Cardiology

Mystery Quiz- The Answer

January 16, 2009

Posted by Daniel Frenkel MD PGY-3 and Jeffrey Lorin MD, Assistant Professor, NYU Division of Cardiology

Edited by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors 

The answer to last week’s mystery quiz is accelerated idioventricular rhythm (AIVR) [a.k.a. accelerated ventricular rhythm or slow ventricular tachycardia]

AIVR is an ectopic ventricular rhythm with intermediate rates between an escape rhythm (<40 bpm) and ventricular tachycardia (>100-120 bpm). It has the usual features of ventricular arrhythmias including AV dissociation, fusion complexes, and capture complexes. However, the underlying mechanism of this arrhythmia is automaticity rather than reentry. Given the slower rate of this rhythm, the ventricles are more likely to be activated by a supraventricular source which results in more frequent fusion and capture complexes and more readily succumb to overdrive pacing. The AIVR emerges when the sinus node slows and the fastest pacemaker in the heart at the time takes over (i.e. the focus of ventricular automaticity). At the initiation of the AIVR, both the sinus node rate and AIVR rate are similar so that depolarization can occur simultaneously from a sinus origin down the normal conduction pathway and from the focus of ventricular automaticity resulting in a hybrid QRS complex known as a fusion complex. These complexes often initiate or terminate AIVR. Similary, if the focus of automaticity slows down transiently, a native beat can be conducted down the native pathway resulting in a capture complex (normal narrow QRS). This is noted in our patient’s EKG at beat 14.

AIVR can occur in numerous conditions including myocardial disease (ischemic cardiomyopathy, dilated cardiomyopathy, congenital, hypertensive disease), rheumatic heart disease, myocarditis, digitalis toxicity, acute coronary syndrome, and reperfusion injury. It occurs in 8 to 46% of acute MI’s and in as many as 90% of patients within the first 24 hours after reperfusion (frequency highest early on and decreasing after 8 to 12 hours).

Accelerated idioventricular rhythm is usually benign and transient (lasting from seconds to hours). It does not impact hemodynamics, progress to more serious ventricular arrhythmias, nor increase mortality. Of note, the coordinated contraction between the atria and ventricles is disrupted, impeding ventricular filling, and in certain patients this can lead to vague symptoms of weakness and unsteadiness. This arrhythmia rarely warrants any treatment and will self-resolve in a matter of hours. If there is hemodynamic compromise in the presence of AIVR, atrial overdrive pacing or atropine can be tried in order to reestablish AV synchrony.

In our patient’s EKG, there is an accelerated idioventricular rhythm at a slow rate (90-120 bpm) with normal sinus conduction at beat 14 (capture beat). There are retrograde p waves representing ventricular to atrial conduction; but interestingly, there is no retrograde p wave in beat 11. In order to decipher beat 11, look further down the EKG strip. The distance between the retrograde p wave in beat 13 to the sinus p wave in beat 14 likely represents sinus recovery time. If this distance is measured out from the retrograde p wave in beat 10, there is likely a sinus p wave superimposed on beat 11 (not visualized), marking the interval that would be expected from the presumed sinus node recovery time. This sinus p wave is not conducted to the ventricle due to ventricular refractoriness. However, the impulse likely goes through the AV node, rendering the AV node refractory to retrograde V-A conduction. Thus, no retrograde p wave is visible after beat 11. This phenomenon has been termed concealed conduction of the AV node. Taking all of these features into account, the complete rhythm diagnosis is AIVR with retrograde excitation of the atria and a competing sinus rhythm with capture and concealed AV conduction.

EKG with labels
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References:

Rho RW, Page RL. Chapter 39. Ventricular Arrhythmias. In: Fuster V, O’Rourke RA, Walsh RA, Poole-Wilson P, Eds. King SB, Roberts R, Nash IS, Prystowsky EN, Assoc. Eds. Hurst’s The Heart. 12th ed. McGraw-Hill; 2008. http://www.accessmedicine.com.ezproxy.med.nyu.edu/content.aspx?aID=3050907. Accessed October 10, 2008.

Surawicz, B, Knilans TK. Chou’s Electrocardiography in Clinical Practice. 5th ed. Pennsylvania: Saunders, 2001:408-411.

Wagner GS. Marriott’s Practical Electrocardiography. 10th ed. Philadelphia, PA: Lippincott Williams and Wilkins, 2001:295-296.

Coronary Artery Disease in South Asians

January 14, 2009

southasia.jpgCommentary by Muhammad Ghumman MD, PGY-3

Faculty Peer Reviewed

South Asia (India, Pakistan, Bangladesh, Sri Lanka, and Nepal) comprises 25% of the global population yet contributes nearly 60% of the global cardiovascular disease burden. There are over 3 million South Asians living in North America (2 million in United States and nearly a quarter million in New York City alone). It is important to recognize that South Asians develop coronary artery disease (CAD) at a younger age, die from CAD at younger ages, and have higher overall CAD-associated mortality.(1-6)

Numerous studies have demonstrated higher CAD rates amongst South Asians at all ages. Prevalence of CAD in rural South Asia is 3-4%, while the CAD prevalence amongst urban South Asians and South Asian immigrants to the western world approaches 10%. (2,7,8) The Coronary Artery Disease in Indians (CADI) study demonstrated a CAD prevalence of 10% amongst first generation South Asian immigrants to the United States, compared to a 2.5% CAD prevalence among the general population in the Framingham study.(2) The higher prevalence is further magnified in younger South Asians. United Kingdom mortality data demonstrates 3 times higher CAD prevalence for South Asians younger than 40 years and 1.5 times higher CAD prevalence for South Asians older than 60 years. Contribution of the younger age group to overall CAD-associated mortality is significantly higher in South Asians. A 1990 World Health Organization showed that the proportion of cardiovascular deaths occurring before 70 years of age was 26% in developing countries but 52% in India.

Despite the increased prevalence of CAD, rates of many traditional CAD risk factors such as smoking, hypertension, and obesity are not higher among South Asians. Smoking is actually lower amongst South Asians and virtually nonexistent among South Asian females.(7,12,17) Diabetes Mellitus (DM) however is significantly more common among South Asians, having a 2% prevalence in rural South Asia but approaching a 20% prevalence in urban South Asia and amongst immigrant South Asians.(7,11,12,13) While total cholesterol and LDL levels may be similar to other ethnic groups, South Asians have characteristic lipid profiles increasing their risk for CAD: higher triglyceride levels, higher lipoprotein(a) levels, increased ratio of apolipoprotein B to apolipoprotein A-1 (apoB/apoA-1), smaller HDL and LDL particle size, and lower levels of HDL.(14,15,16,25) These factors are rarely screened for or targeted by most physicians. Lipoprotein(a) is an emerging independent and compounding risk factor for the development of CAD and, unlike other lipids, its levels are almost entirely determined by genetics. South Asians have the second highest levels of lipoprotein(a) after African Americans and this may explain some of the increased CAD risk in these ethnic groups. Lipoprotein(a) is proposed to be an independent CAD risk factor and also thought to multiply the effect of traditional CAD risk factors (low HDL, high LDL, DM). Screening for lipoprotein(a) is most important in younger South Asians since the lipoprotein(a)-associated CAD risk is highest between 45-55 years of age and declines in old age. (24,25) Because of the multiplicative effect of lipoprotein(a) on other CAD risk factors, South Asians have a higher CAD risk at any given level of LDL and total cholesterol. Physicians should be aware that this leads to a significant underestimation of CAD risk in South Asians by the Framingham risk score.

Most of the increased CAD risk in South Asians can be explained by a higher prevalence of traditional risk factors, especially at a younger age. INTERHEART study (9) (an international case-control study examining risk factors for initial MI in 52 countries, including 12,000 cases of initial MI and 14,000 controls) demonstrated that over 90% of global MI risk can be attributed to 9 modifiable risk factors (smoking, DM, lipids, central obesity, hypertension, diet, physical activity, alcohol consumption, and psychosocial factors). This was true for all populations including South Asians. However, South Asians presented with initial MI at earlier ages (53 yrs vs. 58 yrs) and this can be explained by the presence of more risk factors at an earlier age. Protective factors (moderate daily alcohol consumption, regular physical activity, daily intake of fruits and vegetables) were significantly lower among South Asians. Harmful factors were significantly higher in South Asians (DM and elevated apoB/apoA-1 ratio). When compared to other risk factors, elevated apoB/apoA-1 ratio had the single highest attributable risk in South Asians. When compared to other ethnic groups, certain risk factors had higher attributable risk in South Asians: apoB/apoA-1 ratio, low daily consumption of fruits and vegetables, lack of regular exercise, and high waist hip ratios (marker of central obesity which predisposes to insulin resistance).

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Mystery Quiz

January 8, 2009

Posted by Daniel Frenkel MD PGY-3 and Jeffrey Lorin MD, Assistant Professor, NYU Division of Cardiology

Edited by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors 

The patient is a 68 year old man with history of smoking, hypertension, hyperlipidemia, and stable exertional angina who presented with an acute posterior wall myocardial infarction. He was found to have a totally occluded left circumflex artery requiring bare metal stent placement. Several hours after stent placement, the nurse calls stating that the patient had an arrhythmia and the following ECG was obtained. The patient is without any acute complaints and his vital signs are stable.

Current EKG:

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Baseline EKG (post-cath, several hours prior to event):

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What is the arrhythmia?

View Results

Grand Rounds: “The Cardiovascular Molecular Basis of CPVT and other arrythmias”

January 7, 2009

Grand Rounds Image

Commentary by Anjali Grover MD, PGY-2 

Please also see the clinical vignette presented before December 17th’s grand rounds.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is classified as an inherited disorder which manifests itself as an adrenergically driven polymorphic ventricular tachyarrythmias.  The molecular etiology of this arrythmogenic disorder stems from a disruption in the calcium channels found in the sarcoplasmic reticulum.   This type of arrhythmia is an important cause of syncope and sudden cardiac death in those individuals with structurally normal hearts.  Genetic studies have elucidated two variants of the disease: an autosomal dominant variant with mutations in the cardiac ryanodine receptor (RyR2), and a recessive variant with mutations calsequestrin gene (CASQ2). 

            This disease clinically presents usually as a bi-directional polymorphic ventricular tachycardia induced by exercise or any events activating the sympathetic nervous system inducing a catecholaminergic state. It is often seen as sudden syncope during physical activity or acute emotional stress. Given this, the diagnosis can be made during an exercise stress test.  The resting EKG is usually normal, but during exercise, premature ventricular contractions that occur serve as a substrate for further development and propagation of bi-directional ventricular tachycardia.  This being said, beta blockers are the appropriate medical therapy for this adrenergically driven arrhythmia.

            The current hypothesis on the molecular abnormalities leading to arrythmias in CPVT patients is centered around two well studied mutations.  The first being that of the ryanodine receptor-a modulator of intracellular calcium through the sarcoplasmic reticulum.  Under normal physiologic conditions, the ryanodine receptor, located in the membrane of the sarcoplasmic reticulum, allows the release of calcium from the sarcoplasmic reticulum in the cytoplasm of the cell, allowing for cardiac muscle contraction.

            However, with the RyR2 gene mutation, in high-adrenergic states, the normally regulated intracellular calcium channels leak out calcium, leading to a depolarizing current and subsequently higher rates ventricular arrythmias.  Calsequestrin (CASQ2) is another protein involved in the regulation of intracellular calcium.  It is a calcium binding protein located within the sarcoplasmic reticulum, whose role is to essentially increase the storage of calcium in the cell.  A mutation in the CASQ2 gene leads to a decrease in the calcium binding capacity and the resulting build-up of calcium, in the presence of a high adrenergic state is thought to contribute to the ventricular arrythmias.  In sum, these proteins are responsible for the management of intracellular calcium, and these mutations alter the normal release of calcium from the sarcoplasmic reticulum, thus electrophysiologically predisposing cells to degenerate into a ventricular arrhythmia.

Cardiac MRI: Assessing Myocardial Viability

December 18, 2008

Commentary by Muhammad Ghumman MD, PGY-3

Faculty Peer Reviewed

Clinical Case:

A 65 year old male with hypertension, iron deficiency anemia, and atrial fibrillation (not anticoagulated due to prior gastrointestinal bleed,) presents with new onset lower extremity edema, dyspnea on exertion, orthopnea, and profound fatigue. Physical exam is significant for jugular venous distention to 17 cm, bilateral basilar crackles on lung exam, 3+ pitting edema in the lower extremities to mid thighs, and guaiac positive brown stool. Labs are significant for hemoglobin of 5.4, normal kidney function, and mildly elevated troponin. Patient denies chest pain and is hemodynamically stable with normal vitals. Electrocardiogram shows new ST depressions in lateral leads. Transthoracic echocardiogram shows new segmental wall motion abnormalities along with a newly reduced ejection fraction of 30%.   Capsule endoscopy shows non-bleeding angioectasias in the jejunum.  The patient is started on medical therapy for congestive heart failure and presumed coronary artery disease (ACE-I, Beta blocker, diuretic) and transfused to hemoglobin goal of 10 with improvement in his symptoms of dyspnea and fatigue. Echocardiogram strongly suggests ischemic cardiomyopathy due to the presence of regional wall motion abnormalities and an assessment of the patient’s coronary anatomy is warranted. However, the medical team and cardiology consult are reluctant to perform cardiac catheterization due to the risk of bleeding in a severely anemic patient who may require coronary artery stenting and subsequent long term anticoagulation. What other modalities are available for assessing this patient’s new cardiomyopathy and coronary anatomy?

Introduction:

Cardiac magnetic resonance imaging (CMR) is a rapidly evolving field which provides high contrast and high resolution 3-dimensional images of the heart, coronary vessels, and the great vessels without subjecting the patient to ionizing radiation. CMR is often considered a “one-stop shop” as it can provide a comprehensive assessment of the heart including myocardial wall motion, cavity size, ventricular ejection fraction, wall thickness, valvular function, infarct area, proximal coronary artery lesions, aortic disease including aneurysm and dissection, pericardial disease, congenital heart defects, and myocardial viability.

Myocardial viability: 

Currently, the most important and common clinical use of CMR is assessing myocardial viability. Dysfunctional myocardium is deemed viable if it can regain function (contractility) after regional blood supply is improved via revascularization. Nonviable myocardium is dead or scar tissue which has permanently lost its function irrespective of its regional blood supply. Viability testing guides clinical practice in patients with left ventricular (LV) dysfunction as revascularization of nonviable myocardium would not improve myocardial contractility, ejection fraction, or mortality and may even increase morbidity and mortality by subjecting the patient to an unnecessary interventional procedure.

CMR is excellent at determining myocardial viability using late gadolinium enhancement (LGE or hyperenhancement). When gadolinium is “taken up” by nonviable or scarred myocardium, it is not washed out as quickly as healthy myocardium due to poor blood flow, and thus images taken > 10 minutes after gadolinium injection will exhibit hyperenhancement or late gadolinium enhancement (regions where gadolinium is retained). The transmural extent of LGE signifies the thickness of nonviable or scar tissue and this correlates well to areas that are less viable and are partially or completely damaged in an irreversible manner. Conversely, absence of LGE corresponds to areas of viable myocardium.(1,2,3 ) A study of 50 patients with ventricular dysfunction undergoing revascularization showed that CMR accurately identified viable myocardium before revascularization. Absence of late gadolinium enhancement correlated well with segments which improved function after revascularization (78% of segments without LGE had improved function). Presence of late gadolinium enhancement correlated accurately with segments which had no improvement after revascularization (less than 2% of segments with LGE had improved function). The probability of improvement in segmental function significantly decreased as the extent of transmural LGE (thickness of scar) increased (see Figure 1).(3 )

Figure 1: Relation between the Transmural Extent of Hyperenhancement before Revascularization and the Likelihood of Increased Contractility after Revascularization.  804 dysfunctional segments were identified by CMR in 50 patients who were scheduled to undergo revascularization. As the transmural extent of late gadolinium enhancement increased, the likelihood of post-revascularization improvement in contractility significantly decreased. (adapted from Kim et al.)(3)

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Figure 2: Cardiac MRI displaying late gadolinium enhancement

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Traditionally, radionuclide myocardial perfusion imaging (using thallium, technetium-sestamibi, or positron emission tomography) and dobutamine echocardiography have been utilized to assess myocardial viability. CMR compares very favorably to these modalities and is even superior in some respects. In a study of 208 patients with suspected coronary artery disease referred for revascularization, dobutamine stress MRI had a 86% sensitivity and 74% specificity in terms of predicting viability when compared to dobutamine stress echocardiography which had a 85% sensitivity and 69% specificity.(4) When compared to positron emission tomography with F- 18 deoxyglucose (FDG-PET), CMR had similar sensitivity and specificity (94% and 84% respectively).(5) In comparison to resting thallium-201 perfusion imaging, CMR performs as well in terms of detecting transmural infarctions but is more accurate in detecting subendocardial infarctions.(6) Several studies have suggested that CMR may be more sensitive in detecting viability in regions of severely dysfunctional myocardium, which are often deemed non-viable by traditional techniques. CMR and conventional modalities are both poor at detecting viability in regions of intermediate residual viability but have similar performance in regions with high and low residual viability.

Clinical case applications:

Cardiac MRI can be used to assess for myocardial viability in our patient and thus guide future therapy (revascularization or optimal medical therapy). Furthermore, CMR can accurately determine ejection fraction and extent of proximal coronary artery atherosclerotic lesions, thus risk stratifying this patient. Left main or triple vessel disease may necessitate a surgical intervention in this patient. However, medical therapy or single vessel PCI may be more appropriate than CABG despite multivessel CAD if there is limited or no viability in multiple infarct areas.

In our patient, cardiac MRI/MRA showed mildly dilated LV with moderately reduced LV ejection fraction, hypokinetic myocardium without scar in LAD territory, hypokinetic myocardium with mild scar in RCA territory, and hypokinetic but viable myocardium in LCX territory. Coronary artery origins were incompletely visualized due to motion but there was patent origin of RCA, LAD, and LCX (L main couldn’t be visualized). Patient was discharged home on medical therapy and planned to return for coronary angiogram and possible revascularization as his coronary anatomy was not completely delineated by the Cardiac MRI.

 

 

REFERENCES

1.         Kim, RJ, Fieno, DS, Parrish, TB, et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999; 100:1992.

2.         Fieno, DS, Kim, RJ, Chen, EL, et al. Contrast-enhanced magnetic resonance imaging of myocardium at risk: distinction between reversible and irreversible injury throughout infarct healing. J Am Coll Cardiol 2000; 36:1985.

3.         Kim RJ, Wu E, Rafael A, et al. The use of contrast-enhanced magnetic resonance imaging to identify reversible myocardial dysfunction. N Engl J Med 2000; 343:1445-1453.

4.         Nagel, E, Lehmkuhl, HB, Bocksch, W, et al. Noninvasive diagnosis of ischemia-induced wall motion abnormalities with the use of high-dose dobutamine stress MRI: comparison with dobutamine stress echocardiography. Circulation 1999; 99:763.

5.         Kuhl HP, Beek AM, van der Weerdt AP, et al. Myocardial viability in chronic ischemic heart disease: comparison of contrast-enhanced magnetic resonance imaging with (18)F-fluorodeoxyglucose positron emission tomography. J Am Coll Cardiol 2003;41:1341-8.

6.         Bellenger NG, Burgess MI, Ray SG, et al. Comparison of left ventricular ejection fraction and volumes in heart failure by echocardiography, radionuclide ventriculography and cardiovascular magnetic resonance. Are they interchangeable? Eur Heart J 2000;21:1387-96.

Reviewed by Robert Donnino MD, NYU Division of Cardiology:

The case report and discussion provided by Dr. Ghumman highlights some of the important uses of CMR in patients with ischemic cardiomyopathies.  In this case the CMR provided several important pieces of information relevant to this patient’s care. First, by the distribution of myocardial scar (seen as LGE on CMR) we can confirm with high confidence that this patient’s cardiomyopathy is ischemic in etiology.  In addition, the presence of only mild scar (as opposed to transmural or near-transmural scar) indicates that this patient is very likely to have a significant improvement in left ventricular function after revascularization in all three major coronary vessel distributions.  As mentioned, this assessment of viability using CMR has been proven to be very reliable and is being used with increasing frequency in patients undergoing coronary revascularization (particularly in those being considered for bypass surgery). While it was not possible in this patient due to motion artifact, CMR can also provide an assessment of coronary stenosis, particularly of the proximal and larger vessels. Although there is continuing progress, CMR remains somewhat inferior to CT angiography and invasive x-ray angiography for detection of coronary stenosis, particularly of distal arteries and smaller caliber vessels.  Finally, CMR is considered the gold standard for measurements of left ventricular ejection fraction and chamber volume.  This may further assist the clinician in determining therapies such as biventricular pacemakers or cardiac defibrillators, particularly in those patients with technically challenging echocardiograms.

Meeting Perspectives: American Heart Association Scientific Sessions 2008- Report from the cardiology fellows

December 16, 2008

heart.jpgCommentary by Steven Sedlis, MD Associate Professor of Medicine, Chief, Division of Cardiology Manhattan Veterans Administration Medical Center

The annual scientific session of the American Heart Association was held in New Orleans on November 8-12 2008, the second major cardiology meeting in New Orleans since Katrina. The city has obviously not recovered. The crowds on the streets are sparser and the lines at restaurants considerably shorter than they were before the hurricane. Charity Hospital is closed and a large sign for LSU Interim Hospital is a stark reminder that the health care system is also nowhere near back to normal.

It was hard to feel gloomy however under the blue skies with the temperature in the 70s. The cardiology fellows certainly enjoyed themselves a great deal. The fellows stayed at the JW Marriott on Canal Street, halfway between the convention center and the heart of Bourbon Street. Either way, they were at the heart. I can attest to that, having seen them at the meetings and having heard about all the fine dinners they enjoyed in the French Quarter. This posting will include accounts of the studies that the cardiology fellows thought were particularly interesting or important.

The big news from AHA was the JUPITER trial presented as a late breaking trial on Sunday and simultaneously published online in the New England Journal of Medicine. Eldad Einav presented the trial to our cardiology division and Tatyana Danilov presented the paper at journal club . JUPITER, a randomized trial of rosuvastatin in the prevention of cardiovascular events among 17,802 apparently healthy men and women with elevated levels of C – reactive protein (hsCRP) was an investigator initiated trial funded by Astra- Zeneca that compared outcomes in men over the age of 50 and women over the age of 60 with LDL cholesterol levels < 130 and hsCRP > 2 mg/dl randomized to rosuvastatin 20 mg or placebo. The study was stopped prematurely by the data safety monitoring board after a mean follow-up of less than 2 years because the pre-specified endpoint of first major cardiovascular event or death from any cause was met. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval 0.46 to 0.69; P<0.00001). As Paul Ridker, the principal investigator, pointed out in his late breaking trial presentation these data suggest that the number of patients needed to treat with rosuvastatin for 5 years to prevent one event is as low as 25.

JUPITER has sparked considerable controversy. Many have pointed out that Paul Ridker and Harvard hold a patent for the hsCRP assay. Does this financial incentive bias Ridker’s interpretation of the data? Others have pointed out that by stopping the trial early the data safety monitoring board may have overestimated the degree of benefit. On the other hand, many others (particularly in the field of prevention) say they would have prescribed statins to patients such as the ones enrolled in JUPITER irrespective of the hsCRP. So will JUPITER change practice? Will it change yours? A not particularly scientific survey of nearly 2500 physicians who responded to a poll in the New England Journal of Medicine indicated that the medical community is split nearly down the middle with 50% of respondents saying that the trial indicates that the approach to laboratory screening should be changed. Another 48% of voters responding to a second question thought that the trial provides a basis for a change in the therapeutic use of stains.

My own view is that JUPITER is an important study because it shows that 20 mg of rosuvastatin is a well tolerated and safe dose of a potent statin that will benefit many individuals at risk for atherothrombosis. There was no difference in the side effect profile of rosuvastatin and placebo except for a slight difference in glycemic control favoring placebo. My own bias is that difference is not clinically significant, but obviously some will differ. The importance of statin dose was underscored by a negative study presented at the AHA. The SEARCH trial randomized 12,000 patients with prior myocardial infarction to either 20 mg or 80 mg of simvastatin and found a non significant 6% reduction in vascular events with the higher dose at the cost of significantly more cases of myopathy (53 versus 3). In my view this was a predictable, but instructive finding. The Heart Protection Study showed that 40 mg of simvastatin was a safe and effective dose so I am sure that many patients in SEARCH randomized to the low dose ended up on 40 mg when they or their physicians noted suboptimal control of LDL. On the other hand, 80 mg of simvastatin is not a well tolerated dose and is associated with significant side effects. What this means to practitioners is that for most patients 40 mg of generic simvastatin is cost-effective treatment with 20 mg of rosuvastin or 80 mg of atorvastatin available for patients who do not reach goal with simvastatin and 40 mg of rosuvastatin reserved for patients who require the most potent statin. JUPITER did not address the higher dose of rosuvastatin, but taken together with other trials notably PROVE-IT, TNT, IDEAL and A to Z there is a growing body of evidence to suggest that intensive LDL lowering with statins is beneficial and now JUPITER confirms that 20 mg of rosuvastatin is a safe and effective means of achieving this goal.

Alex Natanson presented the findings of TIMACS (Timing of Intervention in Patients with Acute Coronary Syndromes). This was probably my favorite study from AHA because the findings mean that when I get a call about an ACS admission at night I can with a clear conscience and a happy heart go back to bed for a nice long snooze before I come to the hospital in the morning and take the patient to the cath lab. Now I am, and I hope you are too, a confirmed believer in an early invasive approach for most patients with ACS. The question is what does “early” mean? The TIMACS investigators randomized 3031 patients admitted with ACS to early angiography (within 24 hours) versus delayed angiography (greater than 36 hours) following hospital admission. The median time to cath was 14 hours for the early group and 50 hours for the delayed group. There was no significant difference in the primary endpoint of death, MI or stroke. Not surprisingly, there was a difference in the secondary endpoint of refractory ischemia requiring urgent cath. Clearly patients in the delayed group had more time when they were at risk for refractory ischemia than the early group that had undergone cath and revascularization. TIMACS did show benefit to early cath in their very high risk subgroup with ongoing ischemia or hemodynamic instability, but these are patients who most practitioners would take for early cath. A very important conclusion of TIMACS is that there is no benefit to waiting. There is no need to “cool down” patients – the same finding as in ISAR-COOL which showed no benefit and even harm from a strategy of intensive antiplatelet therapy for 72-120 hours prior to cath and intervention. So the moral is: don’t rush, but don’t delay – get your patient to the cath lab by the end of the day.

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Breaking News: The Jupiter Trial

November 12, 2008

jupiter.jpgCommentary by Ilana Bragin MD, PGY-3

This week online in the NEJM, the results of a trial known as Jupiter were presented in an article that will likely change the way we approach cardiovascular health protection. The Jupiter trial attempts to answer this perturbing question: “Why do half of all myocardial infarctions and strokes occur in apparently healthy men and women with levels of LDL that are below currently recommended thresholds of treatment?” The study addresses the biomarker C-reactive protein, an inflammatory marker that has long been linked to an increased risk of adverse cardiovascular events. While cholesterol has been a target for decreasing cardiovascular risk, physicians have known less what to do about elevated CRPs, using it more as a harbinger of trouble, than as an indication for action. Statins have been previously shown to decrease levels of CRP as well as lipids, and the magnitude of the benefit of statin therapy is known to be in part due to its lowering of CRP. However, while we have guidelines for lowering cholesterol, lowering CRP alone has not been a target of therapy. The study, sponsored by AstroZeneca, thus took individuals who did not have elevated LDL by current treatment guidelines, but did have elevated CRP, treated them with a statin, and then monitored them for cardiovascular events.

More specifically, 17,802 patients with low LDL levels <130mg/deciliter and high sensitivity C-reactive proteins 2.0 mg/liter or higher, were randomized to receive either 20 mg of rosuvastatin daily or placebo. Men above the age of 50 and women above the age of 60 with these criteria were eligible. Patients with a history of cardiovascular disease were excluded. Also excluded were patients on hormonal therapy, with evidence of liver disease, with an elevated CK or elevated Cr (Cr>2), patients with diabetes, uncontrolled hypertension, cancer (other than basal or squamous skin cancer) within 5 years of enrollment, uncontrolled hypothyroidism, recent drug or alcohol history, or any patients with inflammatory conditions, such as lupus, severe arthritis, or inflammatory bowel disease as well as anyone taking immunosuppressive medications or long term glucocorticoids.

The study results were impressive. Although the study was designed to be continued for 5 years or until a primary cardiac event; namely myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes; when a prespecified interim efficacy analysis was performed after less than 2 years, the trial was terminated given the markedly beneficial results of the statin.

After 1 year of therapy, as compared with the placebo group, the rosuvastatin group had a 50% lower average LDL and a 37% lower CRP level. At the time of the termination of the study, 142 first major cardiovascular events had occurred in the rosuvastatin group as compared with 251 in the placebo group. Rosuvastatin also decreased the number of deaths from any cause (hazard ratio for the rosuvastatin group, 0.80; 95% CI, 0.67 to 0.97; P=0.02) With Kaplan-Meir estimates, the number of patients needed to treat with rosuvastatin for 2 years in order to prevent one primary endpoint is 95, and if the risk is projected over a 5 year period, the number needed to treat to prevent the occurrence of one primary endpoint, is 25.

Given that few adverse events occurred with the rosuvastatin group (increased physician-reported diabetes was reported in the rosuvastatin group; although there were no significant elevations of fasting blood glucose and only minimal differences in HgA1c), this could significantly impact how we risk stratify patients and subsequently initiate treatment with statins for cardiovascular prevention.

Some questions remain to be addressed. Does this study mean we should test for CRP levels in all patients, even those who have no other cardiovascular risk? Should the test only be initiated in individuals above the age criteria in this trial (men >50, women>60)? And given that cardiovascular disease is such a multifactorial illness (obesity, HTN, smoking, cholesterol, all play a part), how does CRP, when looked at alone without the other risk factors, fit in? Also, the study, in addition to cutting CRP levels, also cut down LDL from low levels to even lower levels—perhaps that effect is greater than the effect of the lower CRP? And lastly, perhaps this study paved the way for looking more at the inflammatory nature of heart disease, and potentially the benefit of other anti-inflammatory medications on lowering heart disease.

Mystery Quiz- The Answer

November 8, 2008

Posted by Vivian Hayashi MD and Robert Smith MD, Mystery Quiz Section Editors

The answer to the mystery quiz is heart failure.  The CXR shows bibasilar opacities with hilar fullness on the right. The CT images are remarkable for bilateral effusions, with dependent opacities that increase in density along the anterior-posterior axis.  The lung appears clear in the anterior zone (Image 5, arrow; Coronal Image 1); ground glass opacification, characterized by parenchymal haziness which does not obscure the underlying pulmonary vessels, is evident in the mid lung (Image 5, double arrows; Coronal Image 2); and consolidation with air bronchograms is evident in the posterior areas (Image 5, arrowhead; Coronal Image 3).  The coronal images show the same increase in density along the anterior-posterior axis (Coronal Images 1-4).  Although the same density gradient of parenchymal fluid may be seen in non-cardiogenic pulmonary edema, the presence of bilateral effusions makes cardiogenic edema much more likely.

 

The mediastinal windows demonstrate adenopathy in precarinal, subcarinal and hilar areas (Image 6A, Image 7B and 7C, respectively).  The fact that enlarged mediastinal and hilar lymph nodes may accompany congestive heart failure was not appreciated until relatively recently (Slanetz PJ et al.  Mediastinal lymphadenopathy and hazy mediastinal fat: new CT findings of congestive heart failure. Am J Roentgenol 1998; 171: 1307-09).   Animal models indicate that enlarged nodes do not result simply from increased flow through interstitial lymphatics.  An additional requirement is that the efferent draining lymphatic vessels empty into a vein that has an elevated pressure (>15cm H2O), as may occur in heart failure, but less likely to occur in cases of non-cardiogenic pulmonary edema. High venous pressures slow lymphatic outflow and contribute to proximal lymph node enlargement.  The few reported biopsies of such nodes show an absence of inflammation, benign sinus histiocytosis, and slight follicular hyperplasia.

 

The CT images six days later show remarkable resolution of the airspace opacification after diuresis, along with a significant decrease in the lymphadenopathy (Images 6 and 7).  We present this case to highlight an underappreciated cause of reversible lymphadenopathy and review the image findings of pulmonary edema, herein due to hypertensive heart disease.

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Grand Rounds: “Novel Applications of Erythropoietin in Cardiovascular Disease”

October 22, 2008

Bellevue Amphitheater

Commentary by Srikant Duggirala MD, PGY-2

Please also see the clinical vignette presented during this week’s grand rounds

 

On Wednesday, October, 15, 2008, the NYU Department of Medicine Grand Rounds featured one of its own guest speakers, Stuart Katz M.D., Professor of Medicine and Director of Heart Failure at NYU School of Medicine, with his lecture entitled “Novel Applications of Erythropoietin in Cardiovascular Disease.”

Dr. Katz began his lecture with a discussion of oxygen uptake in a various individuals such as elite athletes and comparing their oxygen uptake ability to average individuals and also to heart failure patients. An elite athlete such as Lance Armstrong has an average maximum oxygen uptake 82ml/kg/min and this is compared to an average person who has an average maximum oxygen uptake of 36ml/kg/min and a heart failure patient who has an average maximum oxygen uptake of 12ml/kg/min. Utilizing the Fick equation (VO2 = COmax * (Arterial O2 sat. – Venous 02 sat.), it has been shown that patients with heart failure have increased ability to extract O2 more effectively than the average person. This is usually due to decreased capillary bed transit time and also due to increased erythropoietin levels.

Dr. Katz continued his discussion with the role of erythropoietin in heart failure and its potential use in patients with acute myocardial infarctions. Erythropoietin increases red cell mass and has been shown to increase the aerobic oxygen capacity in patients with heart failure. Additionally, molecular studies have shown that erythropoietin has a role in anti-apoptotic effects on cellular function and also induces expression of angiogenic signaling proteins. Studies have shown that erythropoietin receptors are upregulated in ischemic tissue, suggesting a protective role of erythropoietin during ischemic injury of myocardial tissue. While percutaneous coronary intervention has been shown to decrease the amount of tissue necrosis, erythropoietin has shown a decrease in the levels of apoptosis.

Some of the initial studies in rabbit hearts with the use of recombinant human erythropoietin (rHuEpo) have shown as much as a 60% decrease in infarct size and as much as 50% decrease in apoptotic signaling. In a 2006 study with canines, Epo was given at both 0 hours and at 6 hours. Again, Epo showed promising results with increased neovascularization.

The use of erythropoietin in clinical use has not been without significant controversy. It was a very aggressively marketed medication for treatment of anemia in chemotherapy patients for many years until studies suggested an increased risk of thrombosis in this patient population. The mechanism for increased risk of thrombosis is not entirely clear, but presumed to be at least one several mechanisms including increased red blood cell mass, increased platelet count, increased platelet aggregation and increased endothelial cell activation. Additionally, erythropoietin has been implicated with increased risk of hypertension and also promotion of tumor growth in cancer patients. It is important to highlight that these findings have been studied in cancer patients with long term use of erythropoietin. These findings have not been substantiated in the general population with short term use.

Dr. Katz continued his talk by discussing some of his research study findings with the erythropoietin in patients. His first study looked at the short term affects of erythropoietin and its affects in normal patients. The study utilized three different doses (100mg/kg x3day, 200mg/kg x3day, 400mg/kg x3 days) and a placebo group. All groups were also given high dose aspirin and plavix. The study concluded that high dose Epo was attributed to elevated platelet counts and also attenuated the effects of aspirin. It was presumed that the 200mg/kg dose was safer since these same side effects were not observed. Dr. Katz and his team followed up that study with another small study which showed on echocardiograms, patients had both a decreased left ventricular diastolic and systolic volume compared to placebo after ten days of receiving RhuEPO (Recombinant human erythropoietin). Dr. Katz concluded his discussion by describing a multi-center trial that is now beginning utilizing the erythropoietin in the acute management of STEMI. The initial studies look promising and this study will help define whether or not erythropoietin has a role in the management of acute myocardial infarctions.

Grand Rounds: Thyroid Disease and the Heart

September 24, 2008

Bellevue Amphitheater Commentary by Sarika Modi MD, PGY-2  

Dr. Irwin Klein MD, Professor of Medicine and Cell Biology, of North Shore University Hospital, gave grand rounds on “Thyroid Disease and the Heart” on September 17, 2008.  He began his talk by giving an overview of the broad spectrum of cardiac manifestations seen in hyperthyroidism.  Palpitations are seen in 90% of patients with hyperthyroidism.  Atrial fibrillation is seen in 5-15%, especially in the elderly.  In fact, as Dr Klein pointed out, former president George Bush Senior was diagnosed with Graves’ disease after he was found to be in atrial fibrillation after an episode of shortness of breath while jogging.   Hyperthyroidism in young women can present with angina, but subsequent cardiac catherization will typically reveal normal coronary arteries.  The mechanism of the angina is thought to be vasospasm, similar to Prinzmetal’s angina and migraine headaches.

85% of thyroid hormone produced by the thyroid gland is in the form of T4, but the biologically active form is T3 which arises by peripheral deiodination in the liver and skeletal muscle.  The cardiovascular effects of thyroid hormone include increased heart rate, increased ejection fraction, increased cardiac output (by 150-200%), muscular hypertrophy of the heart, and a fall in systemic vascular resistance.  T3 acts directly on vascular smooth muscle to relax it and decrease systemic vascular resistance.  The kidney senses a decrease in effective arterial volume and activates the renin-angiotensin-aldosterone system, leading to expansion of plasma volume.  The end result is an elevated systolic pressure, a decreased diastolic pressure, with a widened pulse pressure and expanded plasma volume (see Klein NEJM 2001). 

T3 also has a direct effect on transcription in the cardiac myocyte, leading to increased expression of many genes that enhance cardiac contractility, most notably myosin alpha chains and SERCA-2 (a sarcolemmal calcium channel).  In a study of Dr. Klein’s using rat models where an additional “heterotopic” non-functional heart was transplanted into the animal’s circulation in addition to the animal’s own native heart, administration of T4 stimulated left ventricular hypertrophy in the “in-situ” heart, but not in the heterotopic one.  This shows while T3 has direct effects on transcription, the remodeling associated with the heart in hyperthyroidism is dependent on being within a working cardiovascular system. 

Hyperthyroidism also leads to shortened isovolumic relaxation time (the period in cardiac cycle where the ventricular muscle is relaxing prior to filling and where calcium is being actively taken up by the sarcoplasmic reticulum), which in turn leads to increased diastolic flow and a shortened period of isovolumic relaxation  reflecting enhanced diastolic function..  This effect cannot be accounted for simply by the tachycardia seen with hypothyroidism.  Patients with untreated Graves’ disease who were given two weeks of beta blockade to normalize their heart rates continued to have shortened isovolumic relaxation times.  The relaxation time only normalized with anti-thyroid therapy and return to the euthyroid state.  This suggests that there is a direct effect of T3 on the heart through the transcriptional effects described above that is independent of beta-adrenergic tone (See Klein in Braunwald Heart Disease Text 2008).

Dr. Klein then addressed the paradox of hyperthyroidism being a state of elevated cardiac output and hyperdynamic physiology, and patients presenting in heart failure, such as our clinical vignette patient.  In these patients, underlying heart disease should be ruled out.  However, there is also rate-related left ventricular dysfunction, often related to atrial fibrillation, which is often completely reversible once the heart rate is restored to normal.  Hyperthyroidism may also lead to right-sided failure, as increased plasma volume leads to increased flow in the pulmonary vascular beds, leading to pulmonary hypertension and remodeling of the right ventricle in response to higher pressures.

Primary therapy for the hyperthyroidism with cardiovascular complications includes beta blockers (often high doses i.e. propanolol 3-4 times a day) to normalize heart rate and radioactive iodine therapy to return the patient to a euthyroid state.  The speaker also cautioned against the use of intravenous calcium channel blockers in those patients that are otherwise healthy who present with supraventricular tachycardia.  In patients with hyperthyroidism, they can further reduce systemic vascular resistance and can cause patients to go into hypotensive arrest.  The hypotension is responsive to fluids, but it may be worthwhile to consider the diagnosis of hyperthyroidism and check a TSH to exclude thyrotoxicosis prior to the administration of intravenous calcium channel blockers in the setting of supraventricular tachycardias.  Anticoagulation in hyperthyroid patients with atrial fibrillation is not indicated, as most patients will revert to sinus rhythm once their thyroid disease is treated.  It is only indicated for those patients that have another indication for anticoagulation, such as underlying valvular or ischemic heart disease. 

To summarize: 1) Atrial fibrillation from hyperthyroidism is seen most commonly in the elderly and it is not an indication for anticoagulation.  2) T3 directly affects the cardiac myocyte and the vascular smooth muscle cells, leading to increased contractility of the heart, muscle hypertrophy in a working heart, and decreased peripheral vascular resistance.  3) Normalization of the isovolumic relaxation time is a reliable indicator of return to a euthyroid state and is independent of beta-adrenergic blockade.  4) Hyperthyroid related heart failure may be related to underlying heart disease, a rate-dependent left ventricular dysfunction, or right heart failure secondary to pulmonary hypertension.  5) Beta blockade and radioactive iodine therapy are cornerstones for therapy.  Be cautious with IV calcium channel blockers in thyrotoxic patients as they may further decrease systemic vascular resistance and lead to hypotensive arrest.

The Q&A session ended with a brief mention of Dr. Klein’s new research regarding congestive heart failure patients who have been found to have low T3 levels due to impaired peripheral conversion of T4 to T3.  Stay tuned for new evidence suggesting that T3 supplementation in these patients can improve clinical outcomes (See Klein and Danzi J Clin Endo Metab 93, 2008).

Perioperative Beta-blockade: Will POISE Change Management?

September 10, 2008

180px-das_ordinationszimmer_des_chirurgen.jpgCommentary by Michael LoCurcio MD, Michael Janjigian MD and Michael C Brabeck MD, FACP, NYU Division of General Internal Medicine

Cardiovascular complications continue to be a major cause of morbidity and mortality in the perioperative period. Although progress has been made in terms of risk stratification, an effective invasive or pharmacologic intervention that decreases this risk remains elusive. Well designed studies have shown that prophylactic invasive measures are not effective in decreasing this risk, leaving clinicians uncertain as to the best way to maximize the physiology of the patient in the perioperative period.

Enthusiasm for perioperative ß-blockade is based on two landmark studies. About twelve years ago Mangano (1) randomized 200 patients with or at risk for cardiac disease undergoing general noncardiac surgery to atenolol or placebo in the immediate perioperative period and demonstrated a significant reduction in mortality at 6 months (0% vs. 8%), 1 year (3% vs. 14%) and 2 years (10% vs. 21%) favoring atenolol. Subsequently, in the DECREASE trial (2), Poldermans randomized 112 patients with an abnormal dobutamine stress echo undergoing major vascular surgery to bisoprolol or placebo and showed a remarkable decrease in cardiovascular death (3.4% vs. 17%) favoring the ß-blocker group. Both trials were limited by small sample sizes and methodological flaws and these impressive results have not been reproduced in subsequent studies.

Additional trials supporting ß-blockade in the perioperative period have generally been limited to observational and retrospective reviews. Lindenauer (3) analyzed a multicenter administrative database of patients undergoing noncardiac surgery, stratified by the RCRI score, and found an increased risk of death in patients receiving ß-blockers in the lowest risk group with a stepwise decrease in risk actually favoring ß-blockers in patients with an RCRI score of 3 or greater. In DECREASE II (4), Poldermans studied intermediate-risk patients undergoing intermediate-risk surgeries, giving all patients ß-blockers with HR titration, to determine if routine stress testing improved outcomes. While not demonstrating a benefit to routine stress testing, patients with heart rates less than 65 bpm had lower risk than the remaining patients.

A comprehensive systematic review and meta-analysis of published RCT’s of ß-blockers published in the BMJ in 2005 concluded that while ß-blocker use may decrease the incidence of perioperative cardiac events, it did so at the expense of an increased incidence of hypotension and bradycardia requiring treatment(5).

More recently, three randomized trials of patients undergoing vascular surgery (MaVS6 and POBBLE7) and diabetics undergoing noncardiac surgery (DIPOM8) have all shown no benefit to the addition of ß-blockers in the perioperative period.

In October, 2007, the American College of Cardiology/American Heart Association updated its recommendations for perioperative care of patients requiring non-cardiac surgery (9). While acknowledging the lack of robust data, the committee considered the following recommendations to be reasonable for perioperative ß-blockade:

1. Use the RCRI score to determine the patient’s pre-operative risk category.
2. Low risk patients: do not use ß-blockers perioperatively, unless the patient is already taking them.
3. Intermediate risk patients: unclear if ß-blockers are harmful or beneficial.
4. High risk patients facing vascular procedures, especially those with inducible ischemia on pre-operative testing: the perioperative use of ß-blockers is probably beneficial (Class I B).
5. High risk cardiac patients facing intermediate risk surgery: ß-blockers are probably recommended (Class IIa B)
6. Low, intermediate, and high risk patients: continue ß-blockers in the perioperative period if the patient was already on them. (Class I C)
7. Begin ß-blockers several days to weeks before surgery, if possible. Aim for a HR in the low 60’s, and continue for at least one week post-op.
8. Overall, ß-blockers may decrease perioperative cardiac events, but they increase hypotension and bradycardia, which often may need treatment.
9. The use of cardioselective ß-blockers (currently metoprolol or atenolol) in patients with COPD or hyper-reactive airway disease is probably safe.
10. ß-blockers should be started with caution in patients with HF and not at all in patients with second or third degree HB.

Shortly following these recommendations, the results of the much anticipated POISE trial became available (10). In an attempt to further assess the impact of perioperative ß-blockade, the PeriOperative ISchemic Evaluation (POISE) trial randomly assigned 8351 patients undergoing noncardiac surgery to receive long acting metoprolol succinate or placebo starting preoperatively and continued for the next 30 days. This study, the results of which were presented at the American Heart Association meeting in October, 2007, and published online in May in the electronic version of the Lancet, is the largest randomized controlled study to date on the use of perioperative ß-blockers. The results confirmed that the primary endpoint of non-fatal myocardial infarction, cardiac arrest, or death from a cardiovascular cause was decreased in the group treated with metoprolol compared to placebo (5.8% vs. 6.9%, P=0.040). This “benefit,” however, was driven by non-fatal myocardial infarction and was offset by an increase in 30 day overall mortality (3.1 % vs. 2.3%, P=0.032) and increased number of strokes (1% vs. 0.5%, P = 0.005) in the group receiving metoprolol. Hypotension (15% vs. 9.7%, P = 0.0001) and clinically significant bradycardia (6.6% vs. 2.4%, P = 0.03) were also more common in the treatment group. Unexpectedly and somewhat strangely, there appeared to be a statistically significant increase in the number of patients who died from sepsis (27.9% vs. 18.6% of deaths in each group, P = 0.016) in the group receiving metoprolol.

Although the study was well designed and executed (centers in Colombia and Iran were excluded due to concerns of fraudulent data), it is important to note areas of potential bias. Many of the patients included in the study were at relatively low risk for cardiovascular complications and would not be given ß-blockers based on the current ACC/AHA guidelines. Furthermore, the dose of metoprolol was rather high (metoprolol 100 mg extended release tablets were given twice daily or 15 mg intravenously Q6H for those unable able to tolerate oral medication), and were most often started immediately prior to surgery (between 2-4 hours). Patients who were thought to require ß-blockers (and thus may have been most likely to benefit and tolerate the drug) by their doctor were excluded from the study, and patients with a relatively low HR (above 50 bpm) were included in the study. Finally, by pre-specifying ten secondary outcomes and accepting p<=0.05 as statistically significant, the likelihood of a Type I error is substantial.

Will this study change management of the patient in the perioperative period? We think not. The patient population, the dose and the timing of the ß-blockers given in POISE are significantly different than current practice thus making generalization of its results and conclusions problematic. Although POISE does not directly address the issue, it is reasonable to continue ß-blockers throughout the perioperative period in those patients who are already tolerating this type of therapy. The initiation of ß-blockers in the perioperative period should be limited to those with relatively high cardiovascular risk, should be initiated early, if possible, and with the intent to titrate the dose for a goal HR around 60 BPM.

POISE is now being “fast tracked” for publication in Lancet and our expectation is that we have not heard the last about it. The final chapter on the perioperative use of ß-blockade has yet to be written.

1. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med. Dec 5 1996;335(23):1713-1720.
2. Poldermans D, Boersma E, Bax JJ, et al. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med. Dec 9 1999;341(24):1789-1794.
3. Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B, Benjamin EM. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med. Jul 28 2005;353(4):349-361.
4. Poldermans D, Bax JJ, Schouten O, et al. Should major vascular surgery be delayed because of preoperative cardiac testing in intermediate-risk patients receiving beta-blocker therapy with tight heart rate control? J Am Coll Cardiol. Sep 5 2006;48(5):964-969.
5. Devereaux PJ, Beattie WS, Choi PT, et al. How strong is the evidence for the use of perioperative beta blockers in non-cardiac surgery? Systematic review and meta-analysis of randomised controlled trials. BMJ. Aug 6 2005;331(7512):313-321.
6. Yang H, Raymer K, Butler R, Parlow J, Roberts R. The effects of perioperative beta-blockade: results of the Metoprolol after Vascular Surgery (MaVS) study, a randomized controlled trial. Am Heart J. Nov 2006;152(5):983-990.
7. Brady AR, Gibbs JS, Greenhalgh RM, Powell JT, Sydes MR. Perioperative beta-blockade (POBBLE) for patients undergoing infrarenal vascular surgery: results of a randomized double-blind controlled trial. J Vasc Surg. Apr 2005;41(4):602-609.
8. Juul AB, Wetterslev J, Gluud C, et al. Effect of perioperative beta blockade in patients with diabetes undergoing major non-cardiac surgery: randomised placebo controlled, blinded multicentre trial. BMJ. Jun 24 2006;332(7556):1482.
9. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery. J Am Coll Cardiol. Oct 23 2007;50(17):1707-1732.
10. Devereaux PJ, Yang H, Yusuf S, et al. Effects of extended-release metoprolol succinate in patients undergoing non-cardiac surgery (POISE trial): a randomised controlled trial. Lancet. May 31 2008;371(9627):1839-1847.

Image of  the surgeon’s consultation room, a painting by Balthasar van den Bossche, courtesy of Wikipedia.

Case Presentation: Acute Rheumatic Fever

August 29, 2008

streptococcus_pyogenes.jpgCommentary by Bani Chander MD, PGY-3. and Ben Bergman MD, PGY-3

Please also see last week’s Class Act Post on the pathogenesis of Rheumatic Heart Disease 

A 34-year-old Hispanic male presents with the chief complaint of chest pain. The patient had been well until 10 days prior to admission, when he developed a severe sore throat accompanied by fever, rigors, and diffuse myalgias. There was no associated cough. Three days later, he visited his primary care physician at an outside facility and was prescribed penicillin 500 mg twice daily for presumed streptococcal pharyngitis. Five days later, he presented to the emergency room of an outside hospital and stopped his antibiotics after a throat culture there was negative for beta-hemolytic strep. The following morning, the patient awoke in the middle of the night with severe left-sided chest pain and presented again to his local emergency room. The patient described a sensation of left-sided chest pressure which became worse when lying down and somewhat improved upon sitting up.

An electrocardiogram was done and revealed ~2mm ST segment elevations in II, III, aVF, and V3-V6; the initial troponin was 14.7. A diagnosis of an ST-elevation myocardial infarction was made and alteplase was administered for thrombolysis. He was also given intravenous unfractionated heparin, aspirin, clopidogrel, metopolol, simvastatin, and sublingual nitroglycerin. The patient had transient relief of his chest pain after these medications but the pain recurred a few hours later. Given his persistent chest pain and ST segment elevations despite thrombolytics, he was transferred to Bellevue for cardiac catheterization.

Upon admission to the CCU, the patient was febrile to 100.8◦ and was still having persistent chest pain but had no associated dyspnea, palpitations, nausea, vomiting, or diaphoresis. An electrocardiogram showed persistent 2 mm ST elevations in leads II, aVF, and V3-V6 with diffuse PR segment depression and a normal PR interval. On physical examination, he was a well-appearing male in no distress. He had enlarged tonsils but no exudates; a single 0.5 cm tender left anterior cervical lymph node was palpable. There was no jugulovenous distension. The cardiac exam did not reveal any murmurs, rubs, or gallops, and the PMI was non-displaced. His pulmonary, musculoskeletal, dermatologic, and neurologic exams were all unremarkable.

The patient underwent cardiac catheterization on the first day of admission. The coronary arteries were angiographically normal. The anteroapical, apical, and inferoapical walls were hypokinetic, with an estimated ejection fraction of 45 %. The patient was continued on aspirin, clopidogrel, and metoprolol and started on lisinopril and simvastatin. A cardiac MRI was performed, revealing inflammation of the myopericardium, decreased left ventricular systolic function, and no significant valvular regurgitation or lesions. Transthoracic echocardiography showed a normal ejection fraction with apical and inferior wall hypokinesis, with mild mitral and tricuspid insufficiency.

Laboratory testing was remarkable for a leukocyte count of 27.6 and a troponin of 12.7. A serum anti-streptolysin-O antibody was sent and returned as 1541 IU (normal < 200). Tests for echovirus, parvovirus, and coxsackie virus were all negative. Hepatitis serologies and HIV testing were also negative. His TSH was normal at 1.9. Epstein-Barr virus IgM was negative, while IgG was positive. The erythrocyte sedimentation rate was 48 and the C-reactive protein was 83. Over the hospital course, the ASO titer increased to 2982 IU. The patient was started on penicillin G and high-dose aspirin for presumed acute rheumatic fever. After two days, the patient developed mild epigastric pain despite the concurrent use of a proton-pump inhibitor, and high-dose aspirin was discontinued. A repeat transthoracic echocardiogram 5 days after the initial TTE showed improved left ventricular wall motion, and the patient was discharged home with instructions to receive monthly intramuscular injections of penicillin G benzathine 1.2 million units for five to ten years. Prior to his discharge, contact with his outside primary care physician confirmed that his initial culture prior to starting antibiotics was positive for group A beta-hemolytic streptococcus.

Discussion:
Acute rheumatic fever (ARF) is a delayed, non-suppurative sequela of infection with group A beta-hemolytic streptococci or Streptococcus pyogenes. The acute phase of ARF is caused by a proliferative inflammatory reaction that involves the connective and/or collagen tissues and commonly affects the heart, joints, brain and subcutaneous tissues, although any organ may be involved.1

The concept of “rheumatogenicity” came from the observation that only certain strains of Group A streptococcus were associated with acute rheumatic fever. The observed strains include the M serotypes 1, 3, 5, 6, 14, 18, 24, 27, and 29; however, given the genetic diversity among strains, any group A streptococcus may acquire the potential to cause acute rheumatic fever.2 An estimated 60% of cases of acute rheumatic fever lead to rheumatic heart disease, which carries an annual mortality of 1.5% without medical treatment.3 Worldwide it is estimated that the prevalence of RHD is at least 15-20 million with 233,000 deaths per year.

In 1944, Duckett Jones published his famous “Jones Criteria,” which in its updated form is the basis of the current approach to acute rheumatic fever. The diagnosis is made with evidence of a preceding group A streptococcal (GAS) infection (either positive culture or rapid streptococcal antigen test or elevated or rising streptococcal antibody titer) with the presence of two major or one major and two minor criteria (see table 1). The measurement of antistreptolysin-O antibody has become the definitive biochemical test to document the presence of antecedent GAS infection. In patients with acute infection due to GAS, the ASO antibody titer can be elevated after one week, reaching maximal levels in 3 to 5 weeks, and in the absence of re-infection or treatment failure typically falls to pre-infection levels in 6 to 12 months.5,6

Acute rheumatic fever is generally considered to be a disease of the young, although varying age ranges have been published, with case reports of the initial syndrome in adults as old as 38 years. The introduction of antibiotics has lead to a rapid decline in the incidence of ARF and in the United States the incidence following a streptococcal pharyngitis infection has decreased from 100 per 100,000 people at the beginning of the 20th century, to less than 2 per 100,000 at the present time.7 Worldwide the incidence is estimated at 0.23-1.88 patients per 100,000, and in children of Polynesian ancestry in Hawaiian and Maori populations, the incidence is still up to 13.4 patients per 100,000 hospitalized children per year.8

Table 1: The Revised Jones Criteria9
Major criteria
Carditis
Polyarthritis
Chorea
Erythema marginatum
Subcutaneous nodules

Minor criteria
Clinical
Arthralgia
Fever

Laboratory
Elevated erythrocyte sedimentation rate, C reactive protein
EKG
First degree atrioventricular block

Treatment of GAS infection has resulted in a dramatic decrease in the incidence of rheumatic heart disease in the United States. The disease persists with significantly higher incidence and morbidity in many countries with less access to diagnostic testing and antibiotics. While the management of rheumatic heart disease and the prevention of rheumatic fever are key medical successes of the twentieth century, active rheumatic carditis remains poorly understood and relatively untreatable.

There are few proven therapies for acute rheumatic fever and the treatment of rheumatic carditis is even more limited. Carditis occurs in ~50% of patients with ARF and may involve the pericardium, myocardium, or the valve cusps. It can cause permanent damage to the heart valves and may result in death even years after the initial presentation of carditis. This particular patient was treated in the hospital with penicillin G in order to treat the underlying streptococcal infection; however, given that rheumatic carditis is presumed to be an inflammatory disease, we conducted several investigations looking into therapies for treatment including steroids, immunoglobulin, and salicylates.

A recent Cochrane review of treatment with steroids or immunoglobulin for patients with rheumatic carditis failed to show a reduction in cardiac complications at one year.10 Treatment with salicylates and steroids in acute rheumatic fever still remains relatively controversial. Use of high dose salicylates has been studied and there is some evidence that they may reduce symptoms acutely; however, there is no improvement in long-term clinical or cardiac outcomes.11,12 Some physicians recommend treatment with aspirin at a dose of 75 mg/kg/day; however, this dose has only been studied in children and there are no available data with adults. In the US-UK trial of 49 patients aged 16 or less with acute rheumatic fever, treatment with a 12-week course of salicylates versus bed rest showed no apparent difference between them either during their hospital stay or at five- year follow-up. Not only was treatment with salicylates ineffective in controlling disease activity, but it may have been potentially harmful.11 The suggested daily aspirin dose of 75 mg/kg resulted in gastritis in our patient. Data are limited regarding the use of salicylates other than aspirin.

Ultimately, although the prevalence of rheumatic heart disease is significantly lower in recent years, the implications of treatment for active rheumatic carditis on the development of valvulitis and subsequent valvular sequelae still remain poorly understood and relatively undefined.