Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of abnormal loading conditions capable of inducing the degree of hypertrophy observed. HCM is caused by a disease-causing sarcomere variant in up to 60% of probands.1

Coronary microvascular dysfunction (CMD) and ischemia are important pathophysiological features. The etiology of CMD is multifactorial and encompasses reduced capillary density, vascular remodeling, fibrosis, myocyte disarray, extravascular compression secondary to ventricular hypertrophy, diastolic dysfunction and LV outflow obstruction.2–5 Recurrent chronic ischemia has the potential to generate myocyte death and consequently myocardial fibrosis.6,7

As the direct visualization of coronary microcirculation in vivo is not possible, multiple invasive and non-invasive techniques have been developed.5 Coronary microcirculation may be invasively assessed by calculating the index of microcirculatory resistance (IMR). IMR provides information on the state of small vessels and is independent of the presence of epicardial stenosis.8 Three previously published studies with 20 or fewer patients point for a normal value <25.9–11 A larger study including 1096 patients assessed IMR per artery and found 22.0 as the cut-off value for left anterior descending (LAD) artery.12 Despite its well-known use and prognostic prediction in myocardial infarction,13–16 angina without coronary stenosis9,17 and cardiac allograft vasculopathy,18,19 its value in HCM has not been extensively studied. The published data are limited to a case report, reporting elevated IMR in a HCM patient with ischemic abnormalities observed on non-invasive imaging in the absence of epicardial coronary disease.20

Another parameter that may be assessed invasively is coronary flow reserve (CFR), which in the absence of epicardial coronary stenosis, reflects solely microvascular function. Coronary blood flow studies in HCM patients have detected blunted CFR.21–23

In this pilot study, we explored the potential role of IMR in the evaluation of CMD in patients with HCM. We prospectively assessed IMR and CFR in patients with HCM without epicardial coronary disease. The evaluation of the patients was complemented by the detection of perfusion defects and tissue characterization using stress cardiovascular magnetic resonance (CMR).

The study included 14 patients, mean age of 62.8±6.2 years, eight (57.1%) males, nine of whom had obstructive HCM. Angina was a common symptom, and the majority of the patients were on beta blocker (BB) and/or calcium channel blocker (CCB). Baseline characteristics are shown in Table 1.

Evaluation of myocardial ischemia

All patients except one, due to claustrophobia, underwent CMR. Stress CMR demonstrated perfusion defects in 12 out of 13 patients (92%), with an ischemic burden between 3 and 54% of LV (Figure 1).

Figure 1.

Index of microcirculatory resistance and evaluation of ischemia by coronary microvascular dysfunction in a hypertrophic cardiomyopathy patient. A-catheterization of left anterior descending artery coronary and hemodynamic parameters showed on the dedicated software: Distal coronary pressure (Pd)=66 mmHg, resting mean transit time (Bas)=95 ms, hyperemic mean transit time (Hyp)=32 ms, coronary flow reserve (CFR)=3.0. Calculated index of microcirculatory resistance (IMR) was 20.5 (not shown). B-CMR perfusion images with evidence of perfusion defect (arrow).

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Among patients with IMR>22.0, perfusion defects were found in two of the three patients who underwent stress CMR (Table 2).

To the best of our knowledge and despite our small cohort, this is the most extensive study using IMR to assess CMD in HCM patients. Based on IMR and considering the normal cut-off value for LAD of 22.0 as previously published,12 we found CMD in four patients (29%). Invasively, we also documented impaired CFR in more than half of the patients.

In our study, the evaluation was complemented by stress CMR. Imaging methods, such as CMR and positron emission tomography (PET), have been used to study ischemia due to CMD in HCM. Both methods have enabled relate the severity of ischemia to clinical manifestations and outcome. Notably, CMR studies demonstrated the link between CMD and LGE,27–29 and PET studies showed a relationship between CMD and worse outcome, including higher New York Heart Association functional class, left ventricular systolic dysfunction and death.30–32 Compared to PET, CMR has the advantage of presenting high spatial resolution and does not expose the patients to radiation.

The prevalence of CMD by IMR was significantly lower than the detection of ischemia from stress CMR, where we found perfusion defects in 92% of the patients. This finding raises the hypothesis that lower IMR values may be found in HCM patients compared with other diseases, with a possible need to recalibrate the cut-off value in HCM patients, as the pathophysiology is distinct.

We found lower values of Pd, TmnRest and TmnHyper than previously published for controls and patients with ischemic heart disease.16 Pd is proportional to coronary resistance.33 HCM patients present lower coronary resistance compared to the controls,23 leading to lower Pd and consequently lower IMR values. On the other hand, HCM patients had a greater LAD diameter and higher coronary blood flow in the LAD than the controls.23 Coronary flow has an inverse relationship with Tmn.33 If coronary flow in the LAD increases, TmnHyper consequently decreases and further contributes to the lower IMR in HCM.

These findings raise the hypothesis that the reduction in CFR presented in HCM patients may be, at least in part, secondary to near maximal baseline vasodilation of the microcirculation, instead of merely due to narrowing of small vessels or external compression leading to an increase of coronary vascular resistance.34,35

In the presence of CMD, the hemodynamic response to a non-endothelium-dependent vasodilator, such as adenosine, consists in a reduction of CFR and increase in hyperemic microcirculatory resistance. Despite CFR and IMR having been validated for microcirculation assessment, IMR has emerged as the preferential tool since it is more reproducible with a robust prognostic value.36–39 The use of CFR is associated with some limitations, including the incapability to distinguish epicardial from microvascular disease and is influenced by resting hemodynamics namely heart rate, blood pressure and contractility.36 On the other hand, IMR was shown to keep its reproducibility and less hemodynamic dependence even with significant changes in heart rate, blood pressure and contractility, when compared to CFR.37 Interestingly, IMR was demonstrated to be a stronger predictor of survival after ST-elevation myocardial infarction and to have greater value in the prediction of peri-procedural myocardial infarction, compared to CFR.38,39

For a more generalized utilization of IMR in HCM, further studies are needed. In a population where randomized trials are relatively scarce, real-world data are more relevant, and the inclusion of this technique in observational studies might be important.

In the overall study population, 57% of the patients had symptoms of angina, regardless of IMR. Chest pain affects around 25% to 50% of patients with HCM and silent ischemia may occur in up to 50% of those without symptoms.40 Despite this, chest pain is not a reliable marker of ischemia in these patients.41

Since a significant proportion of HCM patients complain of chest pain and undergo a coronary artery assessment, in the absence of epicardial coronary stenosis IMR may be an additional tool during catheterization to clarify the cause of the chest pain.

The assessment of CMD has clinical relevance since chronic and recurrent episodes of ischemia in HCM have the potential to promote adverse tissue changes, such as myocyte death and consequent myocardial fibrosis.32,42–46 In our study, patients with IMR>22.0 tended to present increased ECV and extensive LGE, although our small sample does enable a definitive association to be made.

An important limitation of our study is the small population and the absence of a control group. The main aim was to develop a pilot study for the assessment of the usefulness of IMR in HCM patients. Further research is needed to define clearly the role of this technique and the range of expected values in this population.

Coronary microvascular dysfunction is a pathophysiological finding in HCM, and its evaluation has clinical relevance. IMR is reproducible and specific for assessing the microvasculature with further prognostic value demonstrated in other cardiac conditions. IMR assessment in the scenario of HCM is feasible and safe, with lower Pd, TmnRest and TmnHyper compared to previous reported values in ischemic heart disease. Additionally, patients with abnormal IMR seem to have more significant tissue abnormalities in CMR. Larger studies are needed to clarify the potential of IMR assessment in patients with HCM.

The authors have no conflicts of interest to declare.