Hypertrophic cardiomyopathy (HCM) is a myocardial disorder characterized by the presence of excessive left ventricular thickness in the absence of conditions causing physiologic hypertrophy such as hypertension, valvular aortic stenosis, or the athletic heart. Hypertrophy is severe and usually asymmetric with the ventricular septum disproportionately involved in more than 90% of cases. Echocardiography usually establishes the diagnosis. Cardiac magnetic resonance (CMR) imaging is often used to confirm the diagnosis or provide additional prognostic or anatomic information. A maximum left ventricular thickness of more than 15 mm anywhere in the ventricle is diagnostic of HCM, or more than 13 mm if a genetic mutation known to cause HCM is present. Viewed microscopically, the myocardium demonstrates a characteristic pattern of myocyte fiber disarray and fibrosis. HCM is a genetic disorder with autosomal dominance and variable penetrance. As the most common form of inherited heart disease, it is estimated to affect between 1 in 200 and 1 in 500 persons. Mutations in at least 11 genes coding for cardiac muscle contractile proteins have been described; the great majority of these mutations involve the beta-myosin heavy chain and the myosin-binding protein C. The clinical presentation and natural history of HCM vary widely, from a relatively benign and asymptomatic condition to one characterized by disabling symptoms, heart failure, or sudden cardiac death (SCD).
Interesting hemodynamic consequences arise in patients with HCM, depending on whether or not left ventricular outflow tract obstruction (LVOTO) develops. Hemodynamically, this manifests as a dynamic pressure gradient between the left ventricle (LV) and the aorta. HCM is often classified as obstructive or nonobstructive , based on the presence of this finding. When present, the dynamic nature of obstruction may cause marked variability in pressure gradients depending on the loading conditions and contractile state of the heart. Gradients may be present at rest with variable degrees of obstruction for as many as one-third of patients with HCM, but the obstruction may also be latent , indicating that it is absent at rest and present only after provocation in up to an additional one-third of patients. The nonobstructive forms of HCM lack resting or provocable gradients but may be associated with hemodynamic abnormalities from the profound diastolic abnormalities often present in this condition. Mid-cavitary obstruction is present in around 3% to 5% of patients and is often associated with left ventricular aneurysm formation and a worse prognosis.
Pathophysiology
Excessive and inappropriate increases in left ventricular thickness lead to several important consequences ( Table 7.1 ). The thickened myocardium impairs left-ventricular compliance, causing elevations in the left-atrial pressure, left-atrial size, and pulmonary artery pressures. Sarcomere mutations alter the configuration of myosin heads during diastole, shifting from the physiologic “super-relaxed” state into the more inefficient “disorder-relaxed” state. This directly reduces cardiac lusitrophy and increases basal myocardial energy expenditure. Diastolic dysfunction from all three causes—abnormal compliance, abnormal tissue relaxation speed, and abnormal energy expenditure—can lead to dyspnea and decreased exercise intolerance.
| Pathophysiologic Abnormality | Clinical Syndrome |
|---|---|
| Diastolic dysfunction | Dyspnea |
| Exercise intolerance, fatigue | |
| Arrhythmia | |
| Myocardial ischemia | Angina |
| Dyspnea | |
| Arrhythmia | |
| Obstruction | Dyspnea |
| Exercise intolerance, fatigue | |
| Chest pain | |
| Syncope | |
| Endocarditis | |
| Arrhythmia |
Arrhythmias frequently complicate the course. Atrial fibrillation is the most common comorbidity and ventricular tachycardia is the most feared. Atrial fibrillation may be poorly tolerated because of the associated diastolic dysfunction and the greater importance of the atrial contribution to cardiac output. Importantly arrhythmias (particularly ventricular) represent the primary mechanism of SCD in HCM. An increase in myocardial oxygen consumption from excessive hypertrophy outstrips myocardial blood supply, potentially causing myocardial ischemia and triggering arrhythmia. This may occur despite normal coronary arteries. In addition, ischemia may originate from reduced coronary flow reserve from abnormalities of the small resistance vessels present in the hypertrophied myocardium. Systolic compression of the coronaries (due to intramyocardial bridging) has been observed and may serve as yet another cause of ischemia. In the setting of these ischemic triggers, underlying fibrosis then provides a robust substrate for ventricular tachycardia.
One of the most important physiologic abnormalities in HCM is the presence of LVOTO. A resting or provocable gradient is observed in about 25% to 60% of cases. The mechanism of obstruction had previously been a focus of considerable debate. Extensive investigations over the years have established the role of both systolic anterior motion (SAM) of the mitral valve leaflet and of mitral valve abnormalities themselves as the cause of outflow tract obstruction. Severe hypertrophy distorts the normal relationship between the mitral apparatus and the muscular outflow tract. The asymmetrically hypertrophied proximal intraventricular septum narrows the orifice of the outflow tract. Distortion of the ventricle causes redundancy of the mitral leaflets, leading to SAM of the leaflets, causing obstruction via drag force ( Fig. 7.1 ). It was thought that turbulence within the outflow tract led to a Venturi effect, drawing the anterior mitral leaflet into the outflow tract; however, SAM begins prior to the onset of ejection, suggesting that the Venturi effect contributes little to the outflow tract obstruction. SAM of the mitral valve also results in mitral regurgitation, explaining the frequent finding of significant mitral regurgitation in the presence of outflow tract obstruction. Outflow tract obstruction causes symptoms of dyspnea, fatigue, exercise intolerance, anginal chest pain, and syncope.
Hemodynamic Abnormalities
A wide spectrum of hemodynamic findings may be observed in patients with HCM depending on the consequences of severe hypertrophy on diastolic function and on the presence and extent of LVOTO.
Diastolic Dysfunction
Impaired relaxation of the LV represents the predominant diastolic abnormality associated with the severe hypertrophy of HCM. The associated increase in chamber stiffness from increased myocardial mass and lower chamber volumes also impairs compliance, further worsening diastolic function.
Impaired relaxation limits rapid, passive left-ventricular filling occurring in early diastole. To compensate for reduced rapid filling, atrial systolic filling is exaggerated. This phenomenon, as well as the decreased compliance itself, is clinically observed by a prominent fourth heart sound on physical examination and by the often dramatic clinical deterioration seen when patients with HCM develop atrial fibrillation or loss of atrial synchrony. Contemporary guidelines place a strong emphasis on rhythm control strategies for this reason.
Abnormal diastolic function correlates with the degree of hypertrophy. Patients with severe resting gradients have the highest elevations of left-ventricular end-diastolic pressure compared with those with latent gradients or no obstruction. In addition, there may be abnormalities in early diastolic pressure. Normally, left-ventricular diastolic pressure is low in early diastole; patients with HCM may have marked elevations in pressure at the beginning of diastole, reflecting abnormal ventricular relaxation ( Fig. 7.2 ). Reduced compliance of the LV is apparent by the commonly present prominent a wave on the left-ventricular waveform ( Fig. 7.3 ). Left-ventricular diastolic abnormalities elevate the pulmonary capillary wedge and pulmonary artery systolic pressures, and in some cases pulmonary pressures may be markedly elevated, ultimately causing structural changes and increased pulmonary vascular resistance with fixed pulmonary hypertension similar to that observed in other chronic heart failure syndromes.
Left Ventricular Outflow Tract Obstruction
The dynamic nature of the obstruction in hypertrophic obstructive cardiomyopathy (oHCM) creates characteristic hemodynamic abnormalities distinct from those observed with the fixed obstruction caused by valvular aortic stenosis. In valvular aortic stenosis, fixed orifice obstruction impedes ventricular ejection uniformly throughout systole. This leads to the characteristic delayed upstroke in the aortic pressure waveform and the presence of a large systolic gradient beginning early in systole and peaking at maximum left-ventricular pressure ( Fig. 7.4A ). In the case of oHCM, no obstruction exists at the onset of ventricular ejection. Instead, obstruction progressively develops during systole as the contractile force of the LV builds and the outflow tract narrows. Thus early in systole, left-ventricular ejection is relatively unimpeded, resulting in a brisk initial upstroke of the aortic waveform culminating in a peak systolic pressure ( Fig. 7.4B ). As systole continues and obstruction reaches a maximum, aortic pressure drops, and the aortic pressure waveform transforms to appear similar to valvular stenosis with a delayed upstroke. This pattern of initial unimpeded ejection followed by progressive obstruction leads to the characteristic “spike-and-dome” configuration of the aortic waveform in oHCM and is also responsible for the bifid pulse on physical exam described in this condition ( Fig. 7.5 ).
Another hallmark of dynamic obstruction, and a clinically useful feature distinguishing oHCM from valvular aortic stenosis, is the drop in the aortic pulse pressure in the first normally conducted beat after the compensatory pause from a premature ventricular contraction (PVC). This finding, known as the Brockenbrough sign , was first described over 60 years ago. This phenomenon is due to the augmentation of the contractile force of the post-PVC beat. In valvular aortic stenosis with fixed obstruction , the increased contractile force of the post-PVC beat increases both left-ventricular and aortic pressures. The systolic gradient increases from an associated increase in cardiac output across the valve. Importantly the pulse width on the aortic pressure waveform also increases ( Fig. 7.6 ). In patients with dynamic obstruction exemplified by oHCM, the increased contractile force of the post-PVC beat worsens the degree of obstruction. This increases the left-ventricular systolic pressure and the systolic gradient but decreases aortic systolic pressure, narrowing the pulse pressure ( Fig. 7.7 ). While it is true that the delayed systole increases preload, which can decrease obstruction in oHCM, the increases in preload, however, do not offset the increased contractility, and thus the observed increase in obstruction post-PVC. Note that the Brockenbrough sign requires only an analysis of the post-PVC aortic waveform. The crucial feature of this sign is simply the narrowing of the aortic pulse pressure on the post-PVC beat. The Brockenbrough sign distinguishes fixed from dynamic obstruction but also helps distinguish true outflow tract obstruction from an intraventricular gradient due to severe hypertrophy and midcavity obliteration or catheter entrapment; the Brockenbrough sign is observed only in the presence of true outflow tract obstruction.
The dynamic nature of the gradient between the LV and the aorta in oHCM reflects the loading conditions of the heart as well as the inotropic state of the myocardium. Significant variations in the gradient are frequently observed at rest. Inspiration causes a decrease in the gradient. It is very common to observe beat-to-beat fluctuations in the gradient without changes in catheter position or respiratory status ( Fig. 7.8 ). It is important to recognize this fluctuation, as a single assessment may underestimate the severity or the true extent of the obstruction potentially present and also may misrepresent the magnitude of gradient reduction after a treatment like alcohol septal ablation.
Patients with latent obstruction have minimal or no gradient at rest. Provocative maneuvers should be considered in those without a resting gradient in whom obstruction is suspected. A variety of techniques have been used; any condition reducing preload or afterload, or increasing contractile force augments dynamic obstruction, unmasking a systolic gradient. Physiologic-based methods are considered the best. In the cardiac catheterization laboratory the simplest method to induce PVCs uses a catheter in the right or left ventricle ( Fig. 7.9 ). Exercise may be used and is more likely to accurately reproduce the hemodynamic condition experienced by the patient’s clinical syndrome. This is often difficult to perform in the catheterization laboratory, however, and is best suited for noninvasive assessment by echocardiography. The Valsalva maneuver is helpful in revealing latent obstruction as it increases intrathoracic pressure, lowers preload, and as a consequence augments obstruction. The Valsalva maneuver is an effective method, although it is sometimes difficult for patients under sedation for a cardiac catheterization procedure to comply correctly. To perform the Valsalva maneuver in the cardiac catheterization laboratory, simultaneous left-ventricular and aortic pressures are recorded during the strain and release phases; left-ventricular diastolic and systolic pressures rise during strain, and aortic systolic pressures fall. The provoked gradient appears maximal during and at the end of the strain phase ( Fig. 7.10 ).
Pharmacologic techniques for provocation of a gradient include nitrates to reduce preload and afterload and inotropic stimulation to increase contractility. These techniques are problematic and may not accurately reflect the patient’s true physiologic status. In one study a poor correlation existed between the gradient provoked by nitrates and the gradient provoked by exercise; older patients with narrower outflow tracts had a larger gradient provoked by nitrates than exercise, whereas patients who exercised to higher workloads showed higher gradients with exercise than nitrates. Greater concern relates to the use of direct inotropic stimulation with agents such as dobutamine. It has been well recognized that excessive inotropic stimulation may provoke gradients in normal hearts or in conditions other than HCM such as, for example, in the setting of severe hypertrophy. Thus expert panels do not recommend the use of these agents to decide treatment strategies.
Specific Challenges in Hemodynamic Assessment
Although most patients with HCM can be accurately assessed noninvasively with Doppler echocardiography, we are often asked to evaluate these patients in the cardiac catheterization laboratory to establish the presence, location, and severity of obstruction. It is important to emphasize that sloppy cardiac catheterization technique, improper catheter position, or inattention to details may confuse the operator and lead to erroneous diagnoses and improper treatment. Specific situations in which invasive assessment is requested include (1) patients with no resting gradient to perform provocative measures (as discussed previously), (2) patients with coexisting mitral regurgitation and concern that the outflow tract Doppler signal is contaminated by a mitral regurgitation signal, (3) distinguishing true outflow tract obstruction from midcavity obstruction, and (4) patients with coexisting aortic valve stenosis to tease out the contribution of serial stenosis.
In the cardiac catheterization laboratory outflow tract obstruction is determined by measuring the pressure gradient between the LV and the ascending aorta. To avoid the potential for catheter entrapment artifact, this is ideally done by positioning an end-hole catheter in the LV inflow tract via a transseptal puncture while simultaneously measuring pressure in the ascending aorta with another catheter. This is not a common practice, due primarily to the increased complexity of performing a transseptal puncture. Thus similar to the catheter configuration used to assess aortic valvular stenosis, most operators determine the pressure gradient with a dual-lumen catheter. In patients with HCM, the optimal catheter to record LV pressure and characterize the outflow tract gradient is one with an end hole and two side holes near its tip (a dual-lumen multipurpose catheter is often used for this purpose). A dual-lumen pigtail catheter is adequate for aortic valvular stenosis but should specifically be avoided when interrogating the left ventricular outflow tract (LVOT) gradient in a patient with HCM. This is due to the fact that a pigtail catheter often underestimates or even fails to identify the gradient in obstructive HCM because several of the catheter’s side holes may lie above the obstruction ( Fig. 7.11 ) while the dual-lumen multipurpose catheter with an end hole and two side holes near its tip will more precisely identify an intraventricular pressure gradient, especially in the small ventricular cavities often encountered in this condition.
Assuming the absence of aortic valve stenosis, a gradient between the LV and aorta may not always represent true outflow tract obstruction present at the level of the LV inflow due to SAM of the mitral valve. Another cause of a gradient between the LV and the aorta is midcavity/apical obstruction. If there is severe hypertrophy coupled with hyperdynamic ventricular function and/or reduced ventricular volumes, the LV cavity may be obliterated from the midportion of the ventricle to the apex ( Fig. 7.12 ). A catheter tip positioned in that portion of the ventricle will record high ventricular systolic pressures, and thus a systolic gradient will be recorded. In such cases, other features typical of oHCM, such as the Brockenbrough sign or a spike-and-dome configuration on the aortic waveform, will be absent ( Fig. 7.13 ). SAM of the mitral valve will specifically be absent, as well as associated mitral regurgitation. Careful positioning of the catheter in the outflow tract will fail to record a systolic pressure gradient. Performing a transseptal puncture to allow LV pressure measurement precisely at the level of the LV inflow tract may facilitate this assessment.
