Diagnosing and Managing Pulmonary and Right-Sided Heart Disease: Pulmonary Hypertension, Right Ventricular Outflow Pathology, and Sleep Apnea

Abstract

The past two decades have seen a surge in the available data on hypertrophic cardiomyopathy (HCM), with evolution of comprehensive HCM-related management strategies that have expanded the diagnostic tools and risk stratification algorithms. In addition to employing genotype-to-phenotype nosology to describe HCM, modifications to the current MOGE(S) classification for HCM based on the presence or absence of obstruction and location of hypertrophy within the morphology have been suggested. These available tools, including genetic testing, have led to a greater appreciation for at-risk patients, including susceptible family cohorts. Greater recognition is being paid to the development of pulmonary hypertension in HCM, based primarily on pathophysiology related to heart failure with preserved ejection fraction. In addition, there has been resurgence in the description and recognition of right ventricular outflow pathology in HCM and its associated treatment dilemma. Although slow, a trend to recognize HCM as a treatable disease with a more favorable prognosis is emerging as the sudden death risk stratification process continues to be honed with putative additions of such risk markers as obstructive sleep apnea. This chapter will focus on our current understanding of right-sided heart pathology in HCM, including an expanded debate on sleep apnea as a risk factor for sudden death and intractable symptomatology. The unique mechanistic considerations thereof will be presented.

Questions

• 1. The following are true about pulmonary hypertension (PH) in hypertrophic cardiomyopathy (HCM):

  • A. Development of PH in HCM is a rare phenomenon and when it develops is primarily related to severe left ventricular outflow tract (LVOT) obstruction. Patients with PH in HCM are usually older and in their seventh decade of life and also usually have severe mitral regurgitation.

  • B. PH is universal in HCM.

  • C. PH in HCM is usually associated with irreversible changes in the pulmonary arterioles, and almost all patients have high pulmonary vascular resistance.

  • D. PH in HCM is usually associated with syncope and is a high-risk marker for sudden death.

  • E. None of the above.

• Answer: E

• Explanation:

• The prevalence of PH in HCM is reported to be similar to that in conditions like aortic stenosis and heart failure with preserved ejection fraction, which share similar hemodynamic traits with HCM. PH is neither rare nor universal in HCM. The pathophysiologic basis of PH in HCM is primarily due to diastolic dysfunction resulting in elevated left ventricular (LV) pressures and left atrial hypertension. The coexistence of dynamic LVOT obstruction, diastolic dysfunction secondary to intrinsic myocardial stiffness, mitral regurgitation, and LV hypertrophy in HCM also eventually leads to the development of postcapillary PH, representing the cumulative downstream effect of the hemodynamic derangements (LVOT obstruction, mitral regurgitation, diastolic dysfunction) that cause left atrial hypertension. High pulmonary vascular resistance in PH associated with HCM is not common, and a small percentage of such patients may have elevated pulmonary vascular resistance. Currently, PH is not a high-risk marker for sudden death in HCM and is not used as a risk arbitrator for the implantation of an implantable cardioverter-defibrillator for primary prevention of sudden death.

• 2. Right ventricular (RV) hypertrophy is common in HCM and may pose management dilemmas in the routine care of patients with HCM. The following are true about RV obstructive pathology in HCM:

  • A. The genetics of RV involvement in HCM has been well described in most modern reports.

  • B. Reported incidence of RV obstructive pathology in HCM is miniscule and occurs in <1% of HCM patients when the interventricular septum is >18 mm thick.

  • C. RV obstruction is present in up to 15% of patients with HCM.

  • D. RV obstruction is only present when the interventricular septum is >35 mm in thickness.

  • E. All of the above.

• Answer: C

• Explanation:

• The genetics of RV involvement has not been well characterized, although histological findings appear similar to those in the LV, suggesting a similar pathogenesis. The incidence of RV obstructive pathology has been reported to vary from 15% to 92% in older cardiac catheterization studies, while more modern data on echocardiography (the current gold standard for diagnosis) document it at 15%.

• 3. RV obstruction (subpulmonic) in HCM is more commonly reported in young children and infants than adults. The site of RV obstruction is fairly easy to localize with current imaging techniques. The following are true about this phenomenon:

  • A. The sites of RV obstruction may be in the outflow tract (the vast majority), the mid-base region at the level of the septal band, and the apical trabecular region.

  • B. Combined RV outflow tract (RVOT) and LVOT obstruction is less common than isolated RVOT obstruction.

  • C. The Doppler flow velocity profile of RV obstruction shows the typical dagger-shaped profile characteristic of LVOT obstruction due to systolic anterior motion of the tricuspid valve.

  • D. Echocardiography easily localizes the region of interest of obstruction in RVOT pathology in the same way as LVOT obstruction.

  • E. None of the above.

• Answer: A

• Explanation:

• RV obstruction in HCM is caused by a narrowing of the ventricular cavity as a result of muscle contraction during systole together with a hypertrophied RV free wall and protruding interventricular septum. Obstruction of the RVOT in HCM has been shown to be associated with massive hypertrophy of the LV musculature, which comprises the crista supraventricularis, moderator band, or trabeculae. Combined RVOT and LVOT obstruction is more common than isolated RVOT obstruction, and triple intraventricular obstruction (RVOT, LVOT, and mid-ventricular) also is seen. Isolated RV obstruction has occasionally been described. The Doppler flow velocity profile of RV obstruction appears relatively symmetric and dome-like without the dagger-shaped profile characteristic of LVOT obstruction resulting from the dynamic obstruction caused by systolic anterior motion (SAM) of the mitral valve and SAM-septal contact. There are important caveats that need to be understood during the echocardiographic examination of patients with RVOT obstruction. A concerted effort is needed to investigate the obstructive process under Doppler echocardiography. A short-axis view of the LV that reveals a very thick septum and a crowded RV with severe muscle thickening is an early clue to investigate RVOT obstruction under Doppler.

• 4. The following are thus true about HCM and obstructive sleep apnea (OSA):

  • A. Poor sleep quality may be reported in HCM, but OSA is rare.

  • B. Non-sarcomeric mutations are frequent in patients with OSA and HCM.

  • C. Patients with OSA and HCM usually have a syndromic association with other features such as deafness and lactic acidosis.

  • D. OSA may help protect against the more severe forms of obstructive pathology in HCM.

  • E. Several overlapping pathophysiologic alterations underlie the worsening of HCM symptoms in patients who have both HCM and OSA.

• Answer: E

• Explanation:

• The coexistence of HCM and OSA even in patients without the traditional risk factors for OSA is suggested by recent studies, ranging from 32% to 71%, depending on the methodology and diagnostic criteria used. A large number of candidate gene studies have been performed in OSA, but to date no consistent genetic linkage for OSA has been found. Maternally inherited mutations in mitochondrial DNA have been reported in few patients with concomitant HCM and sleep-disordered breathing. Several pathophysiologic mechanisms help translate the link between these two disease states. The most likely explanation is the altered adrenergic signaling seen in OSA, which also is one of the key features of HCM. This high catecholamine state causes increased hypertrophy and LV filling pressures, decreased cardiac output, and initiation or worsening of LVOT obstruction, dyspnea, dizziness, and mitral regurgitation.

• 5. A 55-year-old man with a known history of nonobstructive HCM (diagnosed about 6 years ago), maintained on metoprolol 50 mg twice a day, sought attention for a syncopal episode while running. He does not have a history of sudden death in the family. Transthoracic echocardiography showed a septum of 20 mm in thickness. Treadmill exercise testing showed appropriate blood pressure response. A 24-hour, ambulatory electrocardiography monitor revealed short runs of atrial tachycardia but no episodes of non-sustained ventricular tachycardia. Cardiac magnetic resonance imaging revealed a < 5% area of the myocardium with delayed enhancement, and a sleep study showed evidence of severe obstructive sleep apnea-hypopnea syndrome. Which of the following would you use as a minor risk arbitrator for recommending an automatic implantable cardioverter-defibrillator (ICD) in this patient?

  • A. LV wall thickness > 20 mm

  • B. Genetic testing for sarcomere gene mutations

  • C. Electrophysiologic testing (programmed ventricular stimulation)

  • D. Sleep study

  • E. None of the above

• Answer: E

• Explanation:

• This is a controversial question. In contemporary practice several risk markers have emerged from observational studies and have achieved a general acceptance in risk stratification for prophylactic use of ICDs in HCM patients. These are traditionally classified as ten conventional risk factors and potential or uncertain risk factors. The conventional risk markers include:

  • 1. Family history of one or more HCM-related sudden death or resuscitated sudden death

  • 2. One or more episodes of unexplained syncope

  • 3. LV wall thickness > 30 mm

  • 4. Non-sustained ventricular tachycardia on Holter monitor

  • 5. Hypotensive or attenuated blood pressure response on exercise stress testing

• The potential and uncertain risk markers include:

• 1. Late gadolinium enhancement by cardiac magnetic resonance imaging

• 2. LV apical aneurysm

• 3. OSA

• 4. LVOT obstruction with a resting gradient >30 mmHg

• 5. Associated epicardial coronary artery disease

• 6. Atrial fibrillation

• 7. Malignant gene mutations (nonsarcomere LAMP 2 or double sarcomere mutations)

• 8. Myocardial bridging

• 9. Myocardial ischemia

• 10. Troponin elevation

• Sudden death is unpredictable in HCM and is the most frequent mode of premature death. Precise risk stratification in HCM remains a challenge due to its clinical heterogeneity of presentation and expression, its relatively low prevalence in general cardiology practice, and the complexity of potential pathophysiologic mechanisms. It is possible that OSA – by affecting mechanisms mediating heart rate variability, including central nervous system coupling between cardiac and ventilatory parasympathetic inputs, the arterial baroreflex, and feedback from pulmonary stretch receptors, i.e., cardiac autonomic dysfunction – can contribute to an elevated risk of sudden death in HCM. Chronic sympathetic overdrive is another mechanism that can contribute to the elevated risk of sudden cardiac death in HCM patients with OSA. These are mechanistic considerations that can stimulate the proposition of a true arrhythmogenic role of OSA in HCM in susceptible patients, but not one that has been proven yet.