Mechanisms of Myocardial Ischemia in Hypertrophic Cardiomyopathy

Background Angina is common in hypertrophic cardiomyopathy (HCM) and is associated with abnormal myocardial perfusion. Wave intensity analysis improves the understanding of the mechanics of myocardial ischemia. Objectives Wave intensity analysis was used to describe the mechanisms underlying perfusion abnormalities in patients with HCM. Methods Simultaneous pressure and flow were measured in the proximal left anterior descending artery in 33 patients with HCM and 20 control patients at rest and during hyperemia, allowing calculation of wave intensity. Patients also underwent quantitative first-pass perfusion cardiac magnetic resonance to measure myocardial perfusion reserve. Results Patients with HCM had a lower coronary flow reserve than control subjects (1.9 ± 0.8 vs. 2.7 ± 0.9; p = 0.01). Coronary hemodynamics in HCM were characterized by a very large backward compression wave during systole (38 ± 11% vs. 21 ± 6%; p < 0.001) and a proportionately smaller backward expansion wave (27% ± 8% vs. 33 ± 6%; p = 0.006) compared with control subjects. Patients with severe left ventricular outflow tract obstruction had a bisferiens pressure waveform resulting in an additional proximally originating deceleration wave during systole. The proportion of waves acting to accelerate coronary flow increased with hyperemia, and the magnitude of change was proportional to the myocardial perfusion reserve (rho = 0.53; p < 0.01). Conclusions Coronary flow in patients with HCM is deranged. Distally, compressive deformation of intramyocardial blood vessels during systole results in an abnormally large backward compression wave, whereas proximally, severe left ventricular outflow tract obstruction is associated with an additional deceleration wave. Perfusion abnormalities in HCM are not simply a consequence of supply/demand mismatch or remodeling of the intramyocardial blood vessels; they represent a dynamic interaction with the mechanics of myocardial ischemia that may be amenable to treatment.

H ypertrophic cardiomyopathy (HCM) afflicts 1 in 500 of the general population (1). Chest pain affects up to one-half of patients and is believed to result from impaired myocardial perfusion (2).
Although it is difficult to treat (3), severe perfusion abnormalities are independently predictive of death (4) and development of heart failure (5).
Several potential mechanisms have been proposed to explain these perfusion abnormalities, including increased oxygen requirements due to hypertrophy, impaired ventricular relaxation, anatomic abnormalities of intramyocardial arterioles, and left ventricular outflow tract (LVOT) obstruction (3,(6)(7)(8). However, the relative contribution of each factor, and the impact of LVOT obstruction compared with myocardial hypertrophy alone, remains unclear.
Wave intensity analysis (WIA) describes the waves that cause acceleration or deceleration of coronary blood (9), and it has allowed elucidation of the dominant mechanisms underlying coronary flow in structurally normal hearts (10) and aortic stenosis (11). Acceler- Coronary flow abnormalities are common in HCM, with flow reversal during systole and higher flow velocities during diastole (12)(13)(14).
The goal of the present study was to elucidate the mechanism of myocardial ischemia and angina in HCM through the combination of coronary WIA and cardiac magnetic resonance (CMR) perfusion.

PATIENTS AND METHODS
Consecutive patients with HCM and an indication for coronary angiography were invited to participate.
Control subjects had a structurally normal heart, atypical chest pain, an indication for coronary catheterization, and angiographically unobstructed coronary arteries. All participants provided written informed consent, and the study was approved by an independent ethics committee.
HCM was defined according to American Heart Association criteria (15

Mechanisms of Myocardial Ischemia in HCM
A balanced steady-state free precession sequence was used to obtain breath-hold cine images in 3 long-axis planes, followed by a contiguous short-axis stack through the ventricle. Myocardial first-pass perfusion imaging was performed by using a rate 3, parallelaccelerated balanced steady-state free precession sequence (19). Three short-axis images and an image of the arterial input function were acquired every cardiac cycle for 70 cycles. Initial proton densityweighted images were used for subsequent surface coil intensity correction.   Raphael et al.  Table 1).
At rest, there was a higher BCW tot and lower FEW in patients with HCM compared with control subjects.
The FCW was significantly lower, but there was no significant difference in the BEW. During hyperemia, there was a significant increase in the size of all waves in both groups. The FCW was smaller and the BCW tot was larger in patients with HCM compared with control subjects (Table 4; absolute values, Online Table 1). There was no difference in the BEW. The ratio of accelerating/decelerating waves at rest was    In control subjects, the ratio of the net cumulative wave intensity of the FCW to the BCW was approximately 2:1 ( Table 4), resulting in acceleration of coronary flow during early systole. In HCM, this ratio was reversed to approximately 1:2, causing deceleration during early systole. The situation was worsened during hyperemia, in which the ratio was reduced to 1:4, and reversal of blood flow direction was even greater.
As the ventricle relaxes, compression of the intramyocardial vessels is relieved, generating a BEW that accelerates coronary flow. In the present HCM cohort, the BCW during ventricular contraction was greater than the BEW during ventricular relaxation, which was the opposite of the pattern seen in control subjects.
Patients with HCM typically have diastolic impairment can be palpated clinically (26). We have shown that it is also transmitted into the proximal coronary artery in the form of FEW a , followed by FCW a when the obstruction is relieved.
Although a larger BCW or smaller BEW might be expected in patients with LVOT obstruction compared with those without, clinically HCM is extremely heterogeneous. Both waves will be affected by the degree of diastolic dysfunction, myocardial fibrosis, and ventricular contractility; it is therefore not surprising that division of the present patient cohort according to presence of LVOT obstruction yielded no significant differences between the 2 subgroups.
The relative timing of systole and diastole further disadvantages patients with LVOT obstruction, which prolongs the duration of LV ejection at the expense of the diastolic phase (27). Despite the favorable reduction in microcirculatory resistance during diastole, the duration of diastolic coronary flow is reduced. Mean coronary resistance was defined as the mean of the instantaneous resistance over the entire cardiac period. Resistance was lowest in HCM patients with LVOT obstruction and highest in control subjects. Abbreviations as in Figure 1.  Abbreviations as in Tables 1 and 3.  The myocardial perfusion reserve (MPR) was measured using cardiac magnetic resonance imaging and compared with the changes in wave intensity between rest and hyperemia.
There was a significant correlation between the MPR and the proportionate increase in percentage of accelerating waves during hyperemia. HCM ¼ hypertrophic cardiomyopathy.
Raphael et al.