Hypertrophic cardiomyopathy is a disease with a wide degree of phenotypic variability. Publications demonstrating inducible ischemia in patients obstructive HCM were published four decades ago using non-quantitative radionuclide imaging [2, 22, 23]. Since then, quantitative perfusion imaging with positron emission tomography, CMR, and MCE in patients with HCM have confirmed that myocardial blood flow in the hypertrophied and non-hypertrophied regions is frequently reduced during exercise or vasodilator stress, and occasionally at rest [1, 3, 4, 7]. In the current study, we demonstrated that vasodilator stress MCE with regadenoson can be used to identify abnormalities in perfusion at rest and during stress in patients with HCM, and that the spatial manifestations of perfusion defects are varied, with subendocardial or patchy abnormalities being more common than transmural diffuse defects in hypertrophied segments. Substantial reduction in hyperemic perfusion during vasodilator stress is commonly found in those with large amounts of fibrosis detected by LGE. We also demonstrated that improvement in hyperemic perfusion in both the hypertrophied and non-hypertrophied regions can occur late after septal myectomy.
In HCM, reduced perfusion reserve in the absence of atherosclerotic CAD has been attributed, in part, to structural abnormalities of the vasculature. On histopathology, medial hyperplasia and lumen narrowing of small coronary arteries and arterioles, and a reduction in myocardial capillary density in hypertrophic regions has been described in HCM [8–10]. The latter feature indicates a failure in compensatory remodeling of the distal circulation to address the increased LV mass, cellular hypertrophy, and increased LV work and wall stress in HCM. Because of the compensatory reserve in the capacity of arterioles to dilate and capillary units to recruit, resting perfusion can be preserved in most patients with HCM. Yet, partial exhaustion of reserve and increased resistance from arteriolar narrowing and reduced capillary density is expected to produce myocardial ischemia during hyperemic stress or increased metabolic demand.
Functional abnormalities of the microcirculation in HCM have also been described. Extravascular compressive forces from high LV systolic and diastolic pressures in combination with the normal transmural pressure drop would be expected to reduce maximal flow in HCM, particularly in the endocardium. This mechanism has been proposed to explain reduced endocardial flow reserve in HCM, particularly in patients with high LV end-diastolic pressures or extreme septal hypertrophy [4, 7]. Abnormalities in the phasic flow of coronary arteries can occur from altered hemodynamic forces in HCM. Studies using invasive coronary flow wires or non-invasive coronary wave intensity measurements have revealed a marked predominance of diastolic flow and more prominent retrograde systolic flow in distal coronary arteries in subjects with HCM, which can be further accentuated by inotropic stress [12, 24]. Exaggerated retrograde flow combined with delayed or shortened diastolic relaxation can result in reduced antegrade discharge from small arteries or large arterioles that normally act as a type of “hydraulic capacitor” [12, 25]. From a clinical perspective, this functional abnormality is likely to worsen as LV end-systolic pressure, myocardial diastolic pressure, and heart rate increase.
In the current study, the spatial distribution of perfusion abnormalities during vasodilator stress, whether from structural or functional causes, was assessed by MCE. This technique provides parametric information on whether abnormalities in perfusion are secondary to reduced MBV, which can occur from either capillary rarefaction or functional non-patency of microvascular units . It also measures microvascular flux rate which can be reduced from high resistance anywhere along the vascular network . At rest, MCE revealed very modest reductions in MBV in both the hypertrophic and non-hypertrophic regions of patients with HCM despite these subjects having higher systolic wall stress and work. There is reason to believe that this abnormality was from abnormalities in phasic flow based on results from previous studies showing a high degree of cyclic video intensity at the LV apex, primarily from low systolic intensity, during resting MCE in patients with apical HCM . Ordinarily, our finding of reduced perfusion at rest and increased work would be expected to result in ischemia. Yet these subjects were not symptomatic and LV systolic function was normal. This paradox could be related to compensatory mechanisms to increase oxygen delivery, even out of proportion to calculated work, based on studies using 11C-acetate PET indicating that myocardial oxygen consumption is not reduced in subjects with HCM who have normal to high LVEF .
Perfusion abnormalities in those with HCM became much more prominent during vasodilator stress, primarily because of a deficit in the ability to appropriately augment microvascular flux rate. This finding is somewhat different from previous quantitative MCE studies that found that reduced MBF in HCM, both at rest and during stress, is attributable to abnormal MBV . We believe differences between the two studies can be explained by much less severe LVOT obstruction in the current study. We found that the dominant spatial pattern for hyperemic flow deficits was subendocardial or patchy in distribution. These patterns do not indicate any one mechanism since they could occur from pre-capillary drop in resistance from arteriolar narrowing, microvascular rarefaction, or phasic functional abnormalities of coronary flow. We observed a marked improvement in hyperemic flow, including in non-hypertrophied territories, after septal myectomy in two subjects who had very high resting LVOT gradients and low hyperemic flow (approximately one-third of control subject average) prior to surgical intervention. This finding suggests that abnormal flow from high systolic compressive forces in combination with delayed relaxation can affect global myocardial perfusion and is reversible late after correction of the high systolic gradient.
There are several important limitations of the study. The total number of subjects studied and the number of subjects undergoing myectomy was low because of strict entry criteria, including the need for recent CMR and exclusion for treatment with a myosin inhibitor which was being investigated concurrently with recruitment for this study. Yet data indicating a potential beneficial effect of myectomy on perfusion can be used to justify a larger prospective study in that narrow population of patients. Although MCE can be used to calculate absolute MBF in mL/min/g, this analysis was not performed because the requisite calculation of absolute MBV is valid only if blood pool microbubble signal is below the upper limit of the dynamic range which generally requires lower contrast infusion rates and appropriate scaling. Perfusion data were also not expressed as MBF normalized to work because of limitations in using end-systolic pressures to reflect total systolic load. Instead, we simply concluded that perfusion deficits in HCM occurred despite greater workload based on high systolic LV pressures. It should also be noted that vasodilator stress rather than exercise stress was used. The latter would provide a better test for stress-induced deficits in MBV, although the level of stress induced would be difficult based on difficulties in determining true afterload in those with dynamic gradients. Finally, ischemia from CAD was excluded by angiography in only about half of the HCM subjects, all of whom had anginal symptoms. One patient was excluded from analysis based on the presence of severe CAD on angiography performed for a typical coronary distribution of perfusion deficits on stress MCE.