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Hypertrophic Cardiomyopathy - 5/16/2013

posted May 16, 2013, 7:42 AM by Rohit Das   [ updated May 16, 2013, 8:14 AM by Purnema Madahar ]

So…it’s been a while. Over the last two weeks, my team and I spent a lot of time pondering about an interesting cardiovascular conundrum – Hypertrophic Cardiomyopathy (HCM). We encountered this disease in a male from Cameroon in his 40s who initially presented with chest pain and shortness of breath, and was ultimately diagnosed with the topic of the day…so…

·         What’s the pathology behind this unique cardiovascular disease, and how common is it?

·         What’s the pathophysiology behind HCM, particularly LVOT obstruction?

·         What are the symptoms of signs of HCM? What else is on the differential?

·         How are the manifestations of HCM managed, and what’s the typical natural history of HCM?

What’s the pathology behind this unique cardiovascular disease, and how common is it?

·         The first reports of HCM came around 1958, when keen observers started attributing “asymmetric hypertrophy of the heart” at autopsy as the cause of sudden cardiac death in a small group of young people. Indeed, HCM is the most common cause of sudden cardiac death in the young. Since then, this disease has adopted numerous different names, but now appropriately referred to as hypertrophic cardiomyopathy – characterized by a thickened, nondilated left ventricle in the absence of other potentially responsible systemic diseases (e.g., hypertension, aortic stenosis, among others).

·         HCM is the most common genetically inherited cardiac problem. It is transmitted with an autosomal dominant inheritance in a typical Mendelian pattern, and has a high degree of penetrance. So far, eleven different mutations of genes encoding for cardiac sarcomere proteins have been identified, the most common of which are beta-myosin heavy chain and myosin-binding protein C…obviously not worth remembering the names of all these proteins, but importantly, the diversity of the HCM phenotype (even among family members) is related to the diversity of sarcomeric gene mutations, in combination with environmental and other factors.

o   Along these lines, screening of relatives in HCM families is recommended (by ECG and/or TTE), beginning at the age of 12 years at 12-18 month intervals. If such studies show no LVH by 18-21 years of age, it’s reasonable to conclude that HCM-causing sarcomeric protein mutations are not present.

·         Epidemiologic studies have estimated a prevalence of around 0.2-0.5% (around 600,000 people in the United States). This is far less than the proportion encountered in practice, reinforcing that a significant amount of people with HCM remain asymptomatic and never present clinically. HCM is a global disease, encountered equally in men and women (the latter being underdiagnosed, and perhaps consequently, at risk for progression to more severe disease), and has no predilection to particular ethnicities (though studies suggest that it is underrecognized in African Americans). HCM is very unique in that it has the potential to present clinically during all phases of life, from infants to the very elderly.

What’s the pathophysiology behind HCM, particularly LVOT obstruction?

·         The central issue in HCM is asymmetric (usually) hypertrophy of the left ventricle, and the consequent left ventricular outflow tract (LVOT) obstruction that this MAY cause. Most patients with HCM do not have resting LVOT obstruction, but it can usually be provoked with certain maneuvers and/or exercise.

o   Virtually any pattern of left ventricular hypertrophy can occur with HCM. Typically, the hypertrophy is diffuse but asymmetric, with often sharp transitions between very thickened and not-so-thickened areas. Bottom line though is that there is no “classic” morphologic form of LVH in these patients, and more importantly, no particular patterns of LVH are consistently related to important outcomes – like sudden cardiac death or heart failure.

o   LVOT obstruction is one of the strongest determinants of incident heart failure and cardiovascular death (though not particularly associated with sudden cardiac death) in HOCM patients. The typical mechanism is via anterior motion of the mitral valve during systole, or SAM, which directly contacts the ventricular septum. This leads to sub-aortic valve LVOT obstruction, marked increases in LV filling pressures, and consequent increase in myocardial stress and oxygen demand. The degree of obstruction (as determined by the pressure gradient across the LVOT) is directly related to the duration of mitral valve-septal contact during systole. Once the gradient gets higher than 30 mmHg, the incidence of heart failure symptoms increases…our patient had a RESTING gradient of 95 mmHg as measured on TTE – UNbelievable.

o   Subaortic gradients, like LVOT obstruction in HCM, are very dynamic – they can be reduced or even abolished with interventions that decrease contractility/increase afterload, and augmented by interventions that decrease afterload/ventricular filling…

·         There are also other important pathophysiologic consequences of HCM. Microvascular dysfunction, probably as a result of the stress encountered by the myocardium with severe LVOT obstruction, is an important component of the disease and eventually leads to myocardial scarring and susceptibility to life-threatening arrhythmias. Additionally, the majority of HCM patients (around 80%) have evidence of diastolic dysfunction (which is interestingly not directly related to the extent of LVH), and contributes to heart failure-related symptoms.

What are the symptoms of signs of HCM? What else is on the differential?

·         As mentioned, symptoms of normal-EF heart failure can occur unpredictably at any age, and is related to both diastolic issues as well as extent of LVOT obstruction. Additionally, patients experience chest pain, probably as a result of microvascular changes that occur due to the pathophysiologic mechanisms mentioned above. Syncope is also a commonly encountered manifestation, and can be due to either LVOT obstruction or malignant ventricular arrhythmias. Unfortunately, sudden cardiac death as a result of ventricular arrhythmias is often the initial manifestation of HCM, and most of such events occur in patients who were previously asymptomatic.

·         There are a couple of physical exam signs that are unique to HCM:

o   LVOT murmurs – patients with outflow tract obstruction typically have a medium-pitched systolic ejection murmur heard best at the lower left sternal border and apex. The murmurs can be augmented by measures that increase the gradient across the LVOT, like the Valsava maneuver (during the 2nd phase – decreased LV filling) or going from a squatting to sitting position (similarly decreases LV filling). The murmur of aortic stenosis typically doesn’t change with Valsava, and thus this is a key maneuver to differentiate between two cardiovascular diseases that present very similarly.

o   Additionally, forceful PMI should raise suspicion for HCM. In patients with significant LVOT obstruction, one can occasionally feel a double or triple apical impulse, which is related to ventricular contraction as well as presystolic accentuated atrial contraction (against very high LV pressures). In that context, an apical S4 can also be heard.

·         Almost all patients with HCM have abnormal ECGs, with typical findings including LVH and related “strain” patterns in the precordial leads, and left atrial enlargement. Importantly, a normal ECG in a HCM patient (occurring around 5% of the time) is representative of a less severe phenotype and predictive of more favorable cardiovascular outcomes.

·         Long-term athletic training can lead to left ventricular changes that are very similar to the appearance of HCM. When in the LV-wall thickness “grey-zone” of 13-15 mm (if greater than 1.5 cm, thick HCM more than anything else), signs more consistent with HCM include LV cavity size of less than < 45 cm, left atrial enlargement, family history of CV disease/sudden cardiac death and diastolic dysfunction. LVH related to athlete’s heart typically regresses after 4-6 weeks of deconditioning.

·         As mentioned, hypertension and aortic stenosis can also lead to similar LV changes. Hypertensive heart disease presents after adolescence (in contrast to HCM, which can present any age), is usually associated with other related end-organ manifestations (nephropathy and/or retinopathy), and rarely leads to LV wall thickness > 1.5 cm. Along with the physical exam signs mentioned above, TTE or cardiac catheterization are definitive ways to differentiate between valvular (aortic stenosis) and subvalvular (HCM) obstruction.

How are the manifestations of HCM managed? What’s the typical natural history of HCM?

There are three clinical issues related to HCM that are worth discussing – heart failure, sudden cardiac death, and atrial fibrillation. I’m not going to talk about atrial fibrillation, since I hope you have a decent knowledge about that already (see my Daily from 12/11/2012…).

·         Heart Failure – though some degree of exertional dyspnea is common in HCM, progression to NYHA Class III or IV symptoms is uncommon, occurring in 10-15% of patients. The principal determinants of progression include diastolic dysfunction, LVOT obstruction and atrial fibrillation. Only about 3% of patients progress to systolic heart failure, which has a very poor prognosis – progression to refractory heart failure and/or sudden death occurs at a 10%/year clip.

o   Medical Management – in contrast to how we normally treat failure, diuretics and afterload reducers may actually WORSEN HCM-related heart failure, mainly due to consequent worsening of LVOT obstruction. So, the treatment for these patients is focused around negative ionotropy – Beta-blockers are the mainstay, but agents we shouldn’t use for run-of-the-mill heart failure are also effective – Verapamil and Disopyramide.

o   Surgical Management – another unique aspect of HCM management. Myectomy is a highly effective, relatively safe surgery for HCM patients with drug-refractory heart failure associated with LVOT gradients above 50 mmHg. Epidemiologic studies have shown that patients who undergo myectomy have a survival free from all-cause mortality that is similar to an age and gender matched population (study attached). Alcohol septal ablation is an alternative to myectomy, but around 20% of patients require repeated procedures and/or develop consequent complete AV-block requiring permanent pacemakers…doesn’t sound that appealing to me.

·         Sudden Cardiac Death (SCD) – just typing those words makes me cringe in fear…SCD due to HCM occurs in all age groups, but most commonly occurs in young adults that are < 30 years to 35 years of age. Anyway. treatment is straightforward – ICD placement…but who gets them?

o   Secondary Prevention – also straightforward – if a patient had cardiac arrest or a sustained ventricular arrhythmia in the context of HCM, they get an ICD.

o   Primary Prevention – this requires risk stratification. There are five clinical risk factors that portend a high risk of SCD – family history of SCD, unexplained syncope, multiple-repetitive bouts of non-sustained ventricular tachycardia, abnormal exercise BP response (failure to augment systolic BP by 20 mmHg from rest to peak exercise), and massive LVH (LV wall thickness > 3.0 cm, as determined by TTE or cardiac MRI, the latter being more accurate…but more expensive). Note that the degree of LVOT obstruction does NOT correlate with the incidence of SCD.

·         The natural history of HCM, despite all of the above, is generally excellent. Recent prognostic studies with community-based cohorts that are hopefully free of referral bias estimate mortality rates of about 1%/year, which is not significantly different from the general population. A significant proportion of patients, around 20-30%, have a normal life expectancy without any intervention from evil MDs. So…the bottom line? Patients without significant heart failure symptoms and high-risk SCD risk factors have an excellent, if not normal, prognosis.

Our guy wasn’t so lucky. He had an incredibly high LVOT gradient at presentation, and was quite dyspneic with impressively high filling pressures. Ultimately, he did a lot better with Metoprolol and Verapamil, didn’t get an ICD placed based on the lack of risk factors mentioned above, and we discharged him with our fingers crossed (he went back to Cameroon to sell spices). Along with the myectomy study, I’ve attached a HCM review paper from a guru in the field. Till next time…


Hypertrophic Cardiomyopathy - A Systematic Review
Maron, JAMA 2002, Volume 287 (10): 1308-1320

Ommen et. al., J Am Coll Cards 2005, Volume 46: 470-476
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