the risk of bias.

Interestingly, the greatest improvement was seen in patients with the worst LVEF and NYHA Class at study initiation. In 2010, Poveshenko et al.[3] randomized 110 patients with IHD, end-stage CHF and no option for revascularization to receive either bone marrow mononuclear cells (BMMCs) with standard medical therapy, or medication alone. BMMCs were aspirated from the iliac crest and injected into the border zone of a prior myocardial infarction, with no periprocedural complications. The authors found a statistically significant and sustained improvement in NYHA class in the treatment arm (3.3 ± 0.2 at baseline, 2.4 ± 0.23 at 3 months, 2.3 ± 0.2 at 6 months, 2.5 ± 0.1 at 12 months) as it worsened in controls (3.5 ± 0.1 at baseline, 3.5 ± 0.8 at 3 months, 3.8 ± 0.1 at 6 months, 3.9 ± 0.1 at 12 months). Similarly, the LVEF increased in the treatment group as it decreased in the control arm (baseline 27.8 ± 3.4 vs. 26.8 ± 3.8 at baseline, 32.3 ±4.1 vs 25.2 ± 4.1 at 12 months). Seventy-three percent of patients in the BMMC group demonstrated improved myocardial perfusion in the areas injected 6 months after treatment. Patients in the treated arm also reported fewer daily episodes of angina, were able to walk greater distances in 6 minutes, and scored better on a standard quality of life indicator (the Minnesota Living with Heart Failure score) compared with baseline and controls.

Cardiac Stem Cells

The heart also has it own resident population of stem cells (CSCs). Multipotent cardiac progenitors have been identified in the hearts of embryonic mammals, capable of differentiating into cardiomyocytes, endothelial cells and smooth muscle.[4],[5] A number of labs have also demonstrated that cardiomyocytes regenerate throughout adult life, with estimated rates of turnover likely close to 1% per year and declining with age.[6],[7] Tremendous controversy exists about the manner of this renewal; evidence shows that it may occur through differentiation of adult progenitor cells, division of pre-existing cardiomyocytes or even through so-called “epithelial-to-mesenchymal transformation” of epicardial cells.

Complicating matters further is that baseline homeostatic mechanisms for renewal may vary substantially from any renewal seen after injury.  Delivery of exogenous CSCs to infarcted myocardium may result in direct engraftment, differentiation and repair. More likely, these exogenous CSCs may work in a paracrine fashion, stimulating native CSCs to complete the repair work.[8] Even the cell surface markers used to define putative cardiac progenitor cells are controversial, and the details are beyond the scope of this review. Suffice it to say that most investigators agree on c-kit as one marker of CSCs and have exploited this feature to isolate and expand CSCs from cardiac samples obtained during CABG or via biopsy.[9] The cells can be grown and differentiated into ex vivo, and transplanted back into heart failure patients.

In the well-publicized randomized open-label Phase I SCIPIO trial[10], investigators enrolled patients with post-infarct, pre-CABG LVEF <40%. During CABG, CSC-containing tissue was harvested from the right atrial appendage and grown in culture. Four months later, the patients either underwent catheterization and received intracoronary infusion of CSCs, or had additional no intervention. There were no CSC-related adverse events. In 14 treated patients, LVEF improved to 38.5% at 4 months post-infusion from 30.3% at baseline (p = 0.001), and increased even further at one year. The LVEF of controls remained unchanged. In 7 treated patients who underwent cMRI, infarct size decreased by 24% at 4 months (p = 0.004) and by 30% at 1 year (p = 0.04) compared with baseline.

In another randomized Phase I trial of CSCs, the CADUCEUS[11] investigators enrolled patients with recent MI and successful PCI (within 1 month) and reduced EF (25-45%). Patients in the treatment arm underwent endomyocardial biopsy, from which CSC-containing “explants” were grown into small balls called “cardiospheres” and further processed into cardiosphere-derived cells (CDCs). The CDCs were infused into the infarct-related artery 1.5 to 3 months after MI. At 6 months after infusion, MRI analysis of the treatment group revealed reduced scar mass, increased viable heart mass, and improved contractility compared with controls (all p < 0.05). Notably, there was no difference between the groups in terms of LVEF and end-systolic and end-diastolic volumes over this period. A second paper published by the CADUCEUS investigators demonstrated that these effects roughly persisted at 1 year.[12] 

The Upshot

While it is unclear how these cells work—and indeed, whether they do work—there are a number of interesting lessons to be learned from the preliminary human experiments conducted so far. Not least among these is the impressive safety profile of stem cell transfusion procedures. Assuming some cells do engraft and presumably differentiate or signal differentiation in an electrically and mechanically dynamic environment, it is impressive how seamlessly coupling occurs, without inducing arrhythmias or worsening wall motion abnormalities.  Preliminary studies also demonstrate that the harvesting, processing and administration of stem cells is feasible with existing technologies. BMDCs are particularly attractive in this regard, as they can be transplanted without the ex vivo expansion required for other cell types.

Importantly, these initial studies underscore the multitude of technical factors that must be considered and optimized prior to wide-scale clinical use of stem cell therapy for IHD. Researchers continue to investigate more robust cell-processing methods, work to optimize cell type and dose and develop more efficient delivery systems. In the studies discussed herein, scientists routinely transplanted millions of stem cells, with the understanding that only a tiny proportion of cells would engraft. Some researchers have started transplanting the cells in mixed populations or supported in gels or glue in order to improve retention. Others have genetically enhanced or exposed cells to hypoxic conditions (“preconditioned” them) to improve homing and survival in the unforgiving ischemic environment.[13] Timing, too, plays a crucial role; transplantation too soon after MI, in the setting of massive inflammation and apoptosis, may result in poorer engraftment.[14],[15]

In order to choose among the infinite combinations of cells, dose, delivery routes and timing, researchers must perform more direct comparisons of the interventions. These would be greatly aided by development of methods to reliably track and assess the fate of transplants, which is a difficult task in human subjects. If, in fact, the stem cells work by exerting paracrine effects, then knowledge of their behavior and interaction with other players (cytokines, growth factors, RNAs etc) will facilitate therapeutic refinement.

As with most first-in-class therapeutic research, the data supporting stem cells for IHD is messy, unclear, and evolving. Studies showing improvement in surrogate endpoints (LVEF, LVESV, NYHA Class) without any appreciable adverse effects are encouraging. However, definitive assessment of will require larger studies conducted over the long-term and powered to assess clinically relevant endpoints (mortality, quality of life) with reproducible results.

Dr. Maxine Wallis Stachel is a 2nd year resident at NYU Langone Health

Peer reviewed by Glenn Fishman, MD, Biochemistry and Molecular Pharmacology, NYU Langone Health

Image courtesy of Wikimedia Commons


[1] Ohnishi S, Ohgushi H, Kitamura S, Nagaya N. Mesenchymal stem cells for the treatment of heart failure. Int J Hematol. 2007 Jul;86(1):17-21. DOI: 10.1532/IJH97.07041.

[2] Fisher SA, Brunskill SJ, Doree C, Mathur A, Taggart DP, Martin-Rendon E. Stem cell therapy for chronic ischaemic heart disease and congestive heart failure. Cochrane Database Syst Rev. 2014 Apr;(4): CD007888. DOI: 10.1002/14651858.CD007888.pub2.

[3] Pokushalov, E., Romanov, A., Chernyavsky, A. et al. Efficiency of intramyocardial injections of autologous bone marrow mononuclear cells in patients with ischemic heart failure: a randomized study. J. Cardiovasc. Trans. Res. 2010 April;3(2):160-168. doi:10.1007/s12265-009-9123-8.

[4] Wu SM, Fujiwar Y, Cibulsky SM, et al. Developmental origin of a bipotential myocardial and smooth muscle cell precursor in the mammalian heart. Cell. 2006 Dec;127(6):1137-1150. DOI: 10.1016/j.cell.2006.10.028.

[5] Moretti A, Caron L, Nakano A, et al. Multipotent embryonic Isl1+ progenitor cells lead to cardiac, smooth muscle and endothelial cell diversification. Cell. 2006 Dec;127(6):1151-1165. DOI: 10.1016/j.cell.2006.10.029.

[6] Bergmann O, Bhardwaj RD, Bernard S, et al. Evidence for cardiomyocyte renewal in humans. Science. 2009 Apr;324(5923):98-102. DOI: 10.1126/science.1164680.

[7] Garbern JC and Lee RT. Cardiac stem cell therapy and the promise of heart regeneration. Cell Stem Cell. 2013 Jun;12(6):689-698. DOI: 10.1016/j.stem.2013.05.008.

[8] Tang XL, Rokosh G, Sanganalmath SK, et al. Intracoronary administration of cardiac progenitor cells alleviates left ventricular dysfunction in rats with 30-day-old infarction. Circulation. 2010;121:293-305. DOI: 10.1161/CIRCULATIONAHA.109.871905.

[9] Smith RR, Barile L, Cho HC, et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007;115(7):896-908.

[10] Bolli R, Chugh AR, D’Amario D, et al. Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial results of a randomised phase 1 trial, The Lancet. 2011;378(9806):1847-1857. DOI: 10.1016/S0140-6736(11)61590-0.

[11] Makkar RR, Smith RR, Cheng K, et al. Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): a prospective randomized Phase 1 trial. The Lancet. 2012; 379(9819):895-904.

[12] Malliaras K, Makkar RR, Smith RR, et al. Intracoronary cardiosphere-derived cells after myocardial infarction: Evidence of therapeutic regeneration in the final 1-year results of the CADUCEUS trial. J Am Coll Cardiol. 2014 Jan;63(2):110-122. DOI: 10.1016/j.jacc.2013.08.724.

[13] Hu X, Yu SP, Fraser JL, et al. Transplanatation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis. J Thorac Cardiovasc Surg. 2008;135(4):799-808. DOI: 10.1016/j.jtcvs.2007.07.071.  

[14] Assmus B, Rolf A, Erbs S, et al. Clinical outcome 2 years after intracoronary administration of bone marrow-derived progenitor cells in acute myocardial infarction. Circulation: Heart Failure. 2010;3:89-96. doi:10.1161/CIRCHEARTFAILURE.108.843243

[15] Traverse JH, Henry TD, Pepine CJ, et al. Effect of the Use and Timing of Bone Marrow Mononuclear Cell Delivery on Left Ventricular Function After Acute Myocardial InfarctionThe TIME Randomized Trial. JAMA. 2012;308(22):2380-2389. doi:10.1001/jama.2012.28726


Gamechanger? Is Spironolactone the Magic Bullet for Resistant Hypertension?

November 9, 2016

high_blood_pressureBy Amar Parikh, MD

Peer Reviewed

Welcome to Gamechangers, a series that takes a critical look at the latest in medical literature to answer one important question: would the results of this article change my practice? Featuring thorough evidence-based review as well as expert commentary, our aim is for this series to help you decide if the results of a given study are, in fact, a gamechanger.

A 65 year-old Hispanic male with type 2 diabetes, hypertension, hyperlipidemia, and erectile dysfunction presents to clinic for follow-up and is found to be hypertensive to a systolic blood pressure (SBP) in the 160s on a regimen of amlodipine 10 mg daily, lisinopril 40 mg daily, and hydrochlorothiazide 25 mg daily. The patient is already on maximum doses of a calcium channel blocker (CCB), angiotensin-converting enzyme inhibitor (ACEi), and a thiazide-like diuretic, and he refuses any beta blocker as he fears it will worsen his erectile dysfunction. What are your options for additional anti-hypertensives, and would you consider spironolactone? 

Why Does This Matter?

Resistant hypertension (rHTN), defined as suboptimal blood pressure control despite treatment with at least three anti-hypertensives including a thiazide or thiazide-like diuretic, is associated with a poor prognosis and poses a unique challenge to physicians. It is estimated that at least one in 10 patients with hypertension are drug-resistant, which amounts to approximately 100 million patients worldwide [1]. The PATHWAY-2 trial is a recent, potentially groundbreaking study that evaluated the use of spironolactone versus placebo and other anti-hypertensives to determine whether it is an optimal, effective treatment for rHTN. The underlying pathophysiology of rHTN is poorly understood, but is hypothesized to be a result of sodium retention. Therefore, the authors of the PATHYWAY-2 trial predicted that spironolactone, which achieves its diuretic action through blockage of mineralocorticoid receptors and thus inhibits a critical mechanism of sodium retention, would be most likely to benefit patients with rHTN [2]. The PATHWAY-2 trial compared spironolactone with other fourth-line agents that target different mechanisms to produce its anti-hypertensive effect, specifically doxazosin, an alpha-1-blocker that reduces peripheral vascular resistance, and bisoprolol, a beta-1-blocker that reduces cardiac output and inhibits renin release. The trial also sought to determine whether patients with low plasma renin, a surrogate marker for sodium retention, were more effectively treated with spironolactone. Such a finding would support the hypothesis that sodium retention is the key mechanism driving rHTN, as well as help to personalize treatment by using a patient’s plasma renin level to predict whether he or she will respond to spironolactone or an alternate agent.

How was the study designed?

The PATHWAY-2 trial was a double-blinded, placebo-controlled, crossover study and was remarkably well designed. Study participants were between ages 18-79, had an SBP reading in clinic of greater than 140 (or 135 in diabetics), home readings with an average SBP > 130, and had to have been treated for at least 3 months with maximum tolerated doses of 3 classes of medications – CCB, ACEi (or angiotensin II receptor blocker), and diuretic – to be classified as having resistant hypertension. Participants were started with 1 month of ‘run-in’ with placebo in addition to their pre-trial regimen of a CCB, ACEi, and diuretic. They were then treated for four 12-week treatment cycles with spironolactone 25 to 50 mg, doxazosin 4 to 8 mg, bisoprolol 5 to 10 mg, or placebo, each participant thus eventually receiving all four treatments separately within a 12-month period. Doses were uptitrated as tolerated at the halfway mark within each 12-week treatment cycle. Importantly, there was no washout period between each of the four treatment cycles.

The study featured three primary measurements – home SBP, clinic SBP, and baseline plasma renin levels. The method that the investigators used to measure blood pressure is a distinctive feature of this trial. In most studies, only clinic SBP readings were used, raising the issue of white coat hypertension as a possible confounder. This effect was demonstrated even in the baseline SBP readings in this study, as clinic SBP was 10 mm Hg higher than home SBP (157 versus 147 mm Hg).  During the study period, investigators had participants check their blood pressure multiple times daily for four consecutive days before one of the scheduled study visits, and the average of these home BP measurements was recorded. Particular attention was given to standardizing the automated home BP monitor participants used, and nurse specialists instructed patients in appropriate self-measurement technique at each follow-up visit. Clinic SBP was calculated as the mean of two SBP readings during each of the nine follow-up clinic visits. The primary endpoints were the difference in home SBP between spironolactone and placebo, as well as the difference in SBP between spironolactone and the average SBP of both bisoprolol and doxazosin.

What were the study results?

The results of PATHWAY-2 were striking. Among the three agents tested, spironolactone produced the largest decrease in average home SBP (12.8 mm Hg) from baseline, significantly greater in magnitude than the decrease in the placebo group (4.1 mm Hg).  Meanwhile, doxazosin (8.7 mm Hg) and bisoprolol (8.3 mm Hg) treatment yielded a comparatively modest decrease.  In addition, average home SBP was significantly lower (3.86 mm Hg) in participants on high dose (50 mg) spironolactone treatment when compared to those on a lower dose (25 mg), whereas the high versus low dose differentials for doxazosin and bisoprolol were 0.88 and 1.49 mm Hg, respectively. These results indicate that spironolactone had the largest dose-response effect.  Overall, roughly 60% of patients on spironolactone achieved a target SBP < 135 mmHg, while just 42% of patients on doxazosin and 43% on bisoprolol met this treatment goal.  Furthermore, the authors observed that lower baseline plasma renin (and thus higher presumed sodium retention) strongly correlated with a larger magnitude decrease in SBP in patients on spironolactone, thus supporting the hypothesis that spironolactone therapy will be most effective in patients with low plasma renin levels.  Finally, adverse effects were uncommon: treatment discontinuation due to acute kidney injury, hyperkalemia, or gynecomastia was not increased in the spironolactone treatment group when compared to other treatments and placebo.

What were the flaws of the study?

There are several key limitations to PATHWAY-2 and unanswered questions regarding its generalizability. It is unclear if there was a carryover effect from each drug since there was no washout period in between each class of agent. The authors argue against this potential caveat by observing that there were identical differences between all agents when only the first cycle of treatment was compared in a parallel group fashion, thus indicating that spironolactone was immediately effective in the first cycle before any carryover effect from bisoprolol or doxazosin could take effect and distort interpretation of the data. Additionally, while there were minimal side effects observed during this study, spironolactone was only evaluated for 12 weeks. The most common and feared side effects of spironolactone, particularly gynecomastia and hyperkalemia, may increase in incidence the longer the patient is on therapy. Gynecomastia has been shown to be exposure-dependent, so this may be a prohibitive side effect for some patients. Finally, bisoprolol and doxazosin are not as commonly used in the US compared to labetalol, carvedilol, or terazosin, so it remains to be seen if those agents would compare favorably to spironolactone.

What is the bottom line?

Overall, PATHWAY-2 is a well-designed study with several strengths. It distinguishes itself from other hypertension trials by including home SBP readings, thus excluding any white coat hypertension effect. It is also the first study comparing multiple fourth-line agents head-to-head, demonstrating that while doxazosin and bisoprolol are more effective than placebo, they are not as effective as spironolactone. These findings altogether suggest a hierarchy for fourth-line treatment options for rHTN: spironolactone, followed by doxazosin or bisoprolol. This study also showed that spironolactone exhibited the greatest dose-response effect of the three agents,, suggesting that there is untapped potential for even better BP control with higher spironolactone doses (eg 100 mg). Lastly, by demonstrating an inverse relationship between plasma renin level and magnitude of SBP decrease on spironolactone, the authors provide support for the hypothesis that sodium retention underlies rHTN pathogenesis. It remains to be seen, however, whether the exposure-dependent side effects of spironolactone will make this a less attractive therapeutic option for patients. Furthermore, many patients with sustained, uncontrolled rHTN are ethnic minorities and have already developed end organ damage as a result, particularly chronic kidney disease (CKD). Since the patients in this trial were mostly Caucasian males with normal GFR, it is unclear if African-American or Hispanic patients would see a similar benefit, or whether those with CKD would safely tolerate spironolactone given the increased risk of hyperkalemia in this patient population. Regardless, we at Clinical Correlations believe that the PATHWAY-2 trial is a gamechanger that offers physicians another effective agent to add to their arsenal in the treatment of rHTN.

Is this study a game changer?

We asked 2 experts in the field – Dr. Matthew Weiss, Preventative Cardiology Fellow, and Dr. Stephen Williams, Hypertension Specialist at the Bellevue Hypertension Clinic, for their opinion:

rHTN, defined as failure to achieve a BP goal of <140/90mmHg despite adherence to maximum tolerated doses of three appropriate antihypertensive drugs including a diuretic, is an increasingly common problem. Analysis of subjects enrolled in ALLHAT, as well as NHANES epidemiologic data, suggest that roughly 25% of hypertensive patients have rHTN. Notably, rHTN is frequently associated with obesity, diabetes, and CKD. Furthermore, obstructive sleep apnea is an increasingly recognized contributor to rHTN, seen in up to 80% of rHTN patients in some studies. While rHTN prevalence increases with age, African-Americans and women are at particularly higher risk for rHTN at any age.

The PATHWAY-2 study is a key trial in treatment of rHTN. Positing sodium retention as a key pathophysiologic driver of rHTN, the PATHWAY-2 trial, part of a larger series of British Heart Foundation BP trials, hypothesized that a diuretic, namely spironolactone, would show increased efficacy in BP reduction in rHTN subjects as compared with either a beta blocker or an alpha blocker. Additionally, a secondary hypothesis was that the superiority of spironolactone could be predicted a priori by measuring baseline plasma renin levels. Both of these hypotheses proved true. While all agents reduced BP, spironolactone reduced BP most dramatically: nearly 9 mmHg compared to placebo and roughly 4 mmHg more than either of the other two agents. Indeed, spironolactone was the most efficacious BP-lowering agent in 60% of patients enrolled. Remarkably, secondary endpoint analysis showed that those who responded most dramatically were those with the lowest baseline plasma renin levels, as would be expected mechanistically in sodium avid rHTN patients. Lastly, in this short-term study, side effects were negligible, a metric that is likely to have changed if the trial had been longer.

PATHWAY-2 is the first randomized controlled trial to compare spironolactone with other BP-lowering agents in an rHTN population and the first trial to use home BP monitoring rather than clinic BPs as a primary endpoint. This latter point is of key importance in an rHTN population who are often mislabeled as such because of in-office diagnostic confounding such as white coat hypertension. The PATHWAY-2 study should change the general notion that rHTN patients are difficult to treat (nearly 70% were successfully treated here) and provide guidance in selecting spironolactone as the most efficacious standard fourth-line antihypertensive agent among patients with rHTN.

Based on the results of the PATHWAY-2 trial, you decide to add spironolactone 25mg daily to his current regimen. You schedule a follow-up BP check 2 weeks later along with labs to check for hyperkalemia. At the follow-up BP check, your patient’s blood pressure is 132/70 and his potassium is normal. You plan to assess him regularly for the development of gynecomastia and hyperkalemia, but are thrilled that you have finally achieved optimal blood pressure control in your patient – as is he!

Dr. Amar Parikh is a Contributing Editor, Clinical Correlations and third year resident at NYU Langone Medical Center

Peer reviewed by Dr. Matthew Weiss former Preventative Cardiology Fellow, and Dr. Stephen Williams, Clinical Assistant Professor Department Population Health, NYU Langone Medical Center

Image Courtesy of Wikimedia Commons


  1. Persell SD. Prevalence of resistant hypertension in the United States, 2003-2008. Hypertension. 2011;57(6):1076-1080.
  2. Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet. 2015;386(10008):2059-2068.


Outpatient Rhythm Monitoring: Available Options and Diagnostic Yield

March 29, 2016

Holter_monitor_NIHBy Iulia Giuroiu, MD

Peer Reviewed

A 70-year-old woman with hypertension, early dementia, and non-specific chest pain of unclear etiology presents with recurrent left-sided chest pain. Unfortunately, she is a poor historian; it appears that her chest pain is similar to past episodes. Prior workups, which included an echocardiogram, had been unremarkable. To confound matters further, the patient’s current pain appears to be reproducible when pressure is applied to her chest. She is admitted overnight for close observation. No electrocardiogram (ECG) changes are found and serial troponin levels remain undetectable. She is discharged with a follow-up appointment in the cardiology clinic; however, while waiting in the discharge pharmacy she slumps over and appears to briefly lose consciousness, leading to readmission to the hospital. Subsequent telemetry monitoring only reveals occasional short bouts of sinus tachycardia and the patient remains asymptomatic. 

This case raises the following question: In an elderly patient with recurrent, intermittent symptoms concerning for a cardiac abnormality and a subsequent new episode of syncope, what is the best approach to correlate symptoms with objective findings in the outpatient setting?

Outpatient telemetry monitoring became available in 1957, when Dr. Norman Holter introduced the first ambulatory ECG (AECG) device [1]. Up until 2009, when the Federal Drug Administration (FDA) approved the Zio Patch (an ECG patch monitor), only two main classes of outpatient cardiac monitoring devices had been available, the Holter monitor and the loop recorder [2]. These older devices have undergone extensive evaluation in clinical trials, which have validated their accuracy in diagnosing a range of cardiac conditions, from arrhythmias to ischemia.

Holter monitors are external devices that continuously record and save up to 24 or 48 hours of ECG tracings, which are then analyzed for the presence of arrhythmias. External loop recorders (ELRs) also continuously record ECG tracings, but save only a few minutes of data before replacing it with new recordings, allowing for prolonged monitoring. Moreover, ELRs also allow patients to trigger the devices upon experiencing symptoms in order to permanently save the recordings occurring before and after the trigger. A hybrid of these two devices, the ECG patch monitor, continuously records up to 14 days of data and also allows patients to record symptoms through a built-in trigger.

The Holter monitor offers either 3-lead or 12-lead ambulatory ECG recordings [3]. In their review of ECG monitoring in syncope, Ruwald and Zareba conclude that Holter monitors prove most useful in diagnosing underlying cardiac etiologies of syncope among patients who experience frequent symptoms and frequent episodes of arrhythmia, which are more likely to occur in the short period of time a patient wears the monitor [3].

ELRs constantly record and subsequently delete 1 or 2-lead ECGs every 5-15 minutes until the patient experiences symptoms and activates the device’s recording feature [3]. Patients who experience an episode of syncope and trigger recording upon regaining consciousness save ECGs that represent activity 1-15 minutes prior to and 1-5 minutes after the episode [3]. In the COLAPS study that randomized 100 patients with syncope or pre-syncope to Holter monitoring versus ELR monitoring, up to 90% of patients experienced their first recurrence of symptoms after a total of 33 days, which could only be captured by ELR monitoring [3,4]. A diagnosis was defined as a correlation, or lack thereof, between symptoms and recorded arrhythmia, and thus 90% of patients in this study carried a diagnosis by 33 days. Most importantly, this study proved useful in ruling out arrhythmias as the cause of syncope among patients with frequent episodes of syncope and no known underlying structural heart disease [5]. Holter monitoring, conversely, revealed significant ECG abnormalities in up to 40% of patients [3,6]. By extending the duration of monitoring up to 8 consecutive weeks, ELRs were shown to increase the negative diagnostic yield of unexplained syncope from 14-22% (with Holter monitoring) to 17-56% [3,5-10].

As expected, external monitoring devices are often cumbersome to patients due to their bulkiness and because these devices must be kept dry. Moreover, patients are responsible for changing leads and electrodes when monitoring exceeds 1-2 days [11,12].

Thus, implanted patient-triggered event recorders (implantable loop recorders, ILRs) were developed in an attempt to improve ease of use and compliance with outpatient ECG monitoring. ILR devices are placed subcutaneously in the left upper chest, much like pacemakers or implantable cardioverter defibrillators (ICDs) [3]. ILRs not only extend the duration of monitoring to months and even years, but also extend the length of the recorded period to 40 minutes prior to symptom-triggered activation and 1-5 minutes after the trigger [3]. Among the 570 patients with unexplained pre-syncope and syncope who were analyzed in the PICTURE observational registry, syncope recurred in up to 38% of patients by 15 months, with the ILR contributing to a diagnosis in over 78% of these patients [13].

Current guidelines offer a Class I recommendation for the use of ILRs in two groups of patients. The first group includes those with recurrent syncope, but without high-risk features such as severe structural or coronary artery disease, clinical or ECG features suggesting an arrhythmic syncope, or co-morbidities like severe anemia and electrolyte abnormalities [14]. The latter patients should be monitored on inpatient telemetry for 24-72 hours [3,14]. The second group includes those at high risk according to the above criteria who remain undiagnosed and untreated even after extensive workup [14]. In spite of the diagnostic advantages of ILRs, the discomfort and risks associated with these invasive devices make them less attractive options for patients, undoubtedly paving the way for the invention of a less invasive device with long term monitoring capabilities. Enter the ECG patch monitor. The ECG patch monitor is a hybrid of its two predecessors—it is an external continuous monitoring device capable of more prolonged patient-initiated recordings before and after symptomatic episodes. A waterproof device, this patch provides up to 14 days of analyzable data. At the end of that period, the device is mailed to a centralized interpreting center. In a prospective trial, Rosenberg et al compared the ECG patch monitor to a 24-hour Holter monitor for the diagnosis of paroxysmal atrial fibrillation [11]. This study of 74 patients revealed a strong correlation between the periods of atrial fibrillation in the first 24 hours recorded by the patch monitor compared to the Holter monitor [11]. Patients continued to wear the ECG patch monitor for a mean of 10.8 days, when the majority (50%) of patients’ triggers correlated to sinus rhythm and 38% correlated to episodes of atrial fibrillation [11]. Most recurrent episodes of atrial fibrillation occurred within 7 days of monitoring on the patch monitor, with a small number of additional episodes occurring by 12 days [11]. More notably, longer monitoring using the patch monitor resulted in a change in management for 28% of the patients enrolled in this study [11]. Of note, the ECG patch monitor proved useful in identifying episodes of atrial fibrillation even in patients who had undergone ablation for atrial fibrillation and frequently remained asymptomatic during these recurrent episodes [11]. A retrospective study by Turakhia et al analyzed data from almost 27,000 distinct uses of the ECG patch monitor in patients aged 60.2 ± 18.7 years who wore it for 7.6 ± 3.6 days for workup of palpitations, atrial fibrillation, and syncope or pre-syncope [12]. First instances of arrhythmia occurred after 48 hours for 29.9% of the patients. Among patients whose arrhythmias correlated to symptoms, 51.1% of recorded arrhythmias occurred after 48 hours, underscoring the importance and usefulness of monitoring patients continuously beyond the 48 hours covered by the Holter monitor [12]. The patch monitor also diagnosed pauses, Mobitz II (or complete atrioventricular block), supraventricular tachycardia (SVT), and ventricular tachycardia (VT) more frequently than the Holter monitor. Time to first arrhythmia was 1.7 ± 2.2 days and time to first symptom-triggered arrhythmia was 3.0 ± 2.9 days [12].

Practice guidelines have not yet been updated to formally include the ECG patch monitor as a diagnostic option for patients with syncope; however, we can offer some early conclusions based on current and past trials comparing ELRs to ILRs, even though the number of enrolled patients in each of these trials was notably small. ELRs have achieved a successful diagnosis (combined positive and negative diagnostic yield) at a rate of up to 50%, but difficulty with data transmission, specifically in patients who are more technologically averse or even those living alone, limits their usefulness [4,5,10,16]. Data from crossover Holter to ELR study arms has provided diagnostic information in up to 45% of patients, suggesting value in extending study duration beyond 24 to 48 hours [5,10]. At its current lifespan, the ECG patch monitor may achieve an intermediate diagnostic yield between Holter monitors and ELRs, with gains in ease of use but losses in duration of coverage. A prospective trial comparing Holter monitoring and the patch monitor activated simultaneously in the same patients showed that the patch monitor conferred a statistically significant improvement in capture of an arrhythmic event [17].

Of note, another external device known as a mobile cardiac outpatient telemetry (MCOT) system also became available in the mid-2000s. It consists of a pager-sized device with 3 external monitoring leads that are applied to the chest for as long as monitoring is desired [18]. The MCOT continuously monitors ECG recordings for arrhythmias and sends ECGs to a technician via a landline or wireless network upon recognition of an event [18]. In a randomized, prospective study of 266 patients, the MCOT established a diagnosis for pre-syncope and syncope in 89% of patients, compared to 69% of patients monitored via ELR [19]. However, studies have not yet compared this device to an ECG patch monitor. Previous concerns regarding a relative lack of user friendliness and expense still hold true [18, 19].

Ultimately, trials directly comparing the ECG patch monitor to loop recorders are expected to offer more direct answers about the potential effects of monitoring duration on diagnostic yield. In our increasingly cost-conscious healthcare economy, we might also benefit from comparing the suggested cost-effectiveness of direct ILR implantation to patch monitor use [15]. Currently, the patch monitor’s overall diagnostic advantage over ELRs lies in its extended duration of ECG recordings. While the ability to correlate arrhythmia to symptoms is lost if patients fail to record symptomatic episodes, the finding of life-threatening arrhythmias irrespective of symptom correlation may prove useful. More trials on the ECG patch monitor’s effectiveness and further technological advances are needed to extend its lifespan.

 Dr. Iulia Giuroiu, is a 3rd year resident, Internal Medicine at NYU Langone Medical Center

Peer reviewed by Scott Bernstein, Medicine, at NYU Langone Medical Center

Image courtesy of Wikimedia Commons


  1. Crawford MH, Bernstein SJ, Deedwania PC, et al. ACC/AHA guidelines for ambulatory electrocardiography: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the Guidelines for Ambulatory Electrocardiography). J Am Coll Cardiol. 1999;34(3):912-948.
  2. iRhythm Technologies, Inc.
  3. Ruwald MH and Zareba W. ECG Monitoring in Syncope. Prog Cardiovasc Dis. 2013;56(2):203-210.
  4. Gula LJ, Krahn AD, Massel D, Skanes A, Yee R, Klein GJ. External loop recorders: Determinants of diagnostic yield in patients with syncope. Am Heart J. 2004;147(4):644-648.
  5. Sivakumaran S, Krahn AD, Klein GJ, et al. A Prospective Randomized Comparison of Loop Recorders versus Holter Monitors in Patients with Syncope or Presyncope. Am J Med. 2003;115(1):1-5.
  6. Gibson TC and Heitzman MR. Diagnostic efficacy of 24-hour electrocardiographic monitoring for syncope. Am J Cardiol. 1984;53(8):1013–1017.
  7. Bass EB, Curtiss EI, Arena VC, Hanusa BH. The Duration of Holter Monitoring in Patients with Syncope: Is 24 Hours Enough? Arch Intern Med. 1990;150(5).1073-1078.
  8. Kühne M, Schaer B, Sticherling C, Osswald S. Holter monitoring in syncope: diagnostic yield in octogenarians. J Am Geriatr Soc. 2011;59(7);1293–1298.
  9. Schuchert A, Maas R, Kretzschmar C, Behrens G, Kratzmann I, Meinertz T. Diagnostic yield of external electrocardiographic loop recorders in patients with recurrent syncope and negative tilt table test. Pacing Clin Electrophysiol. 2003;26(9):1837–1840.
  10. Linzer M, Pritchett EL, Pontinen M, et al. Incremental diagnostic yield of loop electrocardiographic recorders in unexplained syncope. Am J Cardiol. 1990;66:214–219.
  11. Rosenberg MA, Samuel M, Thosani A, Zimetbaum PJ. Use of a Noninvasive Continuous Monitoring Device in the Management of Atrial Fibrillation: A Pilot Study. PACE. 2013;36(3):328-333.
  12. Turakhia MP, Hoang DD, Zimetbaum P, et al. Diagnostic Utility of a Novel Leadless Arrhythmia Monitoring Device. Am J Cardiol. 2013;112(4):520-524.
  13. Edvardsson N, Frykman V, van Mechelen R, et al. Use of an implantable loop recorder to increase the diagnostic yield in unexplained syncope: results from the PICTURE registry. Europace. 2011;13(2):262-269. 
  14. Moya A, Sutton R, Ammirati F, et al. Guidelines for the diagnosis and management of syncope (version 2009). Eur Heart J. 2009;30:2631-2671.
  15. Zimetbaum P and Goldman A. Ambulatory Arrhythmia Monitoring: Choosing the Right Device. Circulation. 2010;122(16):1629-1636. 
  16. Fogel RI, Evans JJ, Prystowsky EN. Utility and Cost of Event Recorders in the Diagnosis of Palpitations, Presyncope, and Syncope. Am J Card. 1997;79(2):207-208.
  17. Barret PM, Komatireddy R, Haaser S, et al. Comparison of 24-hour Holter Monitoring with 14-day Novel Adhesive Patch Electrocardiographic Monitoring. Am J Med. 2014;127:95.e11-95.e17.
  18. Joshi AK, Kowey PR, Prystowsky EN, et al. First experience with a Mobile Cardiac Outpatient Telemetry (MCOT) system for the diagnosis and management of cardiac arrythmia. Am J Cardiol. 2005;95:878-881.
  19. Rothman SA, Laughlin JC, Seltzer J, et al. The Diagnosis of Cardiac Arrhythmias: A Prospective Multi-Center Randomized Study Comparing Mobile Cardiac Outpatient Telemetry Versus Standard Loop Event Monitoring. J Cardiovasc Electrophysiol. 2007;18:241-247.

HDL Quantity, Necessary But Not Sufficient For Cardioprotection

September 30, 2015

CholesterolBy Kerrilynn Carney, MD

Peer Reviewed

Coronary heart disease remains the leading cause of death globally despite the use of statin therapy. Although major statin studies suggest an average 31% reduction in relative risk of coronary events, a residual risk of 69% remains to be addressed. (1) The search for a medical therapy to ameliorate residual risk has become the holy grail of cardiologists and pharmaceutical companies alike. While high-density lipoprotein cholesterol levels (HDL) independently predict cardiovascular disease risk, interventions to raise circulating HDL levels have thus far been unsuccessful in reducing the risk of coronary heart disease. (2)

When controlling for LDL cholesterol, the odds of coronary heart disease fall by about 40% per 7.5 milligram per deciliter rise in HDL cholesterol (3). While this translates to a fall in major adverse cardiovascular events by about 1.1% for each 1 milligram per deciliter rise in HDL cholesterol when LDL cholesterol is 70 mg/dL, attempts at raising HDL cholesterol with pharmacotherapy in the post-statin era have not produced a similar risk reduction. (4)

HDL is a complex molecule with anti-oxidative, anti-inflammatory, anti-thrombotic, antiplatelet, and vasodilatory properties, which help protect LDL from oxidation. Each HDL particle carries between two and five molecules of apolipoprotein A1 (ApoA-I), over 80 proteins, and hundreds of lipid moieties, with many molecules containing antioxidant and antithrombotic properties (5-7).

There are multiple mechanisms by which HDL mitigates the process of atherogenesis, but the efflux capacity, or ability to relocate cholesterol out of macrophages, is believed to be central in reducing major adverse cardiovascular events. In macrophages in atherosclerotic lesions, enlargement of intracellular lipid droplets occurs when cholesterol delivery and storage is greater than cholesterol removal, promoting transformation into foam cells. HDL participates in cholesterol efflux via reverse cholesterol transport, relocating cholesterol from peripheral cell membranes via scavenger receptor class B type 1 to hepatocytes centrally. (8) ATP-binding cassette transporter A-1, present in macrophages, the liver, and the intestine, actively transports cholesterol to lipid-poor apolipoprotein A-I particles carried on HDL. In addition, HDL has a major effect on endothelial function, promotes endothelial repair and progenitor cell health, and also supports production of nitric oxide. (7)

There are several well-known examples in which HDL cholesterol levels have been raised without conferring cardio-protection. In preclinical studies, overexpression of hepatic ATP-binding cassette transporter A-1 in an animal model result in higher HDL cholesterol levels, but impaired HDL function and accelerated atherosclerosis. (9) Cholesteryl ester transfer protein (CETP) deficiency from mutations in the CETP gene also increases HDL cholesterol, but evidence varies about their protection against atherosclerosis. Conversely, patients with a specific genetic ezyme deficiency (lecithin cholesterol acyltransferase) or mutations within the ApoA-I gene resulting in hypo-function of apolipoprotein A-I secretion have marked HDL cholesterol deficiency but do not necessarily develop atherosclerosis at a higher rate than normal patients. (10)

HDL augmentation with pharmacotherapy has been wrought with both equivocal and negative studies. Specifically, raising HDL with estrogen (11, 12), fibrates (13, 14), niacin, or CETP inhibitors (15) has not improved outcomes, and in some cases increased adverse events. After the equivocal AIM-HIGH trial of niacin, the HPS2-THRIVE trial showed that among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant did not significantly reduce the risk of MCVE and actually increased the risk of serious adverse events when compared to statin-based LDL cholesterol-lowering therapy alone (16). CETP inhibitors as a class have variable efficacy in raising HDL levels and conferring cardio-protection, and additionally have shown some evidence for increased harm. (15, 17-19)

The fact remains that when LDL cholesterol is aggressively lowered, low HDL cholesterol levels are inversely related to major coronary vascular events. Raising HDL cholesterol has been a major target in the quest to reduce residual cardiovascular risk in the post-statin era; however raising HDL with pharmacotherapy has not meaningfully effected clinical endpoints and in some cases produced harm. There is a growing impression that HDL functionality, rather than abundance, is clinically important. (7) HDL efflux capacity has been inversely associated with both prevalent and incident cardiovascular disease risk, independent of established cardiovascular risk factors, even after adjusting for HDL cholesterol or apoA-I concentrations, and is an area of active research in the field of lipidology. (20-23)

For now, we should continue using validated risk models to prescribe statin therapy to those who need it and encourage our patients to attempt to raise their HDL levels through diet and exercise.

Dr. Kerrilynn Carney is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Alana Choy-Shan, MD, Cardiology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


  1. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670-1681.
  2. Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, Thompson A, Wood AM, et al. Major lipids, apolipoproteins, and risk of vascular disease. Jama 2009;302:1993-2000.
  3. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-1310.
  4. Carey VJ, Bishop L, Laranjo N, Harshfield BJ, Kwiat C, Sacks FM. Contribution of high plasma triglycerides and low high-density lipoprotein cholesterol to residual risk of coronary heart disease after establishment of low-density lipoprotein cholesterol control. Am J Cardiol 2010;106:757-763.
  5. Heinecke JW. The protein cargo of HDL: implications for vascular wall biology and therapeutics. J Clin Lipidol 2010;4:371-375.
  6. Navab M, Reddy ST, Van Lenten BJ, Fogelman AM. HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms. Nat Rev Cardiol 2011;8:222-232.
  7. Kones R. Molecular sources of residual cardiovascular risk, clinical signals, and innovative solutions: relationship with subclinical disease, undertreatment, and poor adherence: implications of new evidence upon optimizing cardiovascular patient outcomes. Vasc Health Risk Manag 2013;9:617-670.
  8. Rothblat GH, de la Llera-Moya M, Atger V, Kellner-Weibel G, Williams DL, Phillips MC. Cell cholesterol efflux: integration of old and new observations provides new insights. J Lipid Res 1999;40:781-796.
  9. Feng Y, Lievens J, Jacobs F, Hoekstra M, Van Craeyveld E, Gordts SC, Snoeys J, et al. Hepatocyte-specific ABCA1 transfer increases HDL cholesterol but impairs HDL function and accelerates atherosclerosis. Cardiovasc Res 2010;88:376-385.
  10. Haase CL, Tybjaerg-Hansen A, Grande P, Frikke-Schmidt R. Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J Clin Endocrinol Metab 2010;95:E500-510.
  11. Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). Jama 2002;288:49-57.
  12. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, Vittinghoff E. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Jama 1998;280:605-613.
  13. Reyes-Soffer G, Ngai CI, Lovato L, Karmally W, Ramakrishnan R, Holleran S, Ginsberg HN. Effect of combination therapy with fenofibrate and simvastatin on postprandial lipemia in the ACCORD lipid trial. Diabetes Care 2013;36:422-428.
  14. Scott R, O’Brien R, Fulcher G, Pardy C, D’Emden M, Tse D, Taskinen MR, et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care 2009;32:493-498.
  15. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-2122.
  16. Albers JJ, Slee A, O’Brien KD, Robinson JG, Kashyap ML, Kwiterovich PO, Jr., Xu P, et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol 2013;62:1575-1579.
  17. de Haan W, de Vries-van der Weij J, van der Hoorn JW, Gautier T, van der Hoogt CC, Westerterp M, Romijn JA, et al. Torcetrapib does not reduce atherosclerosis beyond atorvastatin and induces more proinflammatory lesions than atorvastatin. Circulation 2008;117:2515-2522.
  18. Johannsen TH, Frikke-Schmidt R, Schou J, Nordestgaard BG, Tybjaerg-Hansen A. Genetic inhibition of CETP, ischemic vascular disease and mortality, and possible adverse effects. J Am Coll Cardiol 2012;60:2041-2048.
  19. Li C, Zhang W, Zhou F, Chen C, Zhou L, Li Y, Liu L, et al. Cholesteryl ester transfer protein inhibitors in the treatment of dyslipidemia: a systematic review and meta-analysis. PLoS One 2013;8:e77049.
  20. Saleheen D, Scott R, Javad S, Zhao W, Rodrigues A, Picataggi A, Lukmanova D, et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. Lancet Diabetes Endocrinol 2015;3:507-513.
  21. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-135.
  22. Li XM, Tang WH, Mosior MK, Huang Y, Wu Y, Matter W, Gao V, et al. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler Thromb Vasc Biol 2013;33:1696-1705.
  23. Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, Neeland IJ, et al. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med 2014;371:2383-2393.


The Role of Fish Oil in Arrhythmia Prevention

July 29, 2015

fishoilBy Steven Bolger

Peer Reviewed

Omega-3 fatty acids were first identified as a potential agent to prevent and treat cardiovascular disease through several epidemiologic studies of the Greenlandic Inuit in the 1970s suggesting that high consumption of fish oil was associated with a decreased risk of cardiovascular disease [1,2]. Fish oil contains two omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), that have been shown to be beneficial in treating hypertriglyceridemia and in the secondary prevention of cardiac events [3-5].

The GISSI-Prevenzione trial, published in 1999, was one of the first multicenter, randomized controlled trials to explore the effect of supplementation with omega-3 fatty acids on patients with recent myocardial infarctions [5]. The trial included 11,324 patients with recent myocardial infarctions. They were randomized to receive daily supplementation with either a capsule containing EPA and DHA in a 1-to-2 ratio or a placebo capsule for 3.5 years, with death from any cause, non-fatal myocardial infarction, and stroke as the composite primary endpoint. The trial demonstrated that supplementation with omega-3 fatty acids resulted in a significant reduction in the primary endpoint, with a relative risk reduction of 10% compared to placebo. The results of this trial suggested that a reduction in sudden cardiac death could be responsible for the decrease in mortality, sparking investigation of the potential anti-arrhythmic properties of omega-3 fatty acids.

Omega-3 fatty acids have been shown to increase the threshold of depolarization of cardiac muscle required for action potential generation in animal models, resulting in a decrease in arrhythmias. A 1994 study using a canine model showed that infusion of a fish oil emulsion resulted in a significantly decreased incidence of ventricular fibrillation compared to a control infusion in response to exercise-induced ischemia [6]. Further studies in rat cardiomyocytes revealed that the mechanism responsible for the reduction in arrhythmias is inhibition of voltage-dependent sodium and L-type calcium channels [7-9]. By shifting the cell membrane potential to a more negative value, omega-3 fatty acids increase the threshold required to generate an action potential, preventing the initiation of arrhythmias.

Several randomized controlled trials have failed to demonstrate that omega-3 fatty acid supplementation results in a reduction in ventricular arrhythmias in patients with implantable cardioverter-defibrillators. A 2005 trial of 200 patients with implantable cardioverter-defibrillators and recent episodes of sustained ventricular tachycardia or ventricular fibrillation showed no reduction in the risk of arrhythmias with fish oil supplementation [10]. The results of this trial furthermore suggested a possible pro-arrhythmic effect of omega-3 fatty acids. A 2006 trial similarly failed to show a reduction in ventricular tachycardia, ventricular fibrillation, or all-cause mortality in 546 patients with implantable cardioverter-defibrillators who received supplementation with omega-3 fatty acids [11].

A 2005 randomized controlled trial of 402 patients with implantable cardioverter-defibrillators, however, demonstrated a trend towards benefit in patients receiving supplementation with omega-3 fatty acids [12]. The primary endpoint selected for the trial was time to first episode of ventricular tachycardia, ventricular fibrillation, or death from any cause. Though the results did not show a significant reduction in the primary endpoint, patients who received omega-3 fatty acid supplementation showed a trend towards a prolonged time to the first episode of these arrhythmias or death from any cause, with a risk reduction of 28% and p-value of 0.057. Furthermore, the risk reduction was significant when probable episodes of ventricular tachycardia and ventricular fibrillation were included in the analysis, with a risk reduction of 31%.

With conflicting results from several trials, a systematic review was performed in 2008 of 12 randomized controlled trials to synthesize clinical data on the effects of fish oil on mortality and arrhythmia prevention [13]. The primary outcomes were defined as the arrhythmic end points of appropriate implantable cardioverter-defibrillator intervention and sudden cardiac death. The results of the meta-analysis showed that fish oil supplementation did not have a significant effect on arrhythmias and all-cause mortality. The review did demonstrate a significant reduction in deaths from cardiac causes consistent with previous studies, including the GISSI-Prevenzione trial.

Fish Oil For Atrial Fibrillation Prevention

In addition to trials investigating ventricular arrhythmias in patients with implantable cardioverter-defibrillators, there have been several observational studies exploring the effect of fish oil on the incidence of atrial fibrillation, which have yielded conflicting results. The Danish Diet, Cancer, and Health Study, a prospective cohort study, found that consumption of omega-3 fatty acids from fish was not associated with a reduction in the risk of atrial fibrillation or flutter [14]. The cohort for this study included 47,949 individuals living in Denmark with a mean age of 56 years. The Rotterdam Study found that consumption of EPA and DHA was similarly not associated with a reduction in the risk of developing atrial fibrillation [15]. The cohort for this study included 5184 patients with a mean age of 67.4 years who lived in the Netherlands. A 12-year prospective, observational study by Mozaffarian and colleagues of 4815 patients over the age of 65, however, found that consumption of fish was associated with a 31% reduction in the risk of atrial fibrillation [16].

The mixed results between these studies may reflect differences in the baseline characteristics of the cohorts of the three studies. The Mozaffarian study placed an age restriction on the cohort of the study, resulting in a mean age of 72.8 years, compared to 56 years for the Danish Diet, Cancer, and Health Study and 67.4 years for the Rotterdam Study. The risk of atrial fibrillation increases with age; thus, the reduction in risk of atrial fibrillation in response to omega-3 fatty acid supplementation may only be appreciable in elderly populations at highest risk [17-18]. The assessment of dietary intake of omega-3 fatty acids also differed between the studies depending on the method of information collection. The Rotterdam study, for example, obtained information via a questionnaire and follow-up interview with a dietician, while the Mozaffarian study employed only a questionnaire.

The 2012 OPERA trial was the first randomized controlled trial to assess the effect of omega-3 fatty acid supplementation on atrial fibrillation [19]. The OPERA trial randomized 1516 patients with a mean age of 64 years who were scheduled for cardiac surgery to receive either a daily fish oil capsule or placebo for 3-5 days before the surgery and for 10 postoperative days or until discharge, whichever came first. The results of the trial showed that perioperative supplementation with fish oil did not reduce the risk of postoperative atrial fibrillation compared to the placebo.

Overall, the results of studies exploring the potential anti-arrhythmic effects of omega-3 fatty acids in reducing the risk of atrial fibrillation have been conflicting. A 2010 meta-analysis of 10 randomized controlled trials examining the role of omega-3 fatty acids in preventing atrial fibrillation found no evidence of significant effects of omega-3 fatty acids on atrial fibrillation prevention [20].

In conclusion, although omega-3 fatty acid supplementation has been shown to provide several potential cardiovascular benefits, trials have failed to consistently show that omega-3 fatty acids have significant anti-arrhythmic effects. The reasons for the inconsistent results are unknown, and perhaps may be related to patient selection, type of fish oil preparation, fish oil dose, or other factors. Meta-analyses of randomized controlled trials have not shown a reduction in either ventricular arrhythmias or atrial fibrillation. Additional studies are necessary to further characterize the role of fish oil in preventing arrhythmias.

Steven Bolger is a 3rd year medical student at NYU School of Medicine

Peer reviewed by Robert Donnino, MD, Cardiology Editor, Clinical Correlations,  NYU Langone Medical Center

 Image courtesy of Wikimedia Commons


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A Primer on CRP and Cardiovascular Risk

July 22, 2015

Heart-beatCindy Fei, MD

Peer Reviewed

A 63-year-old woman with hypertension presents to your clinic for routine follow-up. She came across an online article regarding C-reactive protein and its purported link to heart disease, and she asks you whether she should be tested for it. She is an otherwise asymptomatic non-smoker without a family history of heart disease. Her only medication is hydrochlorothiazide. Her blood pressure measured in the office is 128/81 mmHg, her low-density lipoprotein is 110 mg/dL, and her high-density lipoprotein is 54 mg/dL. What do you tell her?

What is CRP?

C-reactive protein (CRP) is an acute-phase reactant produced by the liver in response to the inflammatory cytokines interleukin-6 and interferon. CRP primarily mediates the inflammatory response by binding to complement and damaged cell membranes, but it has also been noted to bind to low-density lipoprotein (LDL) [1]. Common stimuli of high CRP levels (conventionally defined as >3 mg/L) include infection, cancer, and surgery. CRP also increases to intermediate levels (1-3 mg/L) with age, obesity, smoking, gum disease, and related co-morbidities such as chronic lung disease, diabetes, and hypertension [2]. Interestingly, the variability of multiple CRP measurements in the same person over time exhibits stability comparable to blood pressure and cholesterol [3]. While early measurements of CRP only detected levels greater than 3 mg/L, later studies capitalized on the development of improved high-sensitivity CRP (hs-CRP) assays, which detect levels as low as 0.1 mg/L.

With respect to healthy adults, studies show a positive correlation between elevated CRP levels and development of coronary heart disease, independent of other risk factors. A meta-analysis of 54 observation studies characterized this relationship as a log-linear association when adjusted for age and sex [4]. A 2009 meta-analysis of 11 good-quality studies calculated a relative risk of 1.58 (confidence interval 1.37-1.83) for the development of coronary artery disease in the high versus low serum CRP groups. The studies all adjusted for Framingham risk factors beforehand. The corresponding risk ratio for the intermediate versus low serum CRP groups was 1.22 (confidence interval 1.11-1.33) [5]. This relationship persists in individuals with known cardiovascular disease, with higher CRP values portending a worse prognosis. For instance, stable coronary artery disease subjects with a fairly even distribution of low, intermediate, and high serum CRP categories showed a statistically significant increased risk of cardiovascular death, myocardial infarction, or stroke in the intermediate CRP group compared with low CRP group (adjusted hazard ratio of 1.39). The adjusted hazard ratio rose to 1.52 for high CRP group compared to the low CRP group [6].

Does CRP play a pathologic role in atherosclerosis?

Multiple studies demonstrate an association between elevated CRP and increased risk of heart disease, regardless of prior cardiovascular disease diagnosis. However, it is unclear if a causal mechanism governs this association. Do high CRP levels drive atherosclerosis, or are they simply a marker of disease? Atherosclerotic plaques stain positive for CRP, but the evidence for causality is less clear [1]. Proposed avenues for CRP-induced plaque build-up include monocyte adhesion and recruitment into the vessel walls, macrophage activation, and smooth muscle cell proliferation. Moreover, binding to LDL facilitates LDL oxidation and uptake by macrophages. CRP also interferes with endothelial nitric oxide synthase function and prostacyclin synthesis, leading to decreased vasodilation [7].

In addition, CRP’s classification as an acute-phase reactant and its subsequent association with inflammatory conditions offer numerous confounding variables. On one hand, lower CRP levels after statin therapy are associated with a lower risk of recurrent myocardial infarction or coronary fatalities, regardless of post-statin LDL levels [8]. Post hoc analyses of the PROVE-IT trial demonstrated that lower CRP was significantly and independently associated with slower progression of atherosclerosis as measured by intravascular ultrasound over 18 months [9,10]. This suggests a direct link between CRP and cardiovascular risk independent of LDL levels.

On the other hand, scenarios that attempt to directly influence or change CRP levels do not necessarily maintain this link. For example, murine models of atherosclerosis do not reliably show increased plaque build-up in transgenic mice designed to produce human CRP [7]. One mendelian randomization study from 2008 calculated whether naturally-occurring genetic polymorphisms in the CRP gene and subsequent variations in serum CRP levels could predict cardiovascular outcomes. Genetic variation was responsible for up to 64% change in CRP level, but this did not translate into a statistically significant increased odds ratio for ischemic heart disease. In contrast, different apolipoprotein E genotypes accounted for up to a 14% change in cholesterol level, with a statistically significant increased odds ratio of 1.29 for development of ischemic heart disease [11]. A later mendelian randomization study also did not find a statistically significant relationship between genetically-raised CRP levels and the development of heart disease [12].

How to Use CRP in Clinical Practice

To date, the main randomized clinical trial that examines CRP and cardiovascular risk is the JUPITER trial published in 2008. This trial evaluated rosuvastatin 20mg daily for primary prevention in healthy adults who demonstrated both LDL <130 and hs-CRP >2. The trial was stopped early at the first interim analysis because the statin’s benefit was clear. After a median of 1.9 years of follow-up, a statistically significant reduction in the primary outcome (a composite of heart attack, stroke, unstable angina, revascularization, or cardiovascular death) was found for the statin group as compared to placebo (hazard ratio 0.56, 95% confidence interval 0.46 to 0.59) [13]. This suggested a role for CRP in selecting additional patients who would benefit from statins. Although the trial only included patients with higher levels of hs-CRP, a post hoc analysis demonstrated a consistent association between higher baseline hs-CRP and increased frequency of the primary outcome [14]. Of note, the trial was criticized on the grounds of conflict of interest, as the principal investigator co-owns the patent for the hs-CRP blood test used in the study [15].

In 2003, the Centers for Disease Control and Prevention and the American Heart Association recommended against universal screening for cardiovascular risk with CRP. The document identified intermediate-risk patients as the population for which it is reasonable to measure hs-CRP twice, 2 weeks apart, for further risk stratification [16]. In healthy asymptomatic adults with an intermediate Framingham risk of 5-20%, the addition of CRP appropriately reclassified only 4.3% of subjects into the high-risk category, and only 3.6% into the low-risk category [17]. According to one model developed prior to the updated statin therapy guidelines, testing the CRP of 440 intermediate-risk patients without a coronary heart disease equivalent is needed in order to reclassify 23 individuals as high-risk. If those 23 subjects initiated statin therapy, then 1 cardiovascular event (myocardial infarction, stroke, or fatal coronary heart disease) would be averted. In effect, the number needed to “test” of 440 would avert 1 cardiovascular event over 10 years, assuming appropriate statin interventions based on the 2002 Adult Treatment Panel III guidelines [18]. However, studies that have compared the accuracy of CRP versus coronary artery calcium score and carotid intima-media thickness in reclassifying intermediate-risk patients found that coronary artery calcium score and carotid intima-media thickness both outperformed CRP [17].

More recent guidelines still fail to offer compelling indications for CRP utilization. In fact, the 2009 US Preventive Services Task Force stated that there was insufficient evidence for the use of hs-CRP for cardiovascular risk assessment [19]. Two simultaneously released guidelines in November 2013 from the American College of Cardiology/American Heart Association (ACC/AHA), on the topics of cholesterol and on cardiovascular risk assessment, discuss a possible role for hs-CRP in patients who do not fall into the outlined four major statin benefit groups or who have unclear risk even after quantitative risk assessment. The recommendation to consider hs-CRP use under these select circumstances is based on expert opinion only, and does not distinguish between CRP versus other novel risk factors such as coronary artery calcium score and ankle-brachial index [20,21]. The new guidelines also suggest hs-CRP >2 as the threshold for upgrading the level of cardiovascular risk for a patient.


In summary, existing evidence tentatively suggests that CRP is an independent risk factor for heart disease; however, in the absence of data examining universal CRP screening, hard clinical outcomes, mortality, or cost effectiveness, the current recommendations are to use CRP sparingly under select circumstances. In the clinic, CRP may be used as a tool for further risk stratification of intermediate-risk patients in order to select candidates who may benefit the most from additional interventions and therapies.

With regards to the clinical vignette, this patient does not fall into one of the 4 major statin benefit groups, as outlined in the newly released 2013 ACC/AHA guidelines. Her calculated 10-year risk of atherosclerotic cardiovascular disease is 6%, which does not reach the threshold of 7.5% for starting a statin. According to the 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk document, expert opinion states that hs-CRP may have a role in determining whether to begin statin therapy. If her measured hs-CRP were greater than 2, one may consider upgrading her risk level and adding a statin for primary prevention, with the knowledge that this recommendation is based on very limited data. 

Commentary By Robert Donnino, MD  Assistant Professor of Medicine (Cardiology)

The use of hs-CRP for cardiovascular risk stratification remains highly controversial. Analysis of existing data suggests that CRP is, at best, a weak independent risk factor for clinical cardiovascular events. Without the inclusion of patients with CRP < 2 in the JUPITER trial (Ridker et al., reference 8 from above), it cannot be concluded that the CRP level of >2 conferred any increased risk, nor does it identify patients who would have received additional benefit with statin therapy. This has led many to question whether patients with CRP < 2 would have received similar benefits from statin therapy if they had been included in the trial.

As mentioned in this overview on CRP, data published from the MESA cohort showed CRP was not a very effective tool for reclassifying intermediate risk patients into higher or lower risk groups, reclassifying a total of only 8% of patients (Yeboah, et al; reference 17 from above). For comparison, coronary calcium score in that same cohort reclassified 66% of patients into higher or lower risk groups. Other studies have even lower reclassification ability for CRP. Thus, although supported by current guidelines and followed by some practitioners, I believe the data do not support the use of CRP as a risk stratification tool and that much more powerful stratification tools are available (i.e. coronary calcium score). For more in-depth analysis of CPR for cardiovascular risk, I would recommend the excellent review by Yousuf and colleages (reference 7 from above). Until we have more clarifying data, the role of CRP in clinical practice will remain controversial. 

Dr. Cindy Fei is an internist at NYU Langone Medical Center

Peer review by Robert Donnino, MD, Assistant Professor of Medicine (Cardiology), NYU Langone Medical Center

Image courtesy of Wikimedia Commons


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Neurologic Complications In Infective Endocarditis: To Anticoagulate Or Not To Anticoagulate

July 10, 2015

479px-Pink_tulip_flowerBy Shannon Chiu, MD

Peer Reviewed

The annual incidence of infective endocarditis (IE) is estimated to be 3 to 9 cases per 100,000 persons in developed countries [1-2]. Neurologic complications are the most severe and frequent extracardiac complications of IE, affecting 15-20% of patients [3-4]. They consist of 1) ischemic infarction secondary to septic emboli from the valvular vegetation, which can eventually undergo hemorrhagic transformation; 2) focal vasculitis/cerebritis from septic emboli obstructing the vascular lumen, which can then develop into brain abscess or meningoencephalitis; 3) mycotic aneurysm secondary to inflammation from septic emboli penetrating the vessel wall [5]. Amongst these complications, stroke is the most common and is the presenting feature in 50-75% of patients [6]. To date, an ongoing debate amongst physicians is the appropriateness of anticoagulation in patients with IE and how to balance the risk of thromboembolism against that of hemorrhagic transformation of stroke.

Specific risk factors have been associated with increased risk of symptomatic embolic events. Embolic risk is especially high within the first 2 weeks after diagnosis, decreasing in frequency after initiation of antibiotics [7]. Size, location and mobility of vegetations are key predictors; in fact, surgery may be indicated for prevention of embolism with involvement of anterior mitral leaflet, vegetation size >10mm, or increasing size despite appropriate antibiotics [5,8]. Additional risk factors for embolism in IE include advanced age and S. aureus infection. Importantly, S. aureus prosthetic valve endocarditis is known to be associated with higher overall mortality and severe neurologic complications such as hemorrhagic stroke [3,9-10]. Mechanisms for intracranial hemorrhage (ICH) in patients with IE include hemorrhagic transformation (HT) of ischemic infarct, rupture of mycotic aneurysms, or erosion of septic arteritic vessels [11].

Currently, evidence regarding anticoagulants primarily stems from observational studies. One of the arguments against anticoagulation in IE is the fear of early ICH and HT of ischemic stroke. In Tornos et al.’s retrospective observational series of 56 patients with native and prosthetic S. aureus IE, mortality was higher in prosthetic valve IE than in native valve IE (p=.02; odds ration [OR], 4.23; 95% confidence interval [CI], 1.15-16.25) [12]. The authors inferred that part of this difference stemmed from the deleterious effect of anticoagulation leading to lethal neurologic damage as 90% of patients with prosthetic valve IE due to S. aureus were receiving oral anticoagulant treatment on admission (vs. no patient with native valve IE due to S. aureus was receiving such treatment). Meanwhile, in Heiro et al.’s retrospective study, a sub-analysis of 32 patients with S. aureus IE showed that 57% of patients receiving anticoagulant therapy died within 3 months of admission vs. 20% of those not receiving anticoagulant therapy, though the difference was not statistically significant (p=0.1) [9]. Garcia-Cabrera et al. conducted a retrospective analysis of 1,345 cases of left-sided IE, and likewise found that hemorrhagic complications were significantly associated with anticoagulant therapy that was primarily used in patients with mechanical valves (hazard ration [HR] 2.71, 95% CI 1.54-4.76, p=0.001) [13]. On this basis, these authors have recommended stopping anticoagulants as soon as diagnosis of IE is suspected, at least until past the septic phase of the disease. Despite these reported associations of poor outcome in S. aureus IE and detrimental effect of anticoagulant therapy in these patients, these results arose from nonrandomized retrospective studies without matched cohorts. Moreover, Tornos et al.’s study was primarily designed to compare native valve with prosthetic valve IE patients, and the sample size of those receiving anticoagulation was small (19 out of 56) [12]. Similarly, Heiro et al.’s study was of limited statistical power, as only 2 of the 4 patients with lethal S. aureus IE actually died of hemorrhagic conditions while taking anticoagulant therapy.

On the opposing end, more recent prospective studies show no significant association between anticoagulation and increased risk of hemorrhagic complications, and that ICH due to anticoagulation after IE-related stroke is overestimated. Rasmussen et al. conducted a prospective cohort study of 175 S. auerus IE patients, of which 70 patients (40%, 95% CI 33-47%) experienced major cerebral events during the course of the disease [14]. Stroke was the most common complication (34%, 95% CI 27-41%), but the incidence of cerebral hemorrhage was low (3%, 95% CI 0.5-6%). None of the patients who experienced cerebral hemorrhage were receiving anticoagulant treatment. In fact, Rasmussen et al. found that patients receiving anticoagulation were less likely to have experienced a major cerebral event at time of admission compared to those not receiving such treatment (15% vs 37%, p=0.009). The indication for anticoagulation for the majority of patients in this study was prosthetic heart valves. Anticoagulation at the time of admission was associated with a significant reduction in the number of major cerebral events in patients with native valve IE (0 vs. 39%, p=0.008); however, this was not evident in those with prosthetic valve IE. In-hospital mortality rate was 23% (95% CI 17-29%) with no significant difference between patients with or without anticoagulant therapy.

An added complication to the picture is the decision for cardiac surgery in patients with IE who suffer a neurologic event. Except for clinically severe ICH, neurologic complications are not a contraindication for surgical treatment [5]. The decision to perform cardiopulmonary bypass remains controversial, as the surgery can cause/aggravate cerebral damage in several ways, such as ICH related to heparinization during the procedure, and possible hemodynamic worsening of the ischemic infarction (e.g. additional embolism, hypoperfusion) [5,15]. The timing of the surgery is also hotly debated, and evidence supporting surgical intervention is of limited quality and primarily based on observational studies. However, when needed, cardiac surgery can be performed promptly after a silent cerebral embolism or transient ischemic attack, but must be postponed for at least 1 month following ICH [8].

Despite controversy over anticoagulant therapy, recommendations regarding antiplatelet therapy are more clear-cut: antiplatelets are not recommended for patients with IE. In a double-blind, placebo-controlled trial comparing aspirin 325mg with placebo for 4 weeks in 115 IE patients, there was no significant decrease in the incidence of embolic events (OR 1.62, 95% CI 0.68-3.86) [16]. In fact, there was a trend toward more bleeding in the aspirin group (OR 1.92, 95% CI 0.76-4.86); and aspirin had no effect on vegetation size. While there are conflicting findings from observation studies regarding the use of chronic antiplatelet treatment before IE, in terms risks of death and embolic events, current available evidence suggests that antiplatelet therapy is not indicated in IE [17-19]. Patients on antiplatelet therapy for other indications may continue taking it, in the absence of major bleeding.

So where does this leave us? According to the most recent European Society of Cardiology guidelines, there is no indication to start anticoagulation in patients with IE [8]. For those already receiving anticoagulant therapy, and in which IE is complicated by ischemic or non-hemorrhagic stroke, the oral anticoagulant agent should be replaced by unfractionated heparin for 2 weeks. For those with ICH complication, all anticoagulation should be stopped, except for those with prosthetic valve IE in which case the recommendation is to reinitiate unfractionated heparin “as soon as possible” (no specified time-frame given in guidelines). Critically, the European Society of Cardiology guidelines acknowledge the low level of evidence supporting these recommendations.

Anticoagulation is undoubtedly a double-edged sword. Whenever cerebrovascular complications of IE are suspected, there should be low threshold to perform diagnostic brain imaging to rule out cerebral hemorrhage, which would definitively justify discontinuation of anticoagulation and likely postpone planned cardiac surgery. Repeat echocardiography and neuroimaging play an important role in management of IE patients. At this time, the lack of robust information on anticoagulant therapy in IE stresses the need for more large randomized controlled trials.

Dr. Shannon Chiu is a 2nd year resident at NYU Langone Medical Center

Peer Reviewed by Albert Jung, MD, Internal Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons



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Unraveling The Mysteries of Prinzmetal’s Angina: What Is It And How Do We Diagnose It?

October 8, 2014

By Anjali Varma Desai, MD

Peer Reviewed

Mr. Q is a 55-year-old male smoker who presents with recurrent chest pain in the mornings over the past several months. The patient reports being awakened from sleep at approximately 5:00 a.m. each morning with the same diffuse chest “pressure.” The pain typically lasts on the order of minutes, resolves, and then recurs at five-minute intervals in the same fashion for a total duration of two hours. The pain always occurs at rest and is never precipitated by exertion or emotional stress. The chest pain is generally associated with a sense of palpitations and occasional dizziness and light-headedness. An exercise stress test showed good exercise capacity without ST segment changes, even at target heart rate. Given the history, a diagnosis of coronary artery spasm was suggested. The patient was given a trial of diltiazem therapy, with marked improvement in his chest pain episodes thereafter.

In his landmark article in 1959, Dr. Myron Prinzmetal described a distinct type of “variant angina,” termed Prinzmetal’s angina. This chest pain tended to occur at rest (i.e. was not associated with increased cardiac work), waxed and waned cyclically, occurred at the same time each day, and could be accompanied by arrhythmias including ventricular ectopy, ventricular tachycardia, ventricular fibrillation, and various forms of AV block [1]. The patient’s EKG during painful episodes typically showed ST segment elevations (occasionally accompanied by reciprocal ST depressions), whereas the EKG obtained after the pain had resolved showed resolution of these ST segment changes [1]. Prinzmetal postulated that this separate clinical entity was due to transient spasm (“increased tonus”) of a large arteriosclerotic artery, causing temporary transmural ischemia in the distribution supplied by that artery.

It is important to note that, although ST elevation would be diagnostic, it is frequently not observed in cases of coronary artery spasm. Rather, the diagnosis of coronary artery spasm should be suspected based on the timing of chest pain and the presence of syncope, arrhythmia or cardiac arrest.

It was subsequently demonstrated that such episodes of coronary artery spasm can occur not only in patients with underlying fixed coronary artery obstruction but also in patients whose coronary arteries are anatomically normal [2-7]. Selzer et al. actually compared the syndromes of coronary artery spasm between nine patients with anatomically normal coronary arteries and 20 patients with obstructive coronary lesions [8]. Selzer et al. found that the non-coronary artery disease (CAD) group of patients was more likely to have a long history of nonexertional angina without prior infarction, normal EKG at rest with ST elevations in the inferior leads, conduction disease, and bradyarrhythmias during episodes of arterial spasm. Conversely, the CAD group of patients was more likely to have prior “effort angina” and prior infarction, as well as ST elevation in the anterolateral leads, ventricular ectopy and ventricular tachyarrhythmias.

Castello et al. also compared the syndromes of coronary artery spasm in 77 patients with underlying CAD (fixed coronary stenosis greater than or equal to 50%) and 35 patients with normal or minimally diseased coronary arteries [4]. These authors found, similarly, that angina exclusively at rest tends to occur in patients with structurally normal coronary arteries and that these patients tended to have more diffuse coronary artery spasms affecting more than one artery. In contrast, patients with underlying CAD usually had more focal coronary artery spasms superimposed on their fixed stenotic lesions.

The question arises as to what could be triggering coronary artery spasm in patients with structurally normal coronary arteries? As Prinzmetal suggested, “the distinctive dissimilarities [between typical angina and variant angina] are due to profound physiological and chemical rather than anatomical differences” [1]. These physiological and chemical differences are multi-factorial. Kugiyama et al. demonstrated that there is a deficiency in endothelial nitric oxide (NO) bioactivity in Prinzmetal’s angina-prone arteries; this defect makes those arteries especially sensitive to the vasodilator effect of nitroglycerin and the vasoconstrictor effect of acetylcholine [9]. Miyao et al. used intravascular ultrasound to show that Prinzmetal’s angina patients had diffuse intimal thickening of their coronary arteries, despite an angiographically normal appearance. This intimal hyperplasia was thought to be mediated by deficient NO activity [10]. NO is involved in the regulation of basal vascular tone and helps to mediate flow-dependent vasodilation, as well as suppressing the production of endothelin-1 and angiotensin-II, both of which are powerful vasoconstrictors [11]. As a result of all of these effects, deficient endothelial NO activity predisposes to coronary artery spasm. Endothelial NO is made by the endothelial NOS (e-NOS) gene, which has been found to have many genetic polymorphisms associated with coronary artery spasm [11]. It is important to note, however, that endothelial NO synthase polymorphisms are found in only one-third of patients with coronary spasm; accordingly, other genes or factors are most likely involved [11].

In a review article, Kusama et al. [12] highlighted several additional pathophysiologic contributors to Prinzmetal’s angina, including enhanced vascular smooth muscle contractility mediated by the Rho/Rho-kinase pathway [13-14], elevated markers of oxidative stress [11,15], low-grade chronic inflammation [11], and cigarette smoking [11,15] in addition to genetic polymorphisms of endothelial NO synthase (NOS) [11,15]. Polymorpisms of various genes may explain the higher incidence of Prinzmetal’s angina in the Japanese population as compared to the Caucasian population [12].

As our understanding of the pathophysiology behind Prinzmetal’s angina has evolved, new ways of diagnosing Prinzmetal’s angina have emerged. These diagnostic maneuvers typically involve provoking episodes of Prinzmetal’s angina under controlled settings (e.g. during coronary angiography) with acetylcholine, ergonovine, hyperventilation, and cold pressor stress testing. Okumura et al. showed that intracoronary injection of acetylcholine could be reliably used to induce coronary artery spasm with 99% specificity [16], a conclusion further supported by Miwa et al. [17]. Ergonovine, an ergot alkaloid and alpha-agonist that causes vasoconstriction, can similarly be used to induce episodes of coronary artery spasm accompanied by the characteristic chest pain and EKG changes that occur during spontaneous episodes of Prinzmetal’s angina [18-19]. Song et al. suggested ergonovine echocardiography as an effective screening test for coronary artery spasm, even before coronary angiography, with a sensitivity of 91% and a specificity of 88% [20]. Subsequent studies found that this was indeed an effective, safe, and well-tolerated screening test for coronary artery spasm [21-22].

It is important to note that provocation of arterial spasm with acetylcholine or ergonovine confers a multitude of risks including arrhythmias, hypertension, hypotension, abdominal cramps, nausea, and vomiting [11]. More serious complications include ventricular fibrillation, myocardial infarction, and death [23,24]. Quantitative estimates of the risks incurred by such invasive testing are on the order of 1% [25,26]. In one study, serious major complications, such as sustained ventricular tachycardia, shock, and cardiac tamponade occurred in four out of 715 patients (0.56%) receiving provocative acetylcholine testing [25]. In another study, nine patients out of 921 (1%) had more minor complications (nonsustained ventricular tachycardia [n=1], fast paroxysmal atrial fibrillation [n=1], symptomatic bradycardia [n=6], and catheter-induced spasm [n=1]) after undergoing acetylcholine provocation testing [26]. While such invasive testing is generally considered a safe technique to assess coronary vasomotor dynamics, these maneuvers should only be performed by qualified physicians in carefully controlled settings, where the patient may be properly and quickly resuscitated as needed [11].

Testing a different diagnostic strategy, Hirano et al. noted that a diagnostic algorithm of hyperventilation for six minutes, followed by cold water pressor for two minutes under continuous EKG and echocardiographic monitoring had a 90% Sensitivity, 90% specificity, 95% positive predictive value, and 82% negative predictive value for diagnosing vasospastic angina [27]. The combination of respiratory alkalosis from the hyperventilation as well as the reflex sympathetic coronary vasoconstriction in response to the cold pressor test [28], together, helped to induce coronary artery spasm and diagnose Prinzmetal’s angina. More recently, Hwang et al. suggested that measuring the change in coronary flow velocity of the distal left anterior descending artery (LAD) via transthoracic echo during the cold pressor test may provide additional diagnostic utility, with a sensitivity of 93.5% and a specificity of 82.4% for diagnosing coronary artery spasm [29].

In an article published in JACC in 2013, the Japanese Coronary Spasm Association (JCSA) discussed a comprehensive clinical risk score to aid in prognostic stratification of patients with coronary artery spasm [30]. A multicenter registry study of 1429 patients, median age 66 years, with a median follow-up period of 32 months, was performed. The primary endpoint was defined as major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, hospitalization due to unstable angina pectoris, heart failure, and appropriate ICD shocks during the follow-up period that began at the date of the diagnosis of coronary artery spasm. In particular, cardiac death, nonfatal myocardial infarction and ICD shocks were categorized as hard MACE. The secondary endpoint was all-cause mortality. The study identified seven predictors of MACE: history of out-of-hospital cardiac arrest (4 points), smoking, angina at rest alone, organic coronary stenosis, multivessel spasm (2 points each), ST segment elevation during angina and beta-blocker use (1 point each). Based on total score, three risk categories were defined: low risk (score of 0 to 2, which included 598 patients), intermediate risk (score of 3 to 5, which included 639 patients) and high risk (score of 6 or more, which included 192 patients). The incidences of major adverse cardiac events in the low-, intermediate-, and high-risk patients were 2.5%, 7.0%, and 13.0%, respectively (p<0.001). This scoring system, known as the JCSA risk score, may help provide a comprehensive risk assessment and prognostic stratification scheme for patients with coronary artery spasm.

In terms of treatment, calcium channel blockers (e.g. nifedipine, diltiazem and verapamil) are the mainstay of therapy for coronary artery spasm. The goal of such therapy is to prevent vasoconstriction and promote coronary artery vasodilation. In one study of 245 patients with coronary artery spasm who were followed for an average of 80.5 months, the use of a calcium cannel blocker therapy was an independent predictor of myocardial-infarct-free survival in patients with coronary artery spasm [31]. In another observational study of 300 patients with coronary artery spasm, calcium channel blockers were effective in alleviating symptoms in over 90-percent of patients [32]. The drugs were evaluated and ranked as follows: markedly effective, leading to complete elimination of angina attacks within 2 days; effective, leading to complete elimination of attacks after 2 days or a reduction in the number of attacks to less than half during the periods of drug administration in the hospital; ineffective, leading to no reduction to less than half during the periods of drug administration. Efficacy rates (including markedly effective as well as effective categories) for nifedipine, diltiazem and verapamil were 94.0%, 90.8%, and 85.7%, respectively. Rarely, cases are refractory to medical therapy and literature exists to support the effectiveness of surgical revascularization in these circumstances [33].

It is clear that the phenomenon of “variant angina” is a complicated, multifaceted product of forces that are not only anatomical, but also genetic, chemical, physiological and behavioral in nature. While endothelial nitric oxide bioactivity appears to play a critical role in this process, there are undoubtedly several other factors involved. Over time, our knowledge of the pathophysiology driving Prinzemetal’s angina will continue to expand, as will our diagnostic and therapeutic repertoire for this fascinating clinical entity.

Dr. Anjali Varma Desai is a 3rd year resident at NYU Langone Medical Center

Peer Reviewed by Harmony R. Reynolds, MD, Medicine (Cardio Div), NYU Langone Medical Center


1. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Angina pectoris: I: a variant form of angina pectoris: preliminary report. Am J Med. 1959; 27: 375–388

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9. Kugiyama K, Yasue H, Okumura K, et al. Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina. Circulation 1996 Aug 1; 94(3): 266-71.

10. Miyao Y, Kugiyama K, Kawano H, et al. Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina. J Am Coll Cardiol. 2000 Aug; 36(2): 432-7.

11. Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y. Coronary artery spasm – clinical features, diagnosis, pathogenesis and treatment. J Cardiol 2008; 51: 2-17.

12. Kusama Y, Kodani E, Nakagomi A, et al. Variant angina and coronary artery spasm: the clinical spectrum, pathophysiology and management. J Nihon Med Sch. 2011;78(1):4-12. Review.

13. Shimokawa H, Seto M, Katsumata N, et al. Rho-kinase mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm. Cardiovasc Res 1999; 43: 1029-1039.

14. Masumoto A, Mohri M, Shimokawa H, et al. Suppression of coronary artery spasm by a Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation 2002; 105: 1545-1547.

15. Miwa K, Fujita M, Sasayama S. Recent insights into the mechanisms, predisposing factors and racial differences of coronary vasospasm. Heart Vessels 2005; 20: 1-7.

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17. Miwa K, Fujita M, Ejiri M, Sasayama S. Usefulness of intracoronary injection of acetylcholine as a provocative test for coronary artery spasm in patients with vasospastic angina. Heart Vessels. 1991;6(2):96-101

18. Schroeder JS, Bolen JL, Quint RA, et al. Provocation of coronary spasm with ergonovine maleate: new test with results in 57 patients undergoing coronary arteriography. Am J Cardiol 1977; 40: 487-491.

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22. Djordjevic-Dikic A, Varga A, Rodriguez O, et al. Safety of ergotamine-ergic pharmacologic stress echocardiography for vasospasm testing in the echo lab: 14 year experience on 478 tests in 464 patients. Cardiologia 1999 Oct; 44(10): 901-6.

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25. Sueda S, Saeki H, Otani T, et al. Major complications during spasm provocation tests with an intracoronary injection of acetylcholine. Am J. Cardiol. 2000; 85(3): 391.

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27. Hirano Y, Ozasa Y, Yamamoto T, et al. Diagnosis of vasospastic angina by hyperventilation and cold-pressor stress echocardiography: comparison to I-MIBG myocardial scintigraphy. J Am Soc Echocardiogr. 2002 Jun;15(6):617-23.

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29. Hwang HJ, Chung WB, Park JH, et al. Estimation of coronary flow velocity reserve using transthoracic Doppler echocardiography and cold pressor test might be useful for detecting of patients with variant angina. Echocardiography. 2010 Apr;27(4):435-41.

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From the Bellevue Wards: Wellens’ Syndrome Revisited

September 18, 2014

By Matthew Shou Lun Lee, MD

Peer Reviewed

Clinical Questions

-How common are elevated cardiac enzymes during Wellens’ syndrome?

-Can the EKG changes in Wellens’ syndrome be found with other causes?


This post represents a follow-up to the 2009 article in Clinical Correlations by Dr. Erin Ducharme [1].

Wellens’ syndrome refers to a distinctive combination of clinical and EKG findings in unstable angina associated with high-grade lesions of the left anterior descending artery (LAD) [2]. Initially described in 1982, the criteria has undergone minor changes over 30 years to now include [2,3,4]:

-Recent onset of stable or unstable angina

-Normal or minimally elevated cardiac enzyme levels

-Inverted, symmetrical or positive-negative biphasic T-wave changes in the precordial leads (most noticeable in V2-V4)

-Persistent T-wave changes in absence of chest pain

-Absence of pathological Q-waves

-Absence or minimally-elevated (<1 mm) ST elevations

-Normal precordial R wave progression

-High grade LAD stenosis

The clinical importance of Wellens’ syndrome was established early with a reported incidence of 14.2% in unstable angina cases [3]. It has been known as a “pre-infarction” stage as the initial, pre-PCI study found that 75% of these patients went on to develop anterior myocardial infarctions (MIs) within a mean of 8.5 days if not revascularized [2].

Case Presentation

A 52 year-old Polish woman presented to an outside hospital complaining of intermittent chest pain for 1 week. She had presented to an outpatient clinic 1-week prior after an episode of exertional left-sided chest pain. She was diagnosed with angina and prescribed aspirin and sub-lingual nitroglycerin (EKG unavailable). Throughout the subsequent week, her chest pain episodes worsened in both frequency (up to 10x/day) and quality. Chest pain was described as pressure-like sensation with radiation down her left arm associated with diaphoresis and nausea. She experienced a 10-minute episode at rest the night prior to admission that prompted her to present to the emergency room (ER).

Her medical history was only significant for active cigarette use (40 pack-year history). She had a family history significant for myocardial infarction and cerebrovascular accident in her mother (age 70s).

Vital signs and physical exam were unremarkable. Her initial EKG in the ER [Figure 1] showed left ventricular hypertrophy (LVH), no pathological Q waves, slight T-wave inversions (TWI) < 1mm in V2, V5, biphasic TW in V3 and possibly V4 (poor baseline), and no other ST changes.

Figure 1. Initial EKG from Emergency Room (chest pain free)

Her troponin levels were positive with a peak of 0.153 ng/ml (unclear time course). Other labs and chest x-ray were unremarkable. She was treated with aspirin, clopidogrel, metoprolol, and therapeutic enoxaparin for NSTEMI. She was then transferred to Bellevue for catheterization.

At transfer, troponin levels had downtrended to 0.086 ng/ml (36 hours after initial presentation). She was converted to intravenous heparin and started on rosuvastatin. Subsequent EKG performed while chest pain free and on ACS protocol showed new TW changes with inversions in I, aVL, and V1-V6 (most pronounced in V3 and V4) [Figure 2].

Figure 2. Pre catheterization EKG (36 hours after admission; chest-pain free)

She remained asymptomatic and cardiac catheterization was performed showing a 95% proximal LAD lesion with 40-50% lesions in the left circumflex (LCx) and right coronary arteries (RCA). The LAD lesion was treated with two drug-eluting stents with excellent angiographic results. Post-catheterization EKG [Figure 3] showed persistent TWI in I, aVL, and slight biphasic TW in V2, V3 and TWI in V4-V6. She was discharged with plans for dual anti-platelet therapy for a minimum of 1 year and smoking cessation.

Figure 3. 24 hours post-catheterization EKG


The frequent absence of clear ischemia at initial evaluation has made recognizing Wellens’ syndrome challenging. Our patient’s recent onset and progression of symptoms were consistent with early reports that nearly 70% of patients developed new-onset angina within 6 weeks of admission [2]. Her age fell within previously reported ranges, however a recent paper reported the youngest case of Wellens’ in a 24-year old female [3,5]. Given the increasing prevalence of atherosclerotic risk factors in younger populations, we can expect an earlier age of onset to become more common. Many patients, such as ours, may be chest-pain free as the time interval between last chest pain episode and admission was found to be a mean of 1.3 days [3].

Electrocardiographically, the initial EKG findings were subtle and progression of her TW changes during an asymptomatic period is not uncommon [6]. Only 50-60% of patients may have the characteristic T-wave changes on admission with an additional 30% of patients developing these findings within 24 hours [3]. EKG findings may be the sole clue to Wellens’ as only 11.6-21% of patients will have elevation in cardiac enzymes. Of the small percentage of patients with positive cardiac enzymes, none had elevations above twice the upper limit of normal [2,3]. The presence of positive enzymes is particularly worrisome as it has been associated with a higher incidence of total LAD occlusion and should prompt emergent catheterization evaluation [3]. Of note, the initial studies were limited as currently used cardiac biomarkers (troponin, CK-MB) were not yet available at the time of publication.

More recent studies describe EKG findings similar to Wellens’ syndrome in a number of different clinical contexts and suggest acute myocardial edema may mediate the characteristic changes. A recent case series reported 4 patients believed to have Wellens’ based on initial EKG. Further cardiac work-up revealed that none of these patients had a high-grade LAD stenosis and a different underlying cause was identified in each (myocardial bridge of the LAD, coronary dissection, cholecystitis, and takatsubo’s) [7, 8]. Follow-up with cardiac MRI revealed areas of acute myocardial edema. At 6 to 8 week follow-up, this edema had resolved coinciding with EKG normalization. The authors concluded that myocardial edema rather than left systolic dysfunction led to the EKG repolarization abnormalities although the exact mechanism remains unknown at this time.


Our patient’s clinical presentation and course represents a classic case of Wellens’ syndrome. Although case reports have begun to show that the EKG findings of Wellens’ can occur in the absence of LAD stenosis,suspicion for a critical LAD stenosis should remain high to ensure prompt evaluation and revascularization when indicated.

Dr. Matthew Shou Lun Lee is a 2nd year resident at NYU Langone Medical Center

Peer reviewed by Sohah Iqbal, MD, Medicine (Cardio Vascular), NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Ducharme E. What is Wellens syndrome. Clinical Correlations. 2009 Oct 7; [e-pub].

2. de Zwaan C, Bär FW, Wellens HJ. Characteristic electrocardiographic pattern indicating a critical stenosis in left anterior descending coronary artery in patients admitted because of impending myocardial infarction. Am Heart J. 1982;103:730-736.

3. de Zwaan C, Bär FW, Janssen JH, et al. Angiographic and clinical characteristics of patients with unstable angina showing an ECG pattern indicating critical narrowing of the proximal LAD coronary artery. Am Heart J. 1989;117:657-665.

4. Raheja P, Sekhar A, Lewis D, et al. Wellens’ syndrome over the past three decades. J Cardiovasc Med. 2013 Mar 5; [e-pub].

5. Khan B, Alexander J, Rathod KS, et al. Wellens’ syndrome in a 24-year-old woman. BMJ Case Rep. 2013 Apr 30; [e-pub].

6. Tandy TK, Bottomy DP, Lewis JG. Wellens’ syndrome. Ann Emerg Med. 1999; 33(3): 347-351.

7. Migliore F, Zorzi A, Marra MP, et al. Myocardial edema underlies dynamic T-wave inversion (Wellens’ ECG pattern) in patients with reversible left ventricular dysfunction. Heart Rhythm. 2011;10(8):1629-1634.

8. Vago H, Toth A, Apor A, et al. Images in cardiovascular medicine. Cardiac contusion in a professional soccer player: visualization of acute and late pathological changes in the myocardium with magnetic resonance imaging. Circulation. 2010; 121(22):2456-2461.


Caffeine and the Risk of Atrial Fibrillation

June 6, 2014

By Joshua Michael Lader, MD

Peer Reviewed

As physicians, we are frequently asked to weigh-in on dinnertime discussions about topics that, despite their relevance to everyday life, were never formally addressed in our medical training. For example, at a recent family gathering the conversation turned to a 78 year-old uncle who was recently diagnosed with atrial fibrillation. While this uncle had longstanding and likely poorly controlled hypertension, he would also typically drink 4 to 5 cups of coffee between breakfast and lunch. The debate then began as to whether my uncle’s morning habit of caffeinating himself could have contributed to his new-onset atrial fibrillation. I chimed in, stating that it was likely his more traditional risk factors (hypertension and old age) playing a role. Feeling smart, I quoted a 2005 study from JAMA demonstrating that habitual coffee consumption was not associated with an increased risk of incident hypertension in women [1]. My 28 year-old cousin then followed with a question that prompted me to do the research for this article:

“I heard that coffee can give you an irregular heartbeat. I also drink 5 cups per day. Should I cut back?”

I didn’t know what to say. No one in medical school listed caffeine ingestion as one of the typical risk factors for atrial fibrillation. However, this was probably something of a loaded question. She likely knew that caffeine has been shown to increase serum concentrations of the catecholamines epinephrine and norepinephrine in those naïve to the substance [2,3]. Furthermore, the alkaloid in question has also been shown to augment intracellular levels of cyclic AMP both directly (by stimulating adenyl cyclase) [4] and indirectly (by inhibiting phosphodiesterase) [5]. These molecular changes are widely recognized to shorten the duration of the myocardial action potential and refractory period and could thereby be expected to facilitate the maintenance of tachyarrhythmias [6]. In a 1983 study published in the New England Journal of Medicine, participants underwent electrophysiologic study before and after the administration of 200mg of oral coffee or IV caffeine citrate. As expected, the study demonstrated significant shortening of the effective refractory period in the high and low right atrium as well as in the AV node. These electrophysiologic changes were accompanied by what appeared to be prolonged duration of the provoked arrhythmias (though no statistical tests were run on the data likely due to the limited sample size) [7]. It is no surprise, then, that the majority of coronary care units at that time allowed only decaffeinated beverages (or so I am told). It seemed as though the case was closed and that my cousin should find herself a new breakfast-time beverage.

Not so fast. Certain other electrophysiologic parameters are unchanged by caffeine administration, including the shape of the P-wave (as assessed by signal-averaged electrocardiograms) [8,9] as well as inter- and intra-atrial conduction intervals (as assessed invasively) [7]. To put this in context, the slowing of atrial electrical impulse propagation, which would manifest as prolongation of the P-wave in the former studies and prolonged conduction intervals in the latter, is also arrhythmogenic. Additionally, intravenous administration of caffeine to canines surprisingly resulted in a reduced propensity for the induction of atrial fibrillation [10]. In a prospective examination of nearly 48,000 patients from the Danish Health Registry, Frost et al failed to find any risk of atrial fibrillation or flutter associated with caffeine consumption [11]. Most recently, Klatsky et al showed that in a large cohort from the Kaiser Permanente Medical Care Program, coffee-drinking and caffeine intake were inversely related to the risk of hospitalization for cardiac dysrhythmias in a dose-dependent fashion [12].

The reason for the disconnect between these studies is unknown. Many subsequent studies do not even acknowledge that a connection between caffeine and atrial fibrillation has ever been demonstrated [13]. The most likely explanation is tachyphylaxis, that the catecholaminergic effects of caffeine are significantly attenuated in habitual users [14,15]. Additionally, the fact that caffeine competitively antagonizes adenosine receptors (whose agonism abbreviates atrial refractory period and promotes atrial fibrillation) may also serve to protect against atrial fibrillation [16]. Furthermore, with a recent New England Journal of Medicine article suggesting that the survival benefit associated with coffee ingestion extends to its decaffeinated varietal [17], one must consider the likelihood that coffee’s biological effects may be attributable to substances other than caffeine.

I told my cousin what I had found and she muttered something about how “nature’s homeostatic mechanisms could not have been designed more perfectly” and then told me that she “would have kept drinking coffee regardless of any data.” Go figure.

Dr. Joshua Michael Lader, Cardiologist, NYU Langone Medical Center

Peer reviewed by David Park, MD, Medicine, Cardio Div., NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1) Winkelmayer WC, Stampfer MJ, Willett WC, Curhan GC. Habitual caffeine intake and the risk of hypertension in women. JAMA. 2005 Nov 9;294(18):2330-5.

2) Robertson D, Frolich JC, Carr RK, et al. Effects of caffeine on plasma activity, catecholamines and blood pressure. N Engl J Med. 1978;298:181-6.

3) Levi L. The effect of coffee on the function of the sympathoadrenomedullary system in man. Acta Med Scand. 1967;181:431-8.

4) Rall TW. The xanthines. In: Gilman AG, Goodman LS, Gilman A. eds. The pharmacological basis of therapeutics. 6th ed. New York: Macmillan. 1980:592-607

5) Braunwald E, Sonnenblick EH, Ross J Jr. Contraction of the normal heart. In: Braunwald E, ed. Heart disease: a textbook of cardiovascular medicine. Philadelphia. WB Saunders, 198:419, 1980:413-52

6) Moe GK, Rheinboldt WC, Abildskov JA. A computer model of atrial fibrillation. Am Heart J. 1964 Feb;67:200-20.

7) Dobmeyer DJ, Stine RA, Leier CV, Greenberg R, Schaal SF. The arrhythmogenic effects of caffeine in human beings. N Engl J Med. 1983 Apr 7;308(14):814-6.

8) Donnerstein RL, Zhu D, Samson R, Bender AM, Goldberg SJ. Acute effects of caffeine ingestion on signal-averaged electrocardiograms. Am Heart J. 1998;136:643–6.

9) Caron MF, Song J, Ammar R, Kluger J, White CM. An evaluation of the change in electrocardiographic P-wave variables after acute caffeine ingestion in normal volunteers. J Clin Pharm Ther. 2001;26:145–8.

10) Rashid A, Hines M, Scherlag BJ, Yamanashi WS, Lovallo W. The effects of caffeine on the inducibility of atrial fibrillation. J Electrocardiol 2006;39:421–5.

11) Frost L, Vestergaard P. Caffeine and risk of atrial fibrillation or flutter: the Danish diet, cancer, and health study. Am J Clin Nutr. 2005;81:578–82.

12) Klatsky AL, Hasan AS, Armstrong MA, et al. Coffee, caffeine, and risk of hospitalization for arrhythmias. Perm J. 2011 Summer;15(3):19-25.

13) Schoonderwoerd BA, Smit MD, Pen L, Van Gelder IC. New risk factors for atrial fibrillation: causes of ‘not-so-lone atrial fibrillation’. Europace. 2008 Jun;10(6):668-73.

14) Debrah K, Haigh R, Sherwin R, et al. Effect of acute and chronic caffeine use on the cerebrovascular, cardiovascular and hormonal responses to orthostasis in healthy volunteers. Clin Sci (Lond). 1995 Nov;89(5):475-80.

15) Tarnopolsky MA, Atkinson SA, MacDougall JD, et al. Physiological responses to caffeine during endurance running in habitual caffeine users. Med Sci Sports Exerc. 1989 Aug;21(4):418-24.

16) Grant AO. Mechanisms of atrial fibrillation and action of drugs used in its management. Am J Cardiol. 1998 Oct 16;82(8A):43N-49N.

17) Freedman ND, Park Y, Abnet CC, et al. Association of coffee drinking with total and cause-specific mortality. N Engl J Med. 2012 May 17;366(20):1891-904.




New Cholesterol Guidelines: How Safe Are High-Potency Statins?

May 14, 2014

By Molly Anderson

Peer Reviewed

Managing hyperlipidemia is a mainstay of cardiovascular risk reduction. The 2013 ACC/AHA guidelines no longer target specific low-density lipoprotein (LDL)-cholesterol levels, but recommend lipid-lowering therapies of varying intensity based on the predicted risk of cardiovascular events [1]. Adoption of the new guidelines would result in millions more Americans receiving high-potency statins; it is therefore important to investigate potential dangers associated with aggressive therapy and the long-term implications for patients.

Many studies have shown that strict adherence to lipid-lowering medications improves outcomes for patients who are at risk for or have had cardiovascular events [2-5]. The Adult Treatment Panel III guidelines (2002), still used by many physicians, recommended intensive therapy for those in the “very high risk” category: those with known coronary artery disease plus diabetes, tobacco use, or the metabolic syndrome. The current guidelines now recommend high-dose statins (atorvastatin 40-80 or rosuvastatin 20-40 mg daily) for those with clinical evidence of atherosclerotic cardiovascular disease (ASCVD), LDL >190 mg/dL, or a 10-year ASCVD risk of greater than 7.5%. The recommendations make 12.8 million new patients, many in perfect health, candidates for statin therapy [6].

Eliminating treat-to-target therapy lessens the role for combination therapy with other cholesterol-lowering medications (colesevelam, ezetimibe, fenofibrate, niacin) to reach a certain goal. Despite previous guidelines suggesting addition of these medications, evidence has shown that using them to further decrease non-HDL cholesterol does not further reduce the risk of ASCVD [7,8]. Furthermore, many studies have shown that there is an increased risk of adverse effects when statins are combined with other drugs, particularly with gemfibrozil [9,10].

The incidence of adverse side effects with intensive lipid-lowering therapy is low. The most common side effect associated with statins is myalgia, and this effect does not appear to be dose-dependent. A 2006 retrospective analysis of over 14,000 patients found no difference in the incidence of myalgia between patients taking atorvastatin 80 mg daily (intensive dose) compared to 10 mg (low dose); furthermore, no cases of rhabdomyolysis were reported [11].

Another side effect associated with statins is hepatic dysfunction. A 2007 review showed a dose-dependent increased risk of elevated liver enzymes with increasing statin doses [12]. The elevation is usually benign and returns to baseline with a change in therapy; the risk of progression to liver failure is extremely low [13].

More recently, statin therapy has been associated with a slight (9%) dose-dependent increased incidence of diabetes mellitus in patients with pre-existing risk factors [14,15].

Options for patients who experience adverse side effects include either brief cessation of treatment, decreasing dosing frequency, or switching to a different statin. Recent n-of-1 trials identified cases of statin-related myalgia and elevated liver enzymes and found that, following a 3-week washout interval, the symptoms were not significantly different between those restarted on the same statin and those on placebo [16]. Hydrophilic statins with a better side effect profile, such as rosuvastatin, may be attempted in patients not tolerating other therapy [17,18].

There are concerns that if a physician does not target high-dose statin therapy to a goal LDL, the value may become dangerously low. There have been several case studies suggesting a link between low cholesterol levels and violent or suicidal behavior; however, no causative mechanism has been implicated [19-22]. There have also been trials showing an increased risk of hemorrhagic stroke with lower levels of LDL [23-25]. The SPARCL trial found no association between LDL level and hemorrhagic stroke risk in patients with recent stroke and no known coronary heart disease, but instead found an increased incidence of hemorrhagic stroke in patients receiving 80 mg of atorvastatin [26].

With the new guidelines, an aggressively treated high-risk patient could potentially attain LDL levels below 40 mg/dL. To evaluate potential risks, one study compared patients following an acute coronary event treated to an LDL goal of 80-100 mg/dL to those treated to a more aggressive goal as low as <40 mg/dL. The authors found no adverse effects with lower levels, but found fewer major cardiac events in those with LDL levels below 60 mg/dL compared to higher target levels of LDL [27]. A more recent study of over 6000 patients with LDL levels below 60 mg/dL on statin therapy found no increased risk of malignancy, hepatic dysfunction, or rhabdomyolysis, as well as a 35% reduction in mortality compared to patients not started on statin therapy [28].

Due to the low risk of adverse outcomes, the guidelines recommend starting statin therapy on otherwise healthy adult patients with 10-year ASCVD risk of >7.5% to lower the risk of eventual ASCVD. The JUPITER trial showed that healthy adults with LDL levels <130 mg/dL and high-sensitivity C-reactive protein (CRP) levels >2 mg/l treated with rosuvastatin to achieve LDL levels <50 mg/dL had a lower risk of ASCVD without an increase in reported adverse events when compared to adults with LDL target levels below 130 mg/dL [29]. AFCAPS/TexCAPS, a 1998 primary prevention trial of over 6000 patients, reported that adults with an average LDL level (221 mg/dL) started on lovastatin therapy had a significantly reduced incidence of a first major acute coronary event with no difference in side effects from those not started on statin therapy [30]. The beneficial effect of early treatment has not yet been conclusively demonstrated. More research needs to be done to make physicians feel more comfortable with early treatment.

While there are other lipid parameters available to monitor the progression of atherosclerosis (see Dr. Weintraub’s commentary below), LDL levels should still be closely monitored to evaluate efficacy of therapy and encourage patient participation. A very low LDL concentration, and the means of achieving it, has shown to be safe and effective. Future research should focus on long-term outcomes of aggressive therapy in low-risk populations to examine potential extrapolation to an even broader population. Many practitioners have joked that statins should be added to the water supply, like fluoride for teeth. Are they truly that far off?

Commentary by Dr. Howard Weintraub

There has been a clear evolution in the strategies for lipid lowering and the tools we have to achieve the desired levels of LDL. Dr. Scott Grundy published his views on the topic in a widely cited work in 2004. As noted in this review there have been several papers that have identified lower LDL levels being associated with a reduction in cardiovascular events. Older studies were able to compare active lipid lowering versus placebo. Contemporary studies compared different statins and end- treatment LDL in the setting of gradually improving background care (such as ACE inhibitors, angiotensin receptor blockers, antiplatelet agents, beta-blockers, etc.). Supporters of a more aggressive strategy have been not been disappointed with the results. We have also been able to appreciate the importance of addressing the contribution of additional risk factors for atherosclerosis such as hypertension, obesity, smoking, age, inactivity, metabolic syndrome, and diabetes [31].

What has emerged from the trials is support for related lipid endpoints (such as apolipoprotein B and the number of LDL particles) [32] and inflammatory markers (such as high-sensitivity C-reactive protein) [33] and noninvasive plaque imaging. In many cases these can augment the risk that has been documented in patients with metabolic syndrome and diabetes. The studies have identified a large number of patients who may have been inaccurately felt to be at low risk and are subsequently identified to potentially profit from lower LDL levels. In addition, the perception that HDL is a routinely beneficial biomarker and one that should be targeted with specific therapy has been challenged by several large trials. This is due to our understanding that HDL functions as a “garbage truck” that facilitates the transfer of LDL from cholesterol-laden macrophages that are resident in plaque, to the liver where disposal occurs. However, these studies have questioned the wisdom of adding fibrates or niacin to statin therapy [8, 34]. An explanation for this dilemma has been offered in a recent publication in JACC showing that while niacin raised HDL-C it did not improve reverse cholesterol transport [35].

Hence, as stated in this very good review, we are left with the promise of improved outcomes when levels of atherogenic lipoproteins are aggressively lowered. But it would appear there are a wide variety of patients (other than those post-MI) who may derive great benefit from lowering LDL to very low levels, in addition to attention to the other contributors to “residual risk.”

Molly Anderson is a 4th year medical student at NYU School of Medince

Peer reviewed by Howard Weintraub, MD, Cardio Medicine, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


1. Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013 Nov 7. pii: S0735-1097(13)06028-2. doi: 10.1016/j.jacc.2013.11.002. [Epub ahead of print]

2. LaRosa JC, Grundy SM, Waters DD, et al; Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352(14):1425-1435.

3. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. N Engl J Med. 2004;350(15):1495-1504.

4. Mills EJ, O’Regan C, Eyawo O, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients. Eur Heart J. 2011;32(11):1409-1415.

5. Cholesterol Treatment Trialists’ (CTT) Collaborators, Mihaylova B, Emberson J, Blackwell J, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380(9841):581-590.

6. Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014;370:1422-1431.

7. Guyton JR, Slee AE, Anderson T, et al. Relationship of lipoproteins to cardiovascular events: the AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62(17):1580-1584.

8. The AIM HIGH Investigators, Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255-2267.

9. Chatzizisis YS, Koskinas KC, Misirli G, Vaklavas C, Hatzitolios A, Giannoglou GD. Risk factors and drug interactions predisposing to statin-induced myopathy: implications for risk assessment, prevention and treatment. Drug Saf. 2010;33(3):171-187.

10. Bottorff MB. Statin safety and drug interactions: clinical implications. Am J Cardiol. 2006;97(8A):27C-31C.

11. Newman C, Tsai J, Szarek M, Luo D, Gibson E. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol. 2006;97(1):61-67.

12. Alsheikh-Ali AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol. 2007;50(5):409-418.

13. Younoszai Z, Li Z, Stepanova M, Erario M, Cable R, Younossi ZM. Statin use is not associated with liver related mortality. Ann Hepatol. 2013;13(1):84-90.

14. Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012;380(9841):565-571.

15. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735-742.

16. Joy TR, Monjed A, Zou GY, Hegele RA, McDonald CG, Mahon JL. N-of-1 (single-patient) trials for statin-related myalgia. Ann Intern Med. 2014;160(5):301-310.

17. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165(22):2671-2676.

18. Glueck CJ, Aregawi D, Agloria M, et al. Rosuvastatin 5 and 10 mg/d: a pilot study of the effects in hypercholesterolemic adults unable to tolerate other statins and reach LDL cholesterol goals with nonstatin lipid-lowering therapies. Clin Ther. 2006;28(6):933-942.

19. Asellus P, Nordstrom P, Jokinen J. Cholesterol and CSF 5-HIAA in attempted suicide. J Affect Disord. 2010;125(1-3):388-392.

20. Golomb BA. Cholesterol and violence: is there a connection? Ann Intern Med. 1998;128(6):478-487.

21. Vartiainen E, Puska P, Pekkanen J, Tuomilehto J, Lonnqvist J, Ehnholm C. Serum cholesterol concentration and mortality from accidents, suicide, and other violent causes. BMJ. 1994;309(6952):445-447.

22. Golomb BA, Kane T, Dimsdale JE. Severe irritability associated with statin cholesterol-lowering drugs. QJM. 2004;97(4):229-235.

23. Ebrahim S, Sung J, Song YM, Ferrer RL, Lawlor DA, Davey Smith G. Serum cholesterol, haemorrhagic stroke, ischaemic stroke, and myocardial infarction: Korean national health system prospective cohort study. BMJ. 2006;333(7557):22.

24. Iso H, Jacobs DR Jr., Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med. 1989;320(14):904-910.

25. Yano K, Reed DM, MacLean CJ. Serum cholesterol and hemorrhagic stroke in the Honolulu Heart Program. Stroke. 1989;20(11):1460-1465.

26. Amarenco P, Bogousslavsky J, Callahan A 3rd, et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355(6):549–559.

27. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E, PROVE IT-TIMI 22 Investigators. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46(8):1411-1416.

28. Leeper NJ, Ardehali R, DeGoma EM, Heidenreich PA. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation. 2007;116(6):613-618.

29. Hsia J, MacFadyen JG, Monyak J, Ridker PM. Cardiovascular event reduction and adverse events among subjects attaining low-density lipoprotein cholesterol <50 mg/dl with rosuvastatin: The JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). J Am Coll Cardiol. 2011;57(16):1666-1675.

30. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615-1622.

31. Mora S, Wenger NK, Demicco DA, et al. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study. Circulation. 2012;125(16):1979-1987.

32. El Harchaoui KE, van der Steeg WA, Stroes ES, et al. Value of low-density lipoprotein particle number and size as predictors of coronary artery disease in apparently healthy men and women: . The EPIC-Norfolk Prospective Population Study. J Am Coll Cardiol. 2007;49(5):547-553.

33. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein: the JUPITER Trial. N Engl J Med. 2008:359(21):2195-2207.

34. The ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563-1574.

35. Khera AV, Patel PJ, Reilly MP, Rader DJ. The addition of niacin to statin therapy improves high-density lipoprotein cholesterol levels but not metrics of functionality. J Am Coll Cardiol. 2013;62(20):1909-1910.