Cardiology

Early Repolarization: Not as Innocent as Once Thought!

January 5, 2011

By Rachel Bond, MD PGY-2

Faculty Peer Reviewed

For many years, the electrocardiogram, a seemingly simple transthoracic interpretation of the electrical activity of the heart captured and externally recorded, has fascinated healthcare professionals.  An aspect of the electrocardiogram which has piqued curiosity consist of an interesting pattern referred to as “early repolarization.”  Early repolarization is a slurring or notching producing a hump-like feature called a J wave, typically found at the junction at the end of the QRS complex and the beginning of the ST segment.  In a normal ECG, the transition of ventricular depolarization into ventricular repolarization corresponds on the surface ECG to this J-point, where an abrupt transition from the QRS complex to the ST-segment occurs.  Deviation of the J-point from the isoelectric line leads to the presence of a J-deflection.  This typically produces a concave upward curve towards the T wave, helping to differentiate it from the convex, ‘tomb-stone’ waves seen with infarct.  The leads associated with the J wave, commonly shown as ST-segment elevations (a.k.a. J point elevations) typically involve the anterior precordial leads (V1-V3).  Recently, data has looked into early repolarization localized to the inferolateral leads.

As reported by Wellens[i], approximately 2-5% of the population demonstrates the early repolarization changes on electrocardiogram; this population mostly consists of men, young adults, athletes, and people of African American heritage.  Early repolarization previously was felt to be a rather benign feature; however, experimental studies, isolated case reports and independent case studies have shown its potential arrhythmogenic effects.

One such study by Haïssaguerre et al.[ii] evaluated the clinical association between early repolarization in the inferolateral leads and idiopathic ventricular arrhythmias leading to syncope and/or sudden cardiac death.  The study conducted was a case–control study involving 206 case subjects with a prior history of idiopathic ventricular fibrillation (IVF).  The primary endpoint was to assess the prevalence of early repolarization and evaluate its potential relationship with any observed arrhythmias, as monitored by implantable defibrillators.  In the study, early repolarization prevalence was compared between case subjects who had previously experienced an episode of IVF prior to the study and control subjects with no known heart disease.  Early repolarization occurred statistically more frequently in the case subjects with IVF than the control subjects (31% vs. 5%, P<0.001).  Furthermore, in select subjects, the origin of ectopy that initiated ventricular arrhythmia was mapped to sites concordant with the localization of the early repolarization abnormality and showed accentuation of early repolarization prior to the actual arrhythmia.  In the study, electrocardiography was performed during an arrhythmic period (including frequent premature ventricular contractions and episodes of IVF) in 18 case subjects, and all subjects showed a consistent increase in the amplitude of early repolarization so that the J-point amplitude increased from 2.6±1 mm to 4.1±2 mm (P<0.001).  In six subjects with early repolarization recorded only in inferior leads, all ectopy originated from the inferior ventricular wall.

As mentioned by Haïssaguerre et al, the link between this electrocardiographic pattern and malignant arrhythmias is supported by both the accentuated repolarization before the onset of arrhythmia seen in a few of the case subjects and the origin of triggering beats from the region of early repolarization (as described above).  To further elaborate on this statement, defibrillator monitoring performed in the study showed a higher incidence of recurrent ventricular fibrillation in case subjects with a repolarization abnormality than in those without (41% vs. 23%).  The hazard ratio for recurrence was 2.1 (95% CI, 1.2 to 3.5; P = 0.008).  Among patients with a prior history of IVF, an increased prevalence of early repolarization was found; as such, this case-study was the first to hypothesize this clinical association.

In the NEJM in December 2009, Tikkanen et al[iii] investigated the long-term outcomes associated with early repolarization on the electrocardiogram.  This evaluation was an extension of the data described by Haïssaguerre et al. above, as well as additional case-studies.[iv] The Tikkanen study sought to emphasize the prognostic significance of the J point pattern in the inferolateral leads which were hypothesized to be more arrhythmogenic than the more commonly studied anterior precordial leads (leads v1 through v3).

The study by Tikkanen et al. (iii) was a community-based study to assess the prevalence of the early repolarization pattern and its long-term prognosis in a large, middle-aged Finnish population (mean age, 44 ± 8 years) with a long follow-up time (mean (±SD) period 30±11 years).  The study was conducted by evaluating the inferior and lateral J-point elevations independently to clarify the significance of localization on a resting 12-lead electrocardiogram of 5676 men and 5188 women from the general Finish population.  Two predefined cutoff points (≥0.1 mV and >0.2 mV) were made to assess the significance of the amplitude of J-point elevation from baseline.  Survival data was used to assess the prognosis for subjects who had an early repolarization pattern.

Findings showed that the early repolarization pattern of 0.1 mV was present in 630 subjects (5.8%), 384 (3.5%) of which occurred in the inferior leads and 262 (2.4%) in lateral leads, with elevations in both leads in 16 subjects (0.1%).  Upon further review, it was found that J-point elevation of at least 0.1 mV in the inferior leads was associated with a similar increased risk of death from cardiac causes (adjusted relative risk, 1.28; 95% confidence interval [CI], 1.04 to 1.59; P = 0.03) when compared to these elevations in the lateral leads (adjusted relative risk of 1.34; 95% CI, 1.04 to 1.74; P= 0.03).  In addition, 36 subjects (0.3%) with J-point elevation of more than 0.2 mV in inferior leads had a markedly elevated risk of death from cardiac causes (adjusted relative risk, 2.98; 95% CI, 1.85 to 4.92; P<0.001) when compared to that in the lateral leads, where the data was not statistically significant (adjusted relative risk, 1.61; 95% CI, 0.83 to 3.10; P = 0.19).  In addition, J-point elevations of more than 0.2 mV in the inferior leads had a statistically significant risk of death from arrhythmia (adjusted relative risk, 2.92; 95% CI, 1.45 to 5.89; P = 0.01) when compared to that in the lateral leads where it was not statistically significant.

Based on the findings above, early repolarization in the inferior leads appeared to be a strong predictor of death from cardiac causes or from arrhythmia than J-point elevation in the lateral leads.  In addition to the location of the early-repolarization pattern, the amplitude of the J-point elevation had great prognostic value.  There was a significantly higher risk of death from cardiac causes among subjects with a markedly elevated J point (>0.2 mV) than among those with a more moderate elevation (≥0.1 mV).

In keeping with the study populations demographics and characteristics, case studies found to have the early repolarization pattern were more likely to be of the male sex and have lower baseline heart rates (ii).  Of note, in the patient populations studied, very few belonged to the subgroups that have been shown to have a high prevalence of early repolarization in the anterior precordial leads (e.g., athletes, young males, blacks).  In addition, although early repolarization has more commonly been studied in the anterior precordial leads, the studies discussed above have shown the increased association between arrhythmias and J point elevations originating from the inferolateral portion of the heart.  All of this data is clearly laid out by Haïssaguerre et al and Tikkanen et al; however, what is not clear is how the early repolarization pattern localized to the inferior leads increase the risk of death from cardiac and arrhythmic causes.

One hypothesis is the concept that the J-point elevation is a marker of increased transmural heterogeneity of ventricular repolarization.  In addition, the left ventricular base defined by the inferolateral leads is an area known to have increased current density.  As such, having an episode of early repolarization in an area with known increased current density is what can make the myocardium more vulnerable to ventricular tachyarrhythmias[v] [vi].  This vulnerability may be amplified under certain conditions such as a cardiac ischemic event, the use of specific drugs, various levels of autonomic tone, electrolyte disturbances, channelopathies and/or structural cardiac abnormalities.  This hypothesis can be further defended by the fact the anti-arrhythmic, quinidine, which is known to restore electrical homogeneity, aborted arrhythmias in a certain number of the patient population studied (ii).

So where does this information lead us?

When confronted with a patient with an episode of sudden cardiac death, ventricular tachyarrhythmia or syncope with ECG findings of early repolarization localized to the inferolateral leads, the practitioner should rule out all more commonly studied ischemic and non-ischemic causes, including, but not limited to, the long-QT syndrome, the short-QT syndrome, the Brugada syndrome, and arrhythmogenic right ventricular dysplasia (i).  Once these conditions have been excluded, it can be implied that the inferolateral J point elevation which represents early repolarization in an area with increased current density is what predisposed to the event.  As such, these studies presented above suggest that these inferolateral J point elevations should be used as important diagnostic signs to detect high-risk persons with a history of “unexplained” syncope and/or a familial incidence of sudden death at a young age.

Possible interventions for such situations include the known standard of care with the implantation of defibrillators for secondary prevention in addition to the use of anti-arrhythmic agents and/or cardiac ablation in patients who have been ruled out for all other ischemic and non-ischemic causes.  Haissaguerre et al. (ii) evaluated ICD implantation which was inserted primarily for secondary prevention and used in the study to assess the likelihood of recurrence of the arrhythmic event.  The study also evaluated how the anti-arrhythmic agent quinidine, which has been shown to restore transmural electrical homogeneity and abort arrhythmic activity in patients with J-point elevations, diminished the electrocardiographic pattern and eliminated recurrent arrhythmias in four out of four subjects given the medication.  In addition, catheter ablation was shown to eliminate ectopy in approximately 60% of the population studied (five out of a total of eight subjects evaluated); however, this was only a short term elimination.  Although these interventions were focused on a small number of patients evaluated, there appears to be some promising preventive and/or curative measures which need to be further studied before costly procedures and medications should be prescribed for this particular patient population.

In conclusion, one can postulate that J point elevations in the anterior precordial leads are less arrhythmogenic (i.e. more benign) than J point elevations in the inferior leads, especially in patients presenting to the hospital with an episode of syncope and/or sudden cardiac death.  There should be close monitoring on telemetry and consideration of further causes and treatment options once other, more commonly studied, ischemic and non-ischemic cardiac causes are ruled out.  Unfortunately, there are no studies as of yet looking at appropriate interventions in asymptomatic patients with incidental findings of inferior J point elevations (i.e. ICD implantation for primary prevention); however, based on the data above I would favor letting the patient know of this finding, providing them with a copy of their ECG to keep in their pocket in case of an emergency, suggesting referral to a cardiologist and taking a concise cardiac and family history to prepare for possible future events.

Until there is better data, physicians are left with the observation that in some persons with findings of early repolarization in the inferolateral area on an electrocardiogram, life-threatening ventricular tachyarrhythmias may occur and may progress to sudden cardiac death.  Since there are many persons who fit such a picture but do not appear to have excess risk, further data is needed to reveal how to identify patients who are at high risk for such an arrhythmias and what preventive measures can be done to stop it.  Until then, I would recommend a close caution on these asymptomatic patients, to keep them, just that, asymptomatic.

Dr. Bond is a second year resident at NYU Langone Medical Center

Faculty peer reviewed by Steven Fowler,MD,  Department of Medicine (Cardiology), NYU Langone Medical Center

Image courtesy of Wikimedia Commons

References:

[i] Wellens HJ. Early Repolarization Revisited. N Engl J Med May 8, 2008. 358:2063-2065.  https://www.clinicalcorrelations.org/wp-includes/js/tinymce/plugins/paste/pasteword.htm?ver=327-1235#_ednref1

[ii] Haïssaguerre M, Derval N, Sacher F, et al. Sudden cardiac arrest associated with early repolarization. N Engl J Med 2008; 358:2016-23.  https://www.clinicalcorrelations.org/wp-includes/js/tinymce/plugins/paste/pasteword.htm?ver=327-1235#_edn2

[iii] Tikkanen JT, Anttonen O, Junttila MJ, Aro AL, Kerola T, Rissanen HA, Reunanen A, Huikuri HV. Long-Term Outcome Associated with Early Repolarization on Electrocardiography. N Engl J Med 2009; 361:2529-2537. https://www.clinicalcorrelations.org/wp-includes/js/tinymce/plugins/paste/pasteword.htm?ver=327-1235#_edn3

[iv] Rosso R, Kogan E, Belhassen B, et al. J-point elevation in survivors of primary ventricular fibrillation and matched control subjects: incidence and clinical significance. J Am Coll Cardiol 2008;52:1231-8.  https://www.clinicalcorrelations.org/wp-includes/js/tinymce/plugins/paste/pasteword.htm?ver=327-1235#_edn4

[v] Yan GX, Antzelevitch C. Cellular basis for the electrocardiographic J-wave. Circulation; 1996;93:372-9.  https://www.clinicalcorrelations.org/wp-includes/js/tinymce/plugins/paste/pasteword.htm?ver=327-1235#_ednref5

[vi] Gussak I, Antzelevitch C. Early repolarization syndrome: clinical characteristics and possible cellular and ionic mechanisms. J Electrocardiol 2000;33:299-309.  https://www.clinicalcorrelations.org/wp-includes/js/tinymce/plugins/paste/pasteword.htm?ver=327-1235#_edn6

Does Vitamin D Supplementation Reduce the Risk of Cardiovascular Events?

October 6, 2010

By Karina Vivar, MS4

Faculty Peer Reviewed

Vitamin D deficiency is highly prevalent in the U.S. and worldwide, and the problem appears to be worsening.  By definition, vitamin D deficiency is a serum 25-hydroxyvitamin D (25-OH D) level of less than 20 ng/mL.  Vitamin D insufficiency is defined as a serum 25-OH D level from 20 to 30 ng/mL.  Unless there is a high risk for fracture and a clinical suspicion of deficiency, it is not routine to screen for vitamin D deficiency, due to laboratory variability and cost of testing.  Therefore, rather than screen patients for deficiency, the Institute of Medicine (IOM) recommends that adults 19 to 50 years old receive 200 IU of vitamin D per day, adults 51 to 70 receive 400 IU per day, and adults over 71 receive 600 IU per day, through diet or supplementation. Certain populations–the elderly, the chronically ill, those with dark skin, and those with limited sunlight exposure–require much higher daily doses of vitamin D, at least 800 to 1000 IU per day.  Even healthy, normal-weight patients may require 2000 IU per day to achieve a serum level of 25-OH D over 30 ng/mL, a daily intake significantly greater than that recommended by the IOM.[1],[2]

Interest in vitamin D has increased as epidemiological and clinical studies have revealed potential non-skeletal effects of vitamin D.  From depression to cancer, diabetes to multiple sclerosis, and cognition to chronic pain, these studies have drawn a correlation between vitamin D deficiency and disease, including cardiovascular disease.  Analyses of epidemiological studies such as the Third National Health and Nutrition Examination Survey (NHANES III) and longitudinal cohort studies like the Framingham Offspring Study have found a statistically significant inverse relationship between 25-OH D serum levels and coronary artery disease, as well as the cardiovascular risk factors obesity, hypertension, diabetes, hypertriglyceridemia, and hypercholesterolemia.[3],[4] Moreover, numerous studies have independently associated low 25-OH D levels with congestive heart failure, calcific aortic stenosis, increased body-mass index, and metabolic syndrome.2,[5]

It is known that vitamin D receptors are present on vascular smooth muscle, endothelium, and cardiomyocytes.  However, the exact mechanism behind vitamin D’s cardioprotective effects has yet to be elucidated.  It is hypothesized that vitamin D downregulates the renin-angiotensin-aldosterone system to lower blood pressure, improves insulin secretion and sensitivity, improves vascular remodeling in response to injury and atherosclerosis, and decreases parathyroid hormone levels.  The studies investigating these hypotheses are still in preclinical phases, but these preliminary data have shown that the benefit of vitamin D supplementation may have biological plausibility.[6]

Knowing the observational correlations between low vitamin D levels and increased risk of cardiovascular disease, as well as the potential mechanisms behind this relationship, should clinicians recommend vitamin D supplementation in order to reduce the risk of cardiovascular events?

Only a handful of prospective observational studies and randomized control trials have examined the association between vitamin D supplementation and the risk for cardiovascular disease.  The most consistent evidence supporting vitamin D supplementation is for patients on hemodialysis.  Patients with end-stage renal disease commonly experience secondary hyperparathyroidism, as the kidneys are unable to convert 25-OH vitamin D to 1,25-dihydroxyvitamin D, the active form.  These patients are usually maintained on activated vitamin D.  Cardiovascular disease is the most common cause of mortality in this population.  In a study from 2005, the incidence of cardiovascular-related mortality was lower in hemodialysis patients who received activated injectable vitamin D: 7.6 deaths per 100 person-years, compared with 14.6 deaths per 100 person-years in those who did not receive vitamin D.[7] Other studies have demonstrated a similar effect with oral and injectable vitamin D.1

Generalizability of these results to other populations has not yet been shown. A cohort study of 34,486 postmenopausal women in the U.S. found only a minimal reduction in cardiovascular-related mortality for those who took daily supplemental vitamin D compared to those who did not.[8] A randomized controlled trial from the U.K. examined the effects of a single 100,000 IU dose of vitamin D taken orally every four months for five years in men and women.  This study found a slightly lower incidence of cardiovascular-related mortality in the supplementation group compared to the placebo group, though this difference was not statistically significant.[9] The largest trial of vitamin D supplementation thus far has been the Women’s Health Initiative, in which two groups of generally healthy, postmenopausal women were given a combination of calcium and vitamin D or placebo.  Supplementation over a 7-year period had no effect on coronary risk.[10] However, the amount of vitamin D given per day (400 IU) was probably not adequate to attain a serum 25-OH D level above 30 ng/mL.  More likely, supplementation of at least 1000 IU is required to achieve this serum level.1

Some recommend intentional sun exposure in addition to calcium and vitamin D to elevate vitamin D levels.  Greater than 90% of serum vitamin D is produced cutaneously when ultraviolet (UV) B radiation photoisomerizes 7-dehydrocholesterol to precholecalciferol, which in turn is isomerized by heat to cholecalciferol (vitamin D3).[11] Researchers have demonstrated that an exposure of 1 minimal erythema dose (MED) to the whole body results in the cutaneous synthesis of an equivalent of 10,000 to 25,000 IU of oral vitamin D.  Extrapolating from these data, proponents of “safe sun” maintain that exposing one quarter of the body—arms, face, and hands—to 0.25 MED of sunlight will produce vitamin D3 equivalent to 1000 IU taken by mouth.[12] Several factors influence cutaneous vitamin D production and no recommendation can be made regarding the amount of sunlight exposure required to match oral vitamin D supplementation.  Variables include skin pigmentation, latitude, time of day, altitude, ozone concentration, pollution, cloud cover, and sunscreen use.11 Since UV light exposure is a known cause of skin cancer, the American Academy of Dermatology and the International Agency for Research on Cancer do not advocate intentional, unprotected sun exposure for vitamin D supplementation.  Oral vitamin D supplements are a safer mode of elevating serum vitamin D levels.12

In summary, there is evidence suggesting that vitamin D supplementation contributes to decreasing cardiovascular risk.  While more research must be performed to determine guidelines, it has been demonstrated that low levels of vitamin D are associated with increased cardiovascular disease and that adequate vitamin D supplementation can reduce mortality due to cardiovascular disease.  Supplementation to achieve these protective effects most likely requires higher doses than currently recommended.1 Thus, if a patient is at increased risk of cardiovascular events and has risks of vitamin D deficiency, oral supplementation of at least 1000 IU of vitamin D per day may be beneficial.  For many patients, vitamin D supplementation is already indicated for prevention of osteoporosis.  In light of the above studies, increasing an  existing dose of vitamin D to at least 1000 IU per day may also help improve cardiovascular health.

Karina Vivar is a 4th year medical student at NYU School of Medicine

Peer reviewed by Eugenia Gianos, MD, Attending Physician, Dept. of Medicine (Cardiology), NYU Langone Medical Center

Image courtesy of Wikimedia Commons.

References:

1.  Wang L, Manson JE, Song Y, Sesso HD.  Vitamin D and calcium supplementation in prevention of cardiovascular events.  Ann Intern Med.  2010;152(5):315-323.  http://www.annals.org/content/152/5/315.abstract

2.  Stechschulte SA, Kirsner RS, Federman DG.  Vitamin D: bone and beyond, rationale and recommendations for supplementation.  Am J Med.  2009;122(9):793-802.

3.  Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: data from the Third National Health and Nutrition Examination Survey.  Arch Intern Med. 2007;167(11):1159-1165.  http://archinte.ama-assn.org/cgi/content/full/167/11/1159

4.  Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease.  Circulation.  2008;117(4):503-511.

5.  Adams JS, Hewison M.  Update in vitamin D.  J Clin Endocrinol Metab.  2010;95(2):471-478.  http://jcem.endojournals.org/cgi/content/full/95/2/471

6.  Judd SE, Tangpricha V.  Vitamin D deficiency and risk for cardiovascular disease.  Am J Med Sci. 2009;338(1):40-44.  http://journals.lww.com/amjmedsci/Abstract/2009/07000/Vitamin_D_Deficiency_and_Risk_for_Cardiovascular.17.aspx

7.  Teng M, Wolf M, Lowrie E, et al.  Activated injectable vitamin D and hemodialysis survival: a historical cohort study. J Am Soc Nephrol. 2005;16(4):1115-1125.  http://jasn.asnjournals.org/cgi/content/full/16/4/1115

8.  Bostick RM, Kushi LH, Wu Y, Meyer KA, Sellers TA, Folsom AR. Relation of calcium, vitamin D, and dairy food intake to ischemic heart disease mortality among postmenopausal women. Am J Epidemiol. 1999;149(2):151-161.  http://www.ncbi.nlm.nih.gov/pubmed/9921960

9.  Trivedi DP, Doll R, Khaw KT.  Effect of four monthly oral vitamin D3 supplementation on fractures and mortality in men and women living in the community: randomized double blind controlled trial. BMJ. 2003;326(7387):326-332.

10.  Hsia J, Heiss G, Ren H, et al.  Calcium/vitamin D supplementation and cardiovascular events.  Circulation. 2007;115(7):846-854.  http://circ.ahajournals.org/cgi/content/short/115/7/846

11.   Diehl JW, Chiu MW.  Effects of ambient sunlight and photoprotection on vitamin D status.  Dermatol Ther. 2010;23(1):48-60.  http://www.ncbi.nlm.nih.gov/pubmed/20136908

12.  Terushkin V, Bender A, Psaty EL, Engelsen O, Wang SQ, Halpern AC.  Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes.  J Am Acad Dermatol. 2010;62(6):929.   http://www.ncbi.nlm.nih.gov/pubmed/20363523

Does Heyde Syndrome (The Association Between Aortic Stenosis And Intestinal Angiodysplasia) Exist?

September 29, 2010

By Lara Dunn, MD

Faculty Peer Reviewed

In 1958, EC Heyde published 10 cases of aortic stenosis (AS) and arteriovenous malformations (AVMs) of the gastrointestinal tract in the New England Journal of Medicine [1].  Thus, the association between aortic stenosis and intestinal angiodysplasia became known as Heyde Syndrome.  Yet the existence of this syndrome has been controversial.

Contrasting conclusions have been obtained by studies conducted to evaluate this association.  In a prospective study, Bhutani and colleagues did not find an increased prevalence of AS in 40 patients who were previously diagnosed with AVMs [2].  Further studies confirmed this finding.  Mehta and colleagues found no cases of aortic AS among 29 patients with angiodysplasia, while Oneglia and colleagues found one case of AS among 59 patients with AVMs [3,4].

However, other studies found a significant association between the two conditions.  In a retrospective chart review, Pate and colleagues found a significant association between AS and GI bleeding assumed to be due to angiodysplasia (P<0.0001) [5].  In another retrospective review, Greenstein and colleagues found that gastrointestinal bleeding was more prevalent in patients with AS compared to mitral stenosis (P< 0.0001) [6].

The two studies in support of Heyde Sydrome mentioned above used indirect clinical criteria, such as a cardiac murmur consistent with AS and idiopathic gastrointestinal bleeding, to diagnose AS and AVMs, respectively.  Batur and colleagues conducted the first study that used objective criteria to diagnose AS and AVMs [7].  They determined an association between AS, diagnosed by echocardiography, and AVMs, diagnosed by GI endoscopy or angiography.  This study compared the prevalence of aortic stenosis to mitral stenosis in 73 patients with AVMs who underwent echocardiography.  In addition, the prevalence of AS and MS in patients with AVMs was compared to the prevalence of AS and MS in all patients who had echocardiograms.  The results revealed that AS, but not MS was significantly correlated with AVMs.  The prevalence of AS was 31.7% in patients with AVMs, which was significantly higher than the 14% of AS found among all patients who underwent echocardiography (P<0.001).  The prevalence of MS in patients with AVMs was 1.6% and not significant compared to the 6.0% among all patients with echocardiograms (P=0.14).  Further, the severity of AS showed a stronger correlation to the presence of AVMs.  Moderate-to-severe AS was 2.6 times more common, and severe AS was 4.1 times more common among patients with AVMs.

Given that studies support the entity of Heyde Syndrome, multiple explanations have been speculated.  One theory is that chronic hypoxia from AS leads to sympathetic-induced vasodilation and smooth muscle relaxation and subsequently bleeding from AVMs.  However, Batur et al argued with this explanation given that only severe AS compromises cardiac output and causes hypoxia, since an association was seen with milder forms of AS [7].  Other explanations include colonic hypoxia due to cholesterol embolization from stenotic aortic valves or altered pulse waveforms from aortic stenosis.

In a recent publication, Massyn and Khan advocate that the basis for this association is an acquired coagulopathy caused by aortic stenosis [8].  Aortic stenosis has been shown to cause von Willebrand syndrome type 2A.  von Willebrand factor circulates as large multimers after synthesis by endothelial cells.  The shear stress across a stenotic aortic valve causes degradation of the largest vWF multimers that are most effective in mediating platelet adhesion.  In support of this mechanism, Yoshida and colleagues found abnormal gel electrophoresis in patients with AS, that normalized following aortic valve replacement surgery [9].  Similarly, studies have shown prolonged bleeding time in patients with AS that resolves upon AVR [10,11].   These studies lend strength to the mechanism that aortic stenosis causes acquired vWD-2A and the coagulopathy leads to bleeding from intestinal AVMs.

Recognition of an acquired coagulopathy or vWD-2A as the root of the association allows for effective management of bleeding.  AVR corrects the coagulopathy and has been shown to provide resolution of GI bleeding, while patients who have undergone intestinal resection continue to bleed from other sites.  In a retrospective study of patients with AS and idiopathic GI bleeding, King and colleagues found that GI bleeding resolved in 93% of patients with AVR compared to 5% of patients who underwent intestinal resection [12].   Given these findings, it would be appropriate for physicians to evaluate for aortic stenosis in patients, who are surgical candidates, with GI bleeds secondary to known intestinal angiodysplasia or persistent idiopathic GI bleeds in order to guide management.  Further, aortic stenosis should be dismissed in all patients with intestinal AVMs prior to management involving intestinal resection.

Heyde syndrome appears to be a true entity.  However, as Massyn and Khan advocate, it is a triad of aortic stenosis, an acquired coagulopathy due to vWD-2A, and bleeding from intestinal angiodysplasia [8].  Understanding the mechanism by which AS leads to GI bleeding from AVMs allows for proper treatment and long-term resolution.

Commentary by Rosemarie Gambetta, MD Division of Caridiology

While bleeding from AVM’s are generally seen with higher degrees of aortic stenosis (Vincentilli,Andre et al NEJM2003 349:343-349 )secondary to the generally accepted mechanisms of a decrease in the largest multimers of von Willebrand factor, the hemostatic consequences of severe aortic stenosis are not indications for valve replacement.
At the present time, recommendations for aortic valve replacement are based on symptoms of severe aortic stenosis such as angina, syncope or heart failure(JAAC 2008:52:1-142)

To answer the question Does Heyde syndrome exist?
The next time you have a patient with intestinal bleeding from angiodysplasias take out your stethoscope and take a closer listen to heart sounds and murmurs.

Dr. Dunn is a second year resident at NYU Langone Medical Center

Peer reviewed by Rosemarie Gambetta, MD, Attending Physician, Department of Medicine (cardiology), NYU Langone Medical Center

Image courtesy of Wikimedia Commons (animation showing a moving echocardiogram; a 3D-loop of a heart viewed from the apex, with the apical part of the ventricles removed and the mitral valve clearly visible).

References:

1.  Heyde ED. Gastrointestinal bleeding in aortic stenosis. N Engl J Med.  1958;259:196.

2.  Bhutani MS, Gupta SC, Markert RJ et al. A prospective controlled evaluation of endoscopic detection of angiodysplasia and its association with aortic valve disease.  Gastrointest Endosc 1995;42:398-402.

3.  Mehta PM, Heinsimer JA, Bryg RJ et al.  Reassessment of the association between gastrointestinal arteriovenous malformations and aortic stenosis.  AM J Med 1989;86:27507.

4.  Oneglia C, Sabatini T, Rusconi C et al. Prevelance of aortic valve stenosis in patients affective by gastrointestinal angiodysplasia. Eur J Med 1993;2:75-8.  http://www.ncbi.nlm.nih.gov/pubmed/8258021

5.  Pate GE, Mulligan A.  An epidemiological study of Heyde’s syndrome: an association between aortic stenosis and gastrointestinal bleeding. J Heart Valve Dis 2004;13:713-6.

6.  Greenstein RJ, McElhinney AJ, Reuben D et al.  Colonic vascular ectasias and aortic stenosis: coincidence or causal relationship? Am J Surg 1986;151:347-51.

7.  Batur P, Stewart WJ, Isaacson JH.  Increased prevalence of aortic stenosis in patients with arteriovenous malformations of the gastrointestinal tract in Heyde Syndrome.  Arch Intern Med 2003;163:81:490-4.

8.  Massyn MW, Khan SA. Heyde Syndrome: a common diagnosis in older patients with severe aortic stenosis.  Age and Ageing 2009;38:267-70. http://ageing.oxfordjournals.org/content/38/3/267.full

9.  Yoshida K, Tobe S, Kawatea M et al. Acquired and reversible von Willebrand disease with high shear stress aortic valve stenosis. Ann Thorac Surg 2006;81:490-4.

10.  Olsson M, Hultcrantz R, Schulman S et al. Acquired platelet dysfunction many be an aetiologic factor in Heyde’s syndrome- normalization of bleeding time after aortic valve replacement. J Intern Med 2002;252:516-23.

11.  Morishima A, Marui A, Shimamoto T et al.  Successful aortic valve replacement for Heyde Syndrome with confirmed hematological recovery. Ann Thorac Surg 2007;83:287-8.

12.  King, RM, Pluth JR, Giuliani ER. The association of unexplained gastrointestinal bleeding with calcific aortic stenosis. Am Thorac Surg 1987;44:514-6.

Pass the Salt? A Look at Population-Based Sodium Reduction Interventions

September 24, 2010

By Ryan Macht, MS4

Faculty Peer Reviewed

On January 11th, the New York City Health Department announced its plans for the National Salt Reduction Initiative, a public health proposal designed to decrease sodium consumption throughout the country. High levels of dietary sodium have frequently been associated with increased rates of hypertension and adverse cardiovascular events.[1,2] The mean salt intake in the United States is extremely high in all age groups and well above the current recommendations of 5.8 g (2300 mg sodium) for those under 40 and 3.8 g (1500 mg sodium) for older adults and those with hypertension.[3] Around 75-80% of this sodium intake is from processed foods, with much less from the salt added when cooking or seasoning at the table.[3] The goal of the initiative is to improve cardiovascular health by reducing the amount of salt in packaged and restaurant foods by 25% over five years, which would in turn reduce the nation’s salt intake by an estimated 20%.[4]

The plan consists of specific targets of sodium reduction for 61 categories of packaged food and 25 classes of restaurant food.[5,6] However, these targets would be completely voluntary, only aimed at “quick service” restaurants, and based on the companies’ overall portfolio of food, not individual products. For instance, if a company made two types of equally popular chips, it would be able to keep a saltier variety as long as the average sodium content of both chips was under the target goal. There is no punishment for not reaching the target goals, but companies and restaurants that are successful will be publicly recognized.[4]

This initiative has generated a significant amount of controversy since being announced. A recent post on the New York Times “Room for Debate” blog highlighted the reactions to the proposed plan from a variety of people including a physician, nutritionist, food critic, public policy advocate, and chef.[7] Most of the opposition is focused on the effect it will have on the taste of food, the ethics of government control of what we eat, and how effective the plan will be in reducing clinically significant disease.

The physiology of how salt intake contributes to hypertension is likely multifactorial. One possible mechanism involves the kidney’s decreased functioning with age, which leads to an inability to excrete excess salt, greater plasma volume, and higher blood pressure.[8] Another hypothesis is that a combination of excess sodium and insufficient potassium intake adversely affects vascular smooth muscle cells, which in turn causes reduced vascular elasticity and higher blood pressure.[8] Regardless of the mechanism, high dietary salt has been found to be strongly associated with hypertension and cardiovascular disease, and may also be associated (independent of its effect on blood pressure) with an increased incidence of stroke, left ventricular hypertrophy, renal disease, stomach cancer, renal stones, osteoporosis, and obesity.[9]

A recent study in the New England Journal of Medicine used a computer model to quantify the estimated effect of a population-wide reduction in dietary salt.[10] The authors found that a reduction of 3 grams per day would decrease the annual number of new cases of coronary disease by 60,000 to 120,000, stroke by 32,000 to 66,000, myocardial infarction by 54,000 to 99,000, and the annual number of deaths from any cause by 44,000 to 92,000.[10] Additionally, they reported that even a modest decrease of salt by 1 gram per day would have a substantial reduction in cardiovascular events and deaths. Finally, they estimated that a 3-gram-per-day reduction would produce 194,000 to 392,000 quality-adjusted life-years (QALYs) and save $10 billion to $24 billion in health care costs, indicating that a decrease in salt intake would be very cost effective.[10]

The proposal by the National Salt Reduction Initiative was largely modeled after plans already implemented in other countries and most closely resembles the United Kingdom model. The strategy has been successful in the UK, where since 2003, sodium levels in many processed foods have voluntarily been reduced by 20-30%.[9] Before and after the initiative was in place, the average salt intake of the UK population was estimated using 24-hour urine collections from random samples. They found that salt intake decreased from an average of 9.5 g/day in 2003 to 8.6 g/day in 2008.[11] However, another research group has criticized this study on the grounds that this estimated reduction is based on a normal variation in a relatively narrow and unchanging range of urinary sodium excretion measured in the UK between 1983 and 2008.[12] They argue that sodium is under strict homeostatic control and human salt intake is set within a physiologic range that is unlikely to be altered by public-policy initiatives.[12]

Some of the most compelling evidence for a population-based salt-reducing intervention comes from Finland. As early as the late 1970s, Finland became one of the first countries to institute public health strategies to reduce salt consumption. By 2002, salt intake had decreased by 40%, diastolic blood pressure had decreased by more than 10 mm Hg, and mortality from stroke and coronary heart disease had decreased by 75% to 80%.[13] These changes are largely attributed to the reduction in salt intake, because other risk factors such as obesity and alcohol consumption increased over the same period.[13]

Cardiovascular disease is the leading cause of death in the United States, and hypertension is an important risk factor that accounts for nearly two-thirds of all strokes and half of all ischemic heart disease.[8] Population-based approaches to reducing salt intake represent a relatively new approach to combating hypertension. It is thought that these initiatives can have profound effects on disease reduction, although their feasibility, ethics, and long-term efficacy are all still strongly debated.

Commentary by Dr. Andrew Wallach

Ryan Macht succinctly summarizes the current debate surrounding the recently announced plan by the New York City Department of Health and Mental Hygiene (NYC DOHMH) to restrict sodium content of processed foods–the source of nearly three-quarters of daily sodium intake in the United States.  This plan, similar in scope to the NYC DOHMH’s plan to restrict trans fatty acids and increase consumption of fruits and vegetables and its ban on smoking in restaurants and bars, seeks to address pressing public health issues at the population level.  In doing so, the probability of success and improved health outcomes is greatly improved.  In the current environment of health care reform, which has focused primarily on insurance and financial issues, it is refreshing to see the government re-focus its efforts on prevention measures.  However, how the ethical debate of big government dictating our diet plays out is yet to be seen.

Ryan Macht is a fourth-year medical student at NYU School of Medicine

Andrew Wallach, MD is a Clinical Assistant Professor, Department of Medicine at NYU School of Medicine

Image courtesy of Wikimedia Commons.

References:

1. Intersalt Cooperative Research Group. Intersalt: an international study of electrolyte excretion and blood pressure. Results for 24 hour urinary sodium and potassium excretion. BMJ. 1988;297(6644):319-328.  http://www.bmj.com/content/297/6644/319.abstract

2. He FJ, MacGregor GA. Effect of modest salt reduction of blood pressure: a meta-analysis of randomized trials. Implications for public health. J Hum Hypertens. 2002;16(11):761-770.

3. Appel L, Anderson C. Compelling evidence for public health action to reduce salt intake. N Engl J Med. 2010;362(7):650-652.  http://www.nejm.org/doi/full/10.1056/NEJMe0910352

4. Health Department announces proposed targets for voluntary salt reduction in packaged and restaurant foods [news release].   New York, NY: New York City Department of Health and Mental Hygiene; January 11, 2010.  http://www.nyc.gov/html/doh/html/pr2010/pr002-10.shtml.  Accessed January 26, 2010.  http://www.nyc.gov/html/doh/html/pr2010/pr002-10.shtml

5. National Salt Reduction Initiative packaged food categories and proposed targets.  New York City Department of Health and Mental Hygiene web site.  http://www.nyc.gov/html/doh/downloads/pdf/cardio/cardio-salt-packagedfood-targets.pdf. Accessed January 26, 2010.

6. National Salt Reduction Initiative Restaurant categories and proposed targets. New York City Department of Health and Mental Hygiene web site.  http://www.nyc.gov/html/doh/downloads/pdf/cardio/cardio-salt-restaurantfood-targets.pdf. Accessed January 26, 2010.

7. Kurlansky M, Willett W, Kimball C, Sheraton M, Jacobson MF, Kazaks A, Earl R.  Big Brother and the salt shaker. NYTimes.com Room for Debate blog. January 14, 2010.  http://roomfordebate.blogs.nytimes.com/2010/01/14/big-brother-and-the-salt-shaker/?emc=eta1. Accessed January 26, 2010.

8. Mohan S, Campbell NR. Salt and high blood pressure. Clin Sci (Lond). 2009;117(1):1-11.  http://www.ncbi.nlm.nih.gov/pubmed/19476440

9. He FJ, MacGregor GA. A comprehensive review on salt and health and current experience of worldwide salt reduction programmes. J Hum Hypertens. 2009;23(6):363-384.  http://www.nature.com/jhh/journal/v23/n6/full/jhh2008144a.html

10. Bibbins-Domingo K, Chertow GM, Coxson PG, et al. Projected effect of dietary salt reductions on future cardiovascular disease. New Engl J Med. 2010;362(7):590-599.  http://www.nejm.org/doi/full/10.1056/NEJMoa0907355

11. Food Standards Agency. An assessment of dietary sodium levels among adults (aged 19-64) in the UK general population in 2008, based on analysis of dietary sodium in 24 hour urine samples. June 2008. National Centre for Social Research.  http://www.food.gov.uk/multimedia/pdfs/08sodiumreport.pdf.  Accessed January 26, 2010.

12. McCarron D, Geerling JC, Kazaks AG, Stern JS. Can dietary sodium intake be modified by public policy? Clin J Am Soc Nephrol. 2009;4(11):1878-1882.  http://cjasn.asnjournals.org/cgi/content/full/4/11/1878

13. Karppanen H, Mervaala E. Sodium intake and hypertension. Prog Cardiovasc Dis. 2006;49(2):59-75.  http://www.ncbi.nlm.nih.gov/pubmed/17046432

The Heart in Acromegaly

September 1, 2010

By Ari Pollack, MD

Faculty Peer Reviewed

The onset of acromegaly is subtle, and its progression is usually very slow. In fact, the usual interval from the onset of symptoms until diagnosis is about twelve years.[1] The manifestations of acromegaly result from excessive secretion of growth hormone (GH), which targets the liver, resulting in stimulation of hepatic secretion of insulin-like growth factor-1 (IGF-1), which causes many of the clinical manifestations of acromegaly.  The most common cause of acromegaly is a functional pituitary adenoma.[2] The effects of excess GH and IGF-1 secretion include the growth of many tissues, including skin, connective tissue, cartilage, bone, viscera, and many epithelial tissues.  There are also metabolic consequences such as insulin antagonism and lipolysis. The local mass effect of the adenoma can lead to symptoms of headache, cranial nerve defects, and visual field defects, specifically bitemporal hemianopsia.[3] The mortality rate of patients with acromegaly appears to be increased and is primarily from cardiovascular disease, a risk that may be reversed by curing the disease.[2]

The GH/IGF-1 axis has a direct endocrine effect on the myocardium, resulting in hypertrophy, enhancement of contractile performance, and elongation of the action potential of cardiac fibers.[4] Ultimately, the involvement of the heart in acromegaly is characterized by concentric biventricular hypertrophy. Structural changes of the heart can even occur in patients briefly exposed to GH hypersecretion.[5] This remodeling is further enhanced by the hypertension and glucose intolerance commonly present in the acromegalic patient.  The evolution of cardiomyopathy in acromegaly is characterized by significant worsening of the heart’s ability to function as an efficient pump.  In patients with short disease duration, there is initial cardiac hypertrophy with increased heart rate, contractility, and cardiac output, termed the hyperkinetic syndrome.[4] This is a result of the stimulatory effects of GH and IGF-1 on myocardial contractility as mediated by changes in intracellular calcium.[4] As hypertrophy becomes more prominent, diastolic dysfunction may develop, leading to the development of heart failure with preserved ejection fraction.  Fortunately, the clinical syndrome of heart failure is uncommon (~3%) in patients with acromegaly with either a normal or reduced ejection fraction.[6] However, at the advanced stages of untreated disease, cardiac abnormalities may rarely result in systolic dysfunction with manifestations of congestive heart failure.

Cardiovascular disease is not limited to structural abnormalities in patients with acromegaly.  There is also valvular disease, including mitral regurgitation, aortic regurgitation and tricuspid regurgitation seen in the late stages of acromegaly as a result of ventricular remodeling, as well as increased potential for arrhythmias.[4] The mechanism behind the predisposition for dysrhythmic events involves phenotypic changes in membrane proteins, conduction system disease,[4] and structural uncoupling of cardiac myocytes resulting in an increased number of re-entrant events.  Compared to controls, individuals with acromegaly have a higher prevalence of ectopic beats, paroxysmal atrial fibrillation, paroxysmal supraventricular tachycardia, sick sinus syndrome, ventricular tachycardia, and bundle branch blocks.[7]

The data regarding a direct relationship between the development of coronary artery disease and acromegaly are limited.  Given the frequency of hypertension and diabetes seen with the syndrome, it is likely that patients with acromegaly are at increased risk for developing atherosclerosis.  In terms of the direct effect of GH and IGF-1 on atherosclerosis development, the evidence suggests that it is largely the hypertension and diabetes  associated with acromegaly that predispose patients to the development of atherosclerotic disease.  It is known that GH and IGF-1 cause direct endothelial dysfunction with subsequent decreased vasodilatory capacity, which may have implications for susceptibility to vascular events.[5] In terms of the reversibility of acromegalic cardiomyopathy, suppression of GH and IGF-1 has been shown to be efficacious in improving diastolic function by virtue of reducing left ventricular mass.  However, the effect on systolic function and exercise tolerance are variable and depends largely on the length of exposure to GH and IGF-1, as well as the co-morbidities of acromegaly, including hypertension and diabetes.[8]

It is important to note that the cardiac implications of acromegaly are a result of excessive secretion of GH and IGF-1 and that these hormones play an important role in cardiac development when present at normal physiologic levels.  In fact, patients with GH deficiency, whether childhood- or adult-onset, suffer from structural cardiac abnormalities, including narrowing of cardiac walls and functional impairment, with resultant reduction in diastolic filling and reduced left ventricular response to peak exercise.[9] As in the acromegalic heart, these cardiac abnormalities are partially reversible with GH supplementation.[9] Additionally, attention has been focused on the efficacy of GH to increase cardiac mass and function in chronic non-endocrine-related heart failure including ischemic and idiopathic cardiomyopathies, thereby illustrating the dichotomy between the potential beneficial effects of exogenous GH in carefully selected patients and the disadvantageous effects of excess GH secretion in patients with acromegaly.

Dr. Pollack, Class of 2010, NYU School of Medicine

Peer reviewed by Alex Reyentovich, MD, Cardiology, NYU School of Medicine

Image courtesy of Wikimedia Commons.

References:

[1]  Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev. 2004; 25(1):102-152.

[2]  Melmed S. Medical progress: Acromegaly. N Engl J Med. 2006;355(24):2558-2573.

[3]  Molitch ME. Clinical manifestations of acromegaly. Endocrinol Metab Clin North Am. 1992;21(3):597-614.

[4]  Lombardi G, Galdiero M, Auriemma RS, Pivonello R, Colao A. Acromegaly and the cardiovascular system. Neuroendocrinology. 2006;83(3-4):211-217.

[5]  Vitale G, Pivonello R, Lombardi G, Colao A. Cardiac abnormalities in acromegaly: pathophysiology and implications for management.  Treat Endocrinology. 2004;3(5):309-318.

[6]  Bihan H, Becker KL, Snider RH, Nylen E, et al. Long-term outcome of patients with acromegaly and congestive heart failure. J Clin Endocrinol Metab. 2004;89(11):5308-5313.

[7]  Kahaly G, Olshausen KV, Mohr-Kahaly S, et al.  Arrhythmia profile in acromegaly.  Eur Heart J. 1992;13(1):51-56.

[8]  Colao A, Cuocolo A, Marzullo P, et al. Is the acromegalic cardiomyopathy reversible?  Effects of 5-year normalization of growth hormone and insulin-like growth factor I levels on cardiac performance.  J Clin Endocrinol Metab. 2001;86(4):1551-1557.

[9]  Colao A, Marzullo P, Di Somma C, Lombardi G. Growth hormone and the heart.  Clin Endocrinol (Oxf). 2001;54(2):137-154.

Myths and Realities: Heart and Wine

August 26, 2010

By Aditya Mattoo, MD

Faculty Peer Reviewed

Not too long ago, a patient came to my clinic and said (I’m paraphrasing of course), “I never cared for alcohol, doctor, so I haven’t had much to drink since my college days.  Maybe champagne or wine on the rare special occasion, but I keep hearing about how wine is good for your heart, so I am thinking I should start drinking regularly.”  For years I have been telling patients don’t drink, don’t smoke, don’t do drugs, don’t eat fatty foods, exercise more, and lose weight.  I have become quite accustomed to playing the role of “Dr. Buzzkill” with my patients (the actual name given to me by a patient).  Yet, we have all heard about the potential benefit to light drinking.  Still, I felt a little uneasy about telling someone to start drinking everyday. To ease my discomfort, I decided to review the data behind alcohol and cardiovascular mortality for the current installment of Myths and Realities.

Alcohol and its affects on cardiovascular disease has been studied as far back as 1904, when Dr. Richard Cabot published an article in JAMA attempting to draw a relationship between alcoholism and arteriosclerosis.[1]  The recent reemergence of this discussion has been prompted by the observation that French people, although eating a diet relatively rich in saturated fats, had a relatively lower incidence of cardiovascular disease and mortality from cardiovascular events.  This so called “French Paradox”, coined in 1992 by Dr. Serge Renaud, a scientist from Bordeaux University in France, has been attributed to the higher consumption of wine.

Several mechanisms for the protective effect of alcohol in cardiovascular disease have been proposed.  For example, alcohol related antiatherogenic alterations in plasma lipoproteins, particularly elevations in high-density lipoprotein cholesterol, are thought to offer cardiovascular protection.  Additionally, alcohol associated increased activity of endothelial-type nitric oxide synthase, leading to increased levels of nitric oxide and maintenance of blood vessel patency, has also been implicated.  Finally, the potential anticoagulant and antiplatelet properties of polyphenols, found in wine, may contribute as well.  Some studies have suggested that red wine, because of the disproportionately higher levels of polyphenols as compared to other forms of alcohol (i.e. white wine, liquor and beer), is more protective from a cardiovascular standpoint.

Many clinical studies over the last three decades have attempted to validate this phenomenon.  In 1991, Rimm et al published a study of 51,529 male health professionals followed prospectively for two years.[2]  A questionnaire was distributed at the beginning of the study asking about alcohol intake in the previous 10 years, along with coronary risk factors, diet, etc.  Follow-up questionnaires asked about newly diagnosed coronary disease, and a statistically significant inverse relationship was seen, suggesting a lower incidence of coronary disease in men with increased alcohol consumption.

In 1995, a prospective study of cardiovascular mortality in middle-aged women was published by Fuchs et al.[3]   In this study, a dietary questionnaire was sent to 85,709 nurses beginning in 1980 and continuing for a 12 year follow up period.  A J-shaped relationship was observed, i.e., light-moderate drinking was associated with a decreased risk of death, however, heavier drinking was associated with an increased risk of death from other causes, particularly breast cancer and cirrhosis.

In 1997, Thun et al published a study following 490,000 men and women for nine years.[4]  A similar questionnaire was used to assess alcohol consumption and then cause of death was observed.  As one would expect, excessive alcohol consumption was associated with increased rates of death from cirrhosis, as well as cancers of the mouth, esophagus, pharynx, larynx and liver.  In contrast, the risk of cardiovascular death was 30-40% lower in both men and women who reported one drink daily compared to nondrinkers.

Castelnuovo et al performed a meta-analysis reviewing 26 studies on the relationship of beer and wine and cardiovascular mortality.[5]  Published in 2002, a total of 417,454 persons were studied and a 32% risk reduction of cardiovascular death with moderate wine consumption was observed, whereas a 22% risk reduction was observed with moderate beer consumption.

Finally, in April of this year, the Journal of the American College of Cardiology, published an article by Mukamal et al supporting this growing body of evidence that alcohol consumption prevents cardiovascular disease.[6]   Data from the National Health Interview Survey, which surveyed approximately 245,000 U.S. adults annually between the years 1987 and 2000, showed that light and moderate drinkers had a 31% and 38%, respectively, lower risk of death due to heart disease than abstainers.

Overall, large epidemiological findings have consistently demonstrated a cardiovascular benefit of light alcohol consumption.  Although no head-to-head prospective studies have been conducted to compare cardiovascular outcomes of different types of alcohol, the literature suggests that red wine seems to be the most protective.  However, skeptics note that these studies do not take into account the different drinking patterns of wine, beer and hard liquor drinkers.  Another potential confounder is lifestyle.  Studies have shown that light, particularly wine, drinkers may have different demographics and behavior patterns as compared to the rest of the population.  They have a tendency to eat healthier, exercise more and come from higher socioeconomic backgrounds (which may imply they have better access to medical care).  The contribution of the direct effect of alcohol or the common lifestyle choices of light moderate drinkers is a difficult confounder to tease out from survey-based, uncontrolled data.

So bringing it all back home, how should you counsel your patients?  Although detractors often complain that the data is largely based on patients answering questionnaires reliably, the literature is has reproduced the benefits of light alcohol consumption time and time again.  Furthermore, there is an undeniable paucity of studies that demonstrate light drinking is harmful.  Armed with this, Dr. Buzzkill would probably advise patients to have a glass of wine nightly with dinner.  aybe now my patients will start calling me Dr. Feelgood.

Until the next installment of Myths and Realities–the first round is on me.  Cheers!

Dr. Mattoo is a second year fellow in Nephrology, NYU Langone Medical Center

Peer reviewed by Barbara Porter, Section Editor, Myths and Realities, Clinical Correlations

Image courtesy of Wikimedia Commons.

References:

[1] Cabot, RC. The Relation of Alcohol to Arteriosclerosis. JAMA. 1904; 43(12):774-775.

[2] Rimm, EB. Prospective study of alcohol consumption and risk of coronary disease in men. The Lancet. 1991; 338(8765):464-468.

[3] Fuchs, CS. Alchohol consumption and mortality among women. NEJM. 1995; 332(19):1245–1250.

[4] Thun, MJ.  Alcohol consumption and mortality among middle-aged and elderly U.S. adults. NEJM. 1997 Dec 11;337(24):1705-14.

[5] Di Castelnuovo, A.  Meta-analysis of wine and beer consumption in relation to vascular risk. Circulation. 2002 June 18;105:2836-2844.

[6] Mukamal, KJ.  Alcohol Consumption and Cardiovascular Mortality Among U.S. Adults, 1987 to 2002.  J Am Coll Cardiol. 2010; 55:1328-1335.

Selected Discussion of Presentation From The American College of Cardiology 59th Annual Scientific Sessions

August 24, 2010

By Robert Donnino, MD

Faculty Peer Reviewed

The 59th Annual Scientific Sessions of the American College of Cardiology (ACC) took place in Atlanta on March 14-16, 2010. Despite inclement weather in the northeast causing the cancellation of many flights, a large number of NYU faculty, fellows, and others made it to Atlanta to give talks, presentations, or simply attend the conference.

As usual, the Sessions presented us with many important studies from around the world, some of which may change our clinical practice for years to come. While it is obviously impossible to cover even a small portion of the many important works that were presented, I would like to highlight a few “late-breaking trials”.

The first official day of the meetings was referred to by some as “Negative Sunday” because of the many “negative” trials that were presented. As some pointed out, however, a “negative” trial may be very positive for our patients (and their treating physicians) by providing essential information for their care.

Two trials relating to the Action to Control Cardiovascular Risk (ACCORD) trial were presented: the ACCORD lipid [1]and the ACCORD BP [2] trials.

First, the accord lipid trial investigated the effects of adding fenofibrate to a statin (simvastatin) in all patients with type 2 diabetes at “high risk” for cardiovascular disease with a mean follow-up of 4.7 years. 5,518 diabetics were randomized to statin plus placebo (control group) or statin plus fenofibrate. The study results showed no significant difference in cardiovascular (CV) events—major fatal and nonfatal CV event rates/year were 2.2 in fenofibrate group and 2.4 in control group (p=NS). In a subgroup analysis, a trend toward benefit of fenofibrate was shown in the group of diabetics that had a significant dyslipidemia (low HDL and high triglycerides). Additional subgroup analysis showed a trend toward harm in women (but not men) in the fenofibrate group.

Comment: This trial, while providing very important information, will likely not change current clinical practice as fibrates are generally not used routinely in this population. Given the results from the subgroup analysis in those with elevated triglycerides and low HDL, addition of fibrates in this group of diabetics is reasonable (which is often done currently in clinical practice). The trend toward harm in women is of obvious concern, and should be investigated in future studies.

The second ACCORD trial was the ACCORD blood pressure (BP) trial. This was the first of 2 trials presented on Sunday regarding BP control in diabetics.

This trial randomized 4,733 type 2 diabetics to “intensive” (goal systolic BP <120 mmHg) vs. “standard” (goal systolic BP <140mmHg) BP control arms. Surprising to many, there was no benefit of intensive BP control over standard control regarding the primary endpoint of major fatal and nonfatal cardiovascular (CV) events. There was a reduction in strokes in the intensive control arm, however since the incidence of stroke was very low (less than 0.5% per year), the number needed to treat to prevent one stroke would be 89 patients over 5 years. In addition, the intensive group suffered significantly more adverse effects related to anti-hypertensive treatment than the standard group (3.3% vs. 1.3%).

The second trial presented on Sunday was a retrospective analysis of the INVEST trial [3] which originally investigated the effects of a calcium channel blocker versus beta-blocker (in addition to other BP meds) in 6,400 diabetics with coronary disease, with a goal BP of 130/85. It is important to point out that INVEST did not randomize patients into BP control “strategy” arms, so this analysis was done by dividing the patients into groups based on what BP was achieved with treatment (retrospectively). In this analysis, the investigators found that those patients with uncontrolled BP (>140mmHg) suffered the most cardiovascular events, however those in the “usual” control group (130-140mmHg) did not suffer any more events than those in the “tight” (<130mmHg) control group. And, in fact, there was an increased risk for mortality in the tight group compared to the usual control group, which on further analysis appears to be only significant in those achieving BP of <115mgHg.

Comment: These trials provide extremely valuable clinical information and may impact clinical practice for many physicians. The data suggest that BP control in diabetics is extremely important to a level below 140mmHg. However, a goal lower than 120mmHg may not carry significant benefit and may even cause harm in high risk diabetics. Given the difficulty in clinical practice of pushing BP below 120mmHg and the growing problem of polypharmacy, this is welcome news for physicians and patients alike. Still, some may argue that the stroke benefit in ACCORD was significant and that certain subgroups of diabetics might benefit from tighter control as opposed to a strategy for all diabetics, however further analysis of these trials and others will be necessary to confirm these hypotheses.

Another trial presented on Sunday was the Everest II trial [4] which randomized 279 patients with severe mitral valve regurgitation to either surgery (repair or replacement) or percutaneous repair using the “MitraClip”. Investigators found that the 30 day adverse event rate was significantly lower in the percutaneous group, although the majority of this reduction was related to blood transfusions, which some argue should not be considered a major event. Clinical success, defined as freedom from mitral surgery/reoperation and mitral regurgitation less than or equal to 2+ at 12 months, was 72% in the percutaneous group and 88% in the surgery group (p = 0.0012).

Comment: The results from this trial are very encouraging regarding the potential use of percutaneous valve repair, but they must be interpreted with caution. This study does show that this new percutaneous technique is safe and relatively effective out to 1 year. This is a very short follow-up time, however, and extrapolating this technique over a longer term is not warranted from these data, especially given the fairly high number of patients with residual mitral regurgitation after this procedure. One of the most important pieces of information that we will need to examine in the future will be whether mitral valve repair (as opposed to replacement) will still be feasible if the MitraClip device fails. With a short term failure, we know repair is usually possible, however after the clip has been in place for 1 or more years the effect of scar tissue, etc. on valve repair is unknown. Nonetheless, with this safety and efficacy data, this study gives us a new treatment option for severe mitral regurgitation, which may become especially important in those who would otherwise not be candidates for surgical repair. FDA approval for this device is pending.

Another late-breaking trial presentation set out to answer a very important and controversial question in the cardiology community: how long to continue clopidogrel after the implantation of a drug-eluting stent (DES). This study combined 2 Korean trials (REAL-LATE and ZEST-LATE) [5] in which all patients received both aspirin and clopidogrel following implantation of a DES for 12 months. After 12 months, patients were then randomized to either continue this dual anti-platelet regimen or continue aspirin alone without clopidogrel. After a 19.2 month median follow up, the investigators found no significant difference in the two groups relating to the primary endpoint of nonfatal MI or cardiac death (1.8% in dual drug group vs. 1.2% in aspirin alone group, p=NS).

Comment: This study is very important, but does suffer several limitations. In addition to methodological concerns of combining 2 trials, the event rate was markedly lower than expected, thus reducing the power of the study results. Another limitation was the fact that some patients were randomized after 18 months of dual anti-platelet therapy instead of 12. And finally, the duration of follow up was relatively short. Despite all of these shortcomings, this trial provides evidence that continued dual antiplatelet therapy beyond 1 year in patients with DES may not be warranted (although this is still frequently done in clinical practice). Fortunately, larger trials looking at this question are underway currently and should help to clarify the evidence presented here.

The last trial I will mention is the RACE-2 trial [6].  This trial randomly assigned 614 patients with permanent atrial fibrillation (AF) to 2 different rate control strategies: the “strict” control group (resting heart rate [HR] < 80 bpm and <110 bpm on limited exercise) and the “lenient” control group (resting HR <110 bpm). The primary outcome was a composite of cardiovascular death, stroke, hospitalization for heart failure, systemic embolic event, pacemaker/ICD implantation, life-threatening arrhythmic event, bleeding and adverse events of rate-control drugs. The results demonstrated no significant difference in the primary endpoint between the two treatment groups after 3 years follow-up, with 12.9% vs. 14.9% in the lenient vs strict group, respectively. Health care provider visits were much higher in the strict group (684 vs 75 visits).

Comment: Given the difficulty in achieving strict HR control, these results are again good news for both patients with atrial fibrillation and their providers. While the results may be surprising to some, it is important to point out that post-hoc analysis from previous trials (AFFIRM and RACE) suggested this lack of benefit to stricter HR control in atrial fibrillation. As with all of these trials, however, it is important to keep in mind that care must be individualized and those that remain symptomatic or are at higher risk of heart failure may indeed require tighter rate control. Further analysis and details of this data including quality of life measures will be very important in fine tuning any conclusions from this study.

Final thoughts: Several of the above presentations, while “negative” are actually extremely important for the treatment of our patients. They remind us that, while aggressive patient management is essential to preventing serious clinical events, there is a point at which we reach diminishing returns and may even cause harm with overtreatment. One reason for this almost certainly involves polypharmacy, which is becoming an increasingly important point of concern for all of our patients, especially the elderly and those with multiple co-morbidities. It should also be pointed out that treating (or overtreating) patients with a “one-size-fits-all” approach may not be appropriate and may explain the lack of benefit seen in some of the above presentations. Determining the subset of patients, if any, that might benefit from more intensive control (e.g. of BP, HR, glucose, etc.) will be the goal of future clinical research.

Dr. Donnino is a Section Editor, Cardiology, Clinical Correlations

Peer reviewed by Neil Shapiro, MD, Editor-In-Chief, Clinical Correlations

Image of blood pressure exam courtesy of Wikimedia Commons.

References:

[1]  ACCORD study group. Effects of combination lipid therapy in type 2 diabetes mellitus. NEJM 2010 (published online http://www.nejm.org/)

[2]  ACCORD study group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. NEJM 2010 (published online www.nejm.org)

[3]  Presented by Rhonda Cooper-DeHoff at the ACC.10/i2 Summit, Atlanta, GA, March 2010

[4]  Presented by Dr. Ted Feldman at the ACC.10/i2 Summit, Atlanta, GA, March 2010

[5]  Park SJ, Park DW, Kim YH, et al. Duration of dual antiplatelet therapy after implantation of drug-eluting stents. NEJM 2010 (published online http://www.nejm.org/)

[6]  Van Gelder CI, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial fibrillation. NEJM 2010 (published online http://www.nejm.org/)

Chronic Stable Angina 2.0

August 4, 2010

By Brad Pfeffer, MD

Faculty Peer Reviewed

Case: A 75- year-old non-smoking male with a history of type II diabetes, hypertension and hyperlipidemia comes to clinic with several months of stable anginal chest pain provoked by ten blocks of exercise with no change in exercise tolerance. He has seen you several times over the past year and has been placed on aspirin, beta blockers, calcium channel blockers and long acting nitrates with some relief of symptoms. In addition, he is on atorvastatin with an LDL of 77. His blood pressure is well controlled at 122/78 and his heart rate is 62.  His BMI is 25.   An EKG shows a normal sinus rhythm at 62 with no evidence of prior myocardial infarction. A transthoracic echo shows a normal ejection fraction with no wall motion abnormalities. An adenosine nuclear stress test was performed that showed a small reversible perfusion defect in the territory of the distal circumflex with a normal ejection fraction.  The patient asks if there are any further medical options or if it isnecessary for him to have a percutaneous intervention.

Coronary artery disease continues to be a leading cause of death among both women and men. Angina pectoris is one of several syndromes that results from coronary artery disease. The symptoms of angina manifest as chest discomfort resulting from insufficient supply of oxygen to the heart with increasing demand.  In the United States, 16 million adults suffer from coronary artery disease and of those 9.1 million have angina. The total cost of coronary artery disease is 475.3 billion dollars [1]. Moreover, the number of patients suffering from and the health care cost of angina will continue to rise with a growing aging population.

The traditional medical management of chronic stable angina attempts to balance oxygen supply and demand and prevent thrombosis while minimizing cardiovascular risk factors through smoking cessation, weight loss, blood pressure, cholesterol and diabetic management.  Medical management includes the use of beta-blockers, calcium channel blockers, nitrates, statins and antiplatelet therapy including aspirin or clopidogrel in patients intolerant of aspirin [2-3]. Beta-blockers should be titrated to reduce the resting heart rate to 55-60 beats per minute. In more severe cases of angina, beta-blockers can be titrated to a heart rate less than 50 if no adverse symptoms or heart block occur.  Sublingual nitroglycerin or spray nitroglycerin can be used for immediate relief of angina or prophylaxis prior to anginal causing activities. Long acting nitrates, such as isosorbide dinitrate, mononitrates, transdermal nitroglycerin patches, and nitroglycerin ointment can be used to prevent angina. Patients must have a nitrate free period of 8 to 12 hours in order to prevent nitrate tolerance [4].  Long acting nitrates can be titrated for prevention of symptoms as long as no hypotension or side effects such as headaches develop.

There is little data to suggest that dual antiplatlet therepy is beneficial in patients with stable coronary disease. Data from the CHARSIMA trial has shown that dual antiplatelet therapy with aspirin and plavix does not reduce the rate of cardiovascular events but does increase the rate of bleeding when compared to aspirin alone [5]. However, in post hoc analysis the CHARISMA trial did show a significant reduction in cardiovascular events in patients with stable chronic angina with prior history of MI, stroke or symptomatic peripheral arterial disease [6-7]. As a result, dual antiplatelet therapy may be useful for patients at the highest risk for adverse events or who have recently undergone percutaneous coronary intervention (PCI).

Revascularization continues to be the routine treatment for refractory angina. According to the ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Interventions patients continuing to have angina despite medical optimization (beta-blockers, calcium channel blockers, nitrates and antiplatelets therapy) should undergo PCI if there is a low likelihood of mortality and morbidity and high likelihood of success [8].  However, the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) sought to compare clinical endpoints in patients receiving medical management alone verse medical management plus PCI.

The COURAGE trial compared cardiovascular outcomes of PCI as an initial management for chronic stable angina to optimal medical therapy alone. In the COURAGE trial, 2287 patients with evidence of ischemia or significant coronary artery disease where randomized to receive PCI plus medical optimization therapy or medical optimization alone. All patients received ischemic therapy with beta-blockers, calcium channel blockers, long and short acting nitrates, as well as antiplatelet therapy with either aspirin or clopidogrel and aggressive lipid-lowering therapy, including administration of a statin with or without ezitimibe. In the initial follow up period, there was a statistically significant reduction in the number of anginal free patients in the PCI group, at one and three years (respectively 66% vs 58%, P< 0.001 and 72% vs 67%, P=0.02). The benefit of PCI persisted at five years. However, at five years, the number of patients that were free of angina, between the two groups, was not statistically significant (74% in the PCI group and 72% in the medical therapy group, P=0.35). It is important to note that 36.6% of all patients in the medical therapy group crossed over to the PCI group by five years. The study did not find any statistical difference between the PCI and medical therapy group in composite death, myocardial infarction and stroke (respectively 20% and 19.5%, P=0.62). [9]. This study supports the idea that PCI is not superior to optimal medical management in terms of death, myocardial infarction and stroke in patients with stable coronary artery disease. However, PCI continues to be beneficial for anginal symptom relief, but can be safely deferred in patients with stable coronary artery disease who are optimally medically managed.

How should you treat patients that continue to have anginal symptoms despite lifestyle and dietary modifications and the addition of anginal medications such as beta-blockers, calcium channel blockers, nitrates and antiplatelet therapy? Or how do you treat patients that have undergone catheterization with no known lesion or are not candidates for catheterization? Is there any medical therapy beyond the current guidelines?

Ranolazine (Ranexa) was approved by the Food and Drug Administration for chronic stable angina in 2006. The use of ranolazine has been shown to be effective to improve anginal symptoms in several studies [9-10]. Ranolazine is a piperazine derivative that works through the inhibition of the late inward sodium current in cardiac cells.  Inhibition of late inward sodium current in cardiac cells leads to a decrease in intracellular calcium, increased myocardial relaxation during diastole and inhibits the rapidly activating component of the delayed rectifier potassium current (IKr). Although ranolazine inhibits the delayed rectifier potassium current and causes a modest increase in QTc, it is not associated with proarrhythmic activity [11]. However, given the possibility of prolongation of the QTc, a baseline EKG and EKG after initiation should be obtained. In clinical study, ranolazine does not statistically affect heart rate or blood pressure [12].

The Monotherapy Assessment of Ranolazine In Stable Angina (MARISA) trial, a multi-national, randomized, double-blind, placebo-controlled study, was the first trial of ranolazine SR 500, 1000 and 1500 mg BID  monotherapy in patients with chronic angina. The study population consisted of patients older than 21 years of age with well-documented coronary artery disease, angina pain for at least three months that responded to beta-blockers, calcium channel blockers and/or long acting nitrates. During the study, all patients discontinued their anti-anginal treatment.  Comparison of exercise stress testing before and after treatment showed that exercise duration increased with ranolazine 500, 1,000, and 1,500 mg twice daily by, respectively, 94, 103, and 116 seconds (P< 0.005).  The increase in exercise performance from monotherapy ranolazine is similar to those reported for maximal doses of nitrates, beta-blockers and calcium channel blockers. [12]

The Combination Assessment of Ranolazine In Stable Angina (CARISA) trial examined the exercise tolerance, angina attacks and nitroglycerin use of 823 patients with symptomatic chronic angina taking standard doses of atenolol (50 mg), amlodipine (5 mg), or diltiazem (180 mg once daily) before and 12 weeks after being randomized to receive 750 mg or 1000 mg twice daily of ranolazine or placebo.  Ranolazine reduced the mean number of angina attacks per week from 3.3 ± 0.3 for placebo to 2.5 ± 0.2 for 750 mg (p = 0.006) to 2.1 ± 0.2 for 1000 mg (p < 0.001) ranolazine. It also significantly reduced nitroglycerin consumption (p < 0.02). Exercise duration increased significantly with ranolazine by 115.6 seconds from baseline in both ranolazine groups vs 91.7 seconds in the placebo group (P = .01).  The time to onset of anginal symptoms increased significantly in both the 750 mg and 1000 mg group (respectively 144 seconds, P=0.01 and 140.3 seconds, P=0.03).  There were no clinically significant changes in blood pressure or heart rate. These finding were independent of background therapy, and persisted for 12 weeks [10]. Similar reduction in angina symptoms were reported in the Efficacy of Ranolazine In Chronic Angina (ERICA) trial that examined the use of amlodipine (10 mg) and ranolazine (1000 mg twice daily) [13]. Post hoc analysis of diabetics in the CARISA trial showed a significant reduction in HbA1C levels [14].

Chronic angina is a debilitating disease that impacts millions of Americans. The mainstay of treatment involves dietary and lifestyle modifications along with beta-blockers, calcium channel blockers, nitrates, statins and antiplatelet therapy. Current guidelines reflect these mainstays of treatment. Ranolazine should be used as second line treatment when beta-blockers, nitrates and calcium channel blockers have failed to relieve symptoms. Unlike other anti-anginal medications ranolazine does not affect hemodynamics. As a result, ranolazine should be used in addition or alone when the titration or use of beta-blockers, calcium channel blockers or nitrates is limited by blood pressure or heart rate.  The most common side effects of ranolazine include dizziness (11.8%) and constipation (10.9 %). These symptoms led to discontinuation of ranolazine in 0.9% and 0.5% of patients, respectively [15].  Syncope and orthostatic hypotension has been seen in a minority of patients receiving 1000 mg twice daily. This may be due to alpha blockade with higher doses of ranolazine and possible drug interaction between higher doses of ranolazine and diltiazem [10]. As a result, it is recommended that clinicians start at the lowest possible dose of ranolazine and titrate up to effectiveness and tolerability. Ranolazine is contraindicated in patients with preexisting long QT prolongation intervals and should be used with caution with other medications that prolong QT intervals. It is also contraindicated in clinically significant liver disease. It should be used with caution in patients with Childs-Pugh class A or B liver impairment.  Ranolazine is a potent inhibitor of CYP3A4, thus it should be used with caution in combination with other drugs that utilize CYP3A4 such as diltiazem and verpamil. When used with medications that use CYP3A4 the dose of ranolazine should not exceed 500 mg twice daily.  Ranolazine also interferes with the metabolism of digoxin and simvastatin, thus dose reduction of these drugs may be necessary.

In conclusion, the addition of ranolazine to current guidelines may defer the decision for patients with chronic angina to go for PCI. It is likely that ranolazine may be part of future chronic angina management guidelines and should be considered in patients with chronic stable angina.

Commentary by Sohah Iqbal, MD, Division of Cardiology

As the above thoughtful review has highlighted, medical therapy for coronary disease and chronic stable angina continues to evolve. Ranolazine, anecdotally and in clinical trials, has been shown to improve exercise capacity in those with activity limiting angina. There are 2 key criteria that need to be met before adding ranolazine: (1) Identifying patients with chronic stable angina and (2) Ensuring that these patients are on optimal medical management.

Angina that progressively limits patient in their basic activities of daily living or angina changing in character and pattern need to be identified as unstable in nature and should be treated via a different algorithm. Also, before adding ranolazine, patients with coronary artery disease and chronic stable angina must be on medications that have been shown to reduce clinical end points such as aspirin, beta blockers, statins, and in certain subgroups, ace-inhibitors.  Once these two criteria have been met, ranolazine is an excellent additional agent to manage chronic stable angina.

Dr. Pfeffer is Chief Resident at NYU Langone Medical Center

Peer reviewed by Sohah Iqbal, MD, Division of Cardiology, NYU Langone Medical Center

References:

1.         Rosamond, W., et al., Heart disease and stroke statistics–2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 2008. 117(4): p. e25-146.

2.         Trujillo, T.C. and P.P. Dobesh, Traditional management of chronic stable angina. Pharmacotherapy, 2007. 27(12): p. 1677-92.

3.         Fraker, T.D., Jr., et al., 2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation, 2007. 116(23): p. 2762-72.

4.         Gibbons, R., Abrams, J, Chatterjee, K, et al. ACC/AHA 2002 guideline update for the management of patients with chronic stable angina.   [cited 2009 September 13]; Available from: http://www.acc.org/qualityandscience/clinical/guidelines/stable/stable_clean.pdf.

5.         Bhatt, D.L., et al., Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med, 2006. 354(16): p. 1706-17.

6.         Bhatt, D.L., et al., Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol, 2007. 49(19): p. 1982-8.

7.         Bakhru, M.R. and D.L. Bhatt, Interpreting the CHARISMA study. What is the role of dual antiplatelet therapy with clopidogrel and aspirin? Cleve Clin J Med, 2008. 75(4): p. 289-95.

8.         Smith, S.C., Jr., et al., ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/SCAI Writing Committee to Update 2001 Guidelines for Percutaneous Coronary Intervention). Circulation, 2006. 113(7): p. e166-286.

9.         Wilson, S.R., et al., Efficacy of ranolazine in patients with chronic angina observations from the randomized, double-blind, placebo-controlled MERLIN-TIMI (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Segment Elevation Acute Coronary Syndromes) 36 Trial. J Am Coll Cardiol, 2009. 53(17): p. 1510-6.

10.       Chaitman, B.R., et al., Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA, 2004. 291(3): p. 309-16.

11.       Keating, G.M., Ranolazine: a review of its use in chronic stable angina pectoris. Drugs, 2008. 68(17): p. 2483-503.

12.       Chaitman, B.R., et al., Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol, 2004. 43(8): p. 1375-82.

13.       Stone, P.H., et al., Antianginal efficacy of ranolazine when added to treatment with amlodipine: the ERICA (Efficacy of Ranolazine in Chronic Angina) trial. J Am Coll Cardiol, 2006. 48(3): p. 566-75.

14.       Timmis, A.D., B.R. Chaitman, and M. Crager, Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J, 2006. 27(1): p. 42-8.

15.       Koren, M.J., M.R. Crager, and M. Sweeney, Long-term safety of a novel antianginal agent in patients with severe chronic stable angina: the Ranolazine Open Label Experience (ROLE). J Am Coll Cardiol, 2007. 49(10): p. 1027-34.

Appropriateness for Revascularization in Stable Angina

July 22, 2010

Ramin Shayegan Hastings MD, Jonathan Willner MD, and Steven Sedlis MD

Introduction to Cases:

During the past several weeks, we have posted a series of cases addressing the appropriate treatment for patients with stable coronary artery disease. We have focused on indications for revascularization in stable angina. In all of the cases, the patients have been at high enough risk that stress tests and coronary angiography are performed.

There has been recent data and recommendations on the appropriate indications for revascularization in stable angina. These recommendations are based on clinical symptoms, non-invasive imaging, and catheterization findings. After reading through these cases, we hope you have a better understanding of what the appropriate indications are for revascularization, and the evidence behind them.

Review Case #1

Review Case #2

Review Case #3

Case #4

The patient from Case # 1 (see previous post) comes back to the clinic for a follow up visit.

In review, he is a 54-year-old male with hypertension and tobacco use who presented with anginal chest pain 1 year ago. He was found to have low-risk findings on stress testing, and a cardiac catheterization revealed 2 vessel disease (not affecting the proximal left anterior descending artery (LAD)). He was treated with medical therapy including blood pressure control, treatment of hyperlipidemia with a goal LDL of 100, long-acting nitrates, aspirin, tobacco cessation, and an exercise program.

However, the patient states that his angina has continued despite treatment. Over the past 3 months it has worsened, and now he is not able to continue his work as a plumber because of continuing pain. After walking only short distances, about 2 blocks or one flight of stairs, he develops chest pain. He still has not had any pain at rest, and physical exam is unchanged from previous. ECG is also unchanged from previous.

What is the appropriate next step in treatment?

A. No change in treatment

B. Increase the dose of long-acting nitrates

C. Repeat stress test with catheterization only if new abnormalities are noted

D. Repeat catheterization with subsequent revascularization only if new lesions are noted

E. Repeat catheterization with revascularization of lesions that correlate with areas of ischemia on previous stress or echocardiography

Answer: E

In this case, we have the same patient from the previous post who had low-risk findings on non-invasive testing, CCS class II anginal symptoms off medication, and 2 vessel disease on catheterization. See the previous post about why medical therapy was an appropriate initial treatment strategy for this patient. His symptoms have worsened despite medical therapy.

His symptoms can now be classified as CCS class III angina (1). In addition, his symptoms are now affecting his daily life as he is not able to work. He was started on medical therapy, however we would not consider it optimal medical therapy. Optimal medical therapy would include two or more anti-anginals (beta-blocker, calcium channel blocker, and/or angiotensin converting enzyme (ACE) inhibitor), along with lipid control, exercise program, smoking cessation, and blood pressure control. While recent studies have found there is no mortality benefit with revascularization for the majority of patients with similar findings as this patient (see previous posts), several studies have shown there is a reduction in symptoms of patients undergoing revascularization. Early randomized studies showed that patients often had significant improvements in anginal symptoms after revascularization utilizing coronary artery bypass grafting (CABG). In the Veterans Administration Cooperative Study 38.5% of patients who underwent revascularization were angina free at one year compared with 8.8% in medical therapy (2). However, this improvement was no longer apparent 10 years after randomization (3). Similar findings were noted in the Coronary Artery Surgery Study (CASS), as patients randomized to revascularization had significant improvements in chest pain through 5 years after randomization (63% chest pain free with CABG vs. 38% with medical therapy after 5 years) (4). These studies were before the advent of some newer medical therapies known to improve coronary artery disease.

Studies comparing revascularization with Percutaneous Transluminal Coronary Angioplasty (PTCA, balloon angioplasty) to medical therapy in patients with stable angina painted a similar picture. The Second Randomized Intervention Treatment of Angina (RITA-2) Trial randomized 1,018 patients with stable angina to PTCA or medical therapy. Although they found no mortality benefit with PTCA (see previous post), patients treated with revascularization had a significant improvement in anginal symptoms. 3 months after randomization 19.4% of the PTCA group had angina class II or worse compared to 35.9% of the medical therapy group. This difference remained for five years, however after eight years no significant improvement in symptoms were noted with the group treated with PTCA (4). Newer data shows the improvement in symptoms with revascularization may not be as great as once though. The most applicable study for this patient is the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial which randomized 2,287 patients with stable angina to percutaneous coronary intervention (PCI) with aggressive medical therapy or aggressive medical therapy alone (5). There was no difference in the primary outcome of death and myocardial infarction (MI, see previous post). Subsequent analyses found patients randomized to PCI had an improvement in symptoms at 1 year, although this was no longer present at 3 years (At 1 year 57% were free of angina with PCI vs. 50% free of angina in medical therapy; after 3 years that changed to 59% and 56% respectively).

Based on these data, the American College of Cardiology (ACC) and American Heart Association (AHA) recommend PCI or CABG “for patients who have not been successfully treated with medical therapy and can undergo revascularization with acceptable risk,” as a class IB recommendation (6). Medical treatment has failed this patient, as his symptoms have continued to worsen despite adequate medical treatment. In addition, he is having disabling angina and the appropriateness criteria for revascularization released by the ACC rated revascularization appropriate in patients with CCS class III or IV angina with almost any disease noted on angiography (except 1-2 vessel disease off treatment with low/intermediate risk findings on stress) (7). Revascularization with PCI or CABG would be appropriate in this patient, even if no further disease is noted on cardiac angiography. In addition, as stated above, an increase in his medical management with beta-blockers, calcium channel blockers, and ACEI is indicated as well.

As you can see, we have laid out two different indications for revascularization in patients with stable angina. The first is to improve survival, as may be the case in patients with high-risk findings on angiography or non-invasive testing (see previous post). The other is for symptom control in patients who have disabling angina or when symptoms are not adequately controlled with medical therapy alone.

 

References

1. Campeau L. The Canadian Cardiovascular Society grading of angina pectoris revisited 30 years later. Can J Cardiol2002 Apr;18(4):371-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=11992130

2. Peduzzi P, Hultgren HN. Effect of medical vs surgical treatment on symptoms in stable angina pectoris. The Veterans Administration Cooperative Study of surgery for coronary arterial occlusive disease. Circulation1979 Oct;60(4):888-900. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=113129

3. Eighteen-year follow-up in the Veterans Affairs Cooperative Study of Coronary Artery Bypass Surgery for stable angina. The VA Coronary Artery Bypass Surgery Cooperative Study Group. Circulation1992 Jul;86(1):121-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1617765

4. Rogers WJ, Coggin CJ, Gersh BJ, Fisher LD, Myers WO, Oberman A, Sheffield LT. Ten-year follow-up of quality of life in patients randomized to receive medical therapy or coronary artery bypass graft surgery. The Coronary Artery Surgery Study (CASS). Circulation1990 Nov;82(5):1647-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=1977531

5. Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk WJ, Knudtson M, Dada M, Casperson P, Harris CL, Chaitman BR, Shaw L, Gosselin G, Nawaz S, Title LM, Gau G, Blaustein AS, Booth DC, Bates ER, Spertus JA, Berman DS, Mancini GB, Weintraub WS. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med2007 Apr 12;356(15):1503-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17387127

6. Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM, Grunwald MA, Levy D, Lytle BW, O’Rourke RA, Schafer WP, Williams SV. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation1999 Jun 1;99(21):2829-48. http://circ.ahajournals.org/cgi/content/full/99/21/2829

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10351980

7. Patel MR, Dehmer GJ, Hirshfeld JW, Smith PK, Spertus JA. ACCF/SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness Criteria for Coronary Revascularization: A Report of the American College of Cardiology Foundation Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and Interventions, Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, and the American Society of Nuclear Cardiology: Endorsed by the American Society of Echocardiography, the Heart Failure Society of America, and the Society of Cardiovascular Computed Tomography. Circulation2009 Mar 10;119(9):1330-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19131581

 

Appropriateness for Revascularization in Stable Angina

July 1, 2010

Introduction to Cases:

During the upcoming weeks, we will post a series of cases addressing the appropriate treatment for patients with stable coronary artery disease. We will be focus on indications for revascularization in stable angina. In all of the cases, the patients will be at high enough risk that stress tests and coronary angiography will be performed.

There has been recent data and recommendations on the appropriate indications for revascularization in stable angina. These recommendations are based on clinical symptoms, non-invasive imaging, and catheterization findings. After reading through these cases, we hope you have a better understanding of what the appropriate indications are for revascularization, and the evidence behind them.

Review Case #1

Review Case #2

Ramin Shayegan Hastings MD, Jonathan Willner MD, and Steven Sedlis MD

Case #3:

A 62-year-old male with hypertension and hyperlipidemia comes to the office for evaluation of chest pain. He states that for the past several weeks he has been having some mild (3/10) chest pain after walking briskly or jogging for 10 to 15 minutes. The pain is substernal, non-radiating, and not associated with any other symptoms. The pain resolves quickly with rest, and he has not had any pain at rest. He is on metoprolol 50 mg twice a day and amlodipine 10 mg daily for his blood pressure as well as simvastatin 40 mg daily for hyperlipidemia.

In the office, he has a BP of 128/56, HR 62. Physical exam is otherwise unremarkable.

Electrocardiogram (ECG) done in the office is normal sinus rhythm with q-waves noted in the lateral leads (V4-V6). These findings are new from his previous ECG done one year ago. He is referred for echocardiography and nuclear stress. He is noted to have a slightly depressed ejection fraction (EF) to 40% with hypokinesis of the left ventricular lateral wall. There were no reversible areas of ischemia noted on his nuclear stress test. Cardiac catheterization reveals a 100% occlusion of the mid left circumflex artery, with minimal other disease.

What is the most appropriate treatment for this patient?

A. No change in treatment is necessary

B. More aggressive medical therapy including beta-blockers, angiotensin converting enzyme (ACE) inhibitor, anti-platelet medication, aggressive blood pressure control, lipid reduction with goal LDL 100, an exercise program, and nitrates as needed

C. Revascularization with percutaneous coronary intervention (PCI)

D. Revascularization with coronary artery bypass grafting (CABG)

Read more »

Appropriateness for Revascularization in Stable Angina

June 9, 2010

Introduction to Cases:

During the upcoming weeks, we will post a series of cases addressing the appropriate treatment for patients with stable coronary artery disease. We will be focus on indications for revascularization in stable angina. In all of the cases, the patients will be at high enough risk that stress tests and coronary angiography will be performed.

There has been recent data and recommendations on the appropriate indications for revascularization in stable angina. These recommendations are based on clinical symptoms, non-invasive imaging, and catheterization findings. After reading through these cases, we hope you have a better understanding of what the appropriate indications are for revascularization, and the evidence behind them.

Ramin Shayegan Hastings MD, Jonathan Willner MD, and Steven Sedlis MD

Case #2:

A 59-year-old male with hypertension and hyperlipidemia comes into your clinic for evaluation of chest pain. The patient states that for the past few months he has been having chest pain on exertion. He describes a substernal chest pain that radiates to the L arm after walking about 10 blocks or climbing 2 flights of stairs. The pain is relieved with approximately 5 minutes of rest. He denies any other associated symptoms, and has never had the pain at rest. He has had hypertension for the past 15 years, currently being treated with hydrochlorothiazide 25 mg daily and lisinopril 10 mg daily. His resting BP is 136/88. He also takes simvastatin 40 mg daily for an elevated LDL, which is now 110.

Electrocardiogram (ECG) done in the office reveals normal sinus rhythm with HR of 72 and non-specific ST segment and T wave changes in the anterior-lateral leads. He is referred for an exercise stress test with nuclear imaging. His exercise stress was notable for 3 mm ST depressions in the anterior leads after 10 minutes of exercising. He had to stop the test secondary to chest pain after the 10 minutes. The nuclear portion of the stress test showed a large reversible perfusion defect affecting the anterior wall of the left ventricle, with an ejection fraction of 45%. Subsequent cardiac catheterization reveals a 75% stenosis of the proximal left anterior descending (LAD) artery, along with 80% stenosis of the mid left circumflex artery.

What is the appropriate next step in management of this patient?

A. No further treatment necessary

B. Medical therapy alone, including anti-anginal medication, aggressive blood pressure control, lipid reduction, smoking cessation, and an exercise program.

C. Cardiac viability study followed by revascularization if tissue is viable, along with medical therapy

D. Revascularization of the lesions with either percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) along with medical therapy

Read more »

Appropriateness for Revascularization in Stable Angina

May 19, 2010

Introduction to Cases:

During the upcoming weeks, we will post a series of cases addressing the appropriate treatment for patients with stable coronary artery disease. We will be focus on indications for revascularization in stable angina. In all of the cases, the patients will be at high enough risk that stress tests and coronary angiography will be performed.

There has been recent data and recommendations on the appropriate indications for revascularization in stable angina. These recommendations are based on clinical symptoms, non-invasive imaging, and catheterization findings. After reading through these cases, we hope you have a better understanding of what the appropriate indications are for revascularization, and the evidence behind them.

Ramin Shayegan Hastings MD, Jonathan Willner MD, and Steven Sedlis MD

Case 1:

A 54-year-old male with a past medical history of hypertension (well-controlled on hydrochlorothiazide 25 mg daily) and tobacco use (20 pack-year) presents for evaluation of chest pain. The patient states that for the past 3 months he has noted chest pain on exertion. During normal walking he does not have chest pain, however whenever he runs or walks fast for more than a couple of minutes, he experiences chest pain. The pain is substernal, non-radiating, and associated with mild shortness of breath and slight diaphoresis. He also notes chest pain after climbing 2-3 flights of stairs.

Patient denies any chest pain at rest, paroxysmal nocturnal dyspnea, orthopnea, or lower-extremity edema. He has a family history of coronary artery disease in his father who had a myocardial infarction (MI) at the age of 40. He takes no other medications except for hydrochlorothiazide 25 mg daily.

Physical exam is largely unremarkable with BP 126/62 and HR 82. Electrocardiogram (ECG) done in the office reveals normal sinus rhythm with slight ST depressions and t-wave flattening in the lateral leads.

He is then referred for an exercise stress test. After 15 minutes on the Bruce Protocol he develops 2 mm ST depressions in leads V2-V4, with no associated chest pain. His nuclear stress test reveals a small reversible perfusion defect in the lateral left ventricular wall. His EF is noted to be 50%. Cardiac catheterization reveals a focal 85% stenosis in the second obtuse marginal branch of the proximal Left Circumflex Artery along with a focal 70% stenosis of his distal Right Coronary Artery.

Which of the following is the best treatment approach?

A. No treatment is necessary

B. Medical therapy alone, including anti-anginal medication, aggressive blood pressure control, lipid reduction, smoking cessation, and an exercise program

C. Revascularization of the Obtuse Marginal branch of the Left Circumflex Artery

D. Revascularization of the Right Coronary Artery

E. Revascularization of both the Obtuse Marginal branch of the Left Circumflex and Right Coronary Arteries

Read more »