1

Case

We report a case of a 65 year old white male, ex-smoker with prior history of hypertension and familial hypertrophic cardiomyopathy (HCM).

He presents to the emergency department with a three month history of exercise-induced chest discomfort and shortness of breath. The echocardiogram showed a normal left ventricular systolic function with an ejection fraction of 69% by biplane method and a septal wall thickness of 22 mm. There a was systolic anterior mitral motion of the mitral valve leaflet which causes moderate mitral regurgitation and a dynamic left ventricular outflow tract obstruction (peak gradient of 62 mmHg).

Single-photon emission computed tomography (SPECT) images revealed a reversible inferior-basal and apical perfusions defects ( Fig. 1 ).

Myocardial perfusion SPECT showing hypoperfusion during stress (A) compared to rest (B) to apical (top) and inferobasal (bottom).

Therefore, a diagnostic coronary angiography was performed through radial access. It did not show any significant stenosis to explain the identified evidence of ischemia. We decided to further interrogate both the epicardial artery and the microcirculation. Accordingly fractional coronary flow reserve (FFR), coronary flow reserve (CFR) and index of microvascular resistance (IMR) of the left anterior descending (LAD) artery were performed as previously described using a pressure-temperature coronary wire . Intravenous adenosine (140 ugr./Kg/min) was administered to induce steady-state maximal hyperemia. Results are shown in Table 1 . In our case, the CFR and the IMR in the LAD artery were consistent with high microvascular resistance with an abnormally CFR and an elevated IMR value (39 U), FFR was 0.91, which supports the lack of an occult epicardial obstruction in the LAD territory.

2

Discussion and review

HCM is a genetically determined disease with a wide range of clinical manifestations and pathophysiological substrates. Although several factors have been associated with an unfavorable outcome, the identification of patients at risk for sudden death or progression to heart failure remains a formidable challenge .

Symptoms and sings of myocardial ischemia are often found in patients with HCM despite angiographically normal coronary arteries and it is generally believed to be due to impairment of the coronary microcirculation. Myocardial ischemia may be clinically silent in many patients with HCM. Conversely, chest pain is a frequent complaint, but is not a reliable marker of ischemia. Typical angina related to effort or meals is relatively rare, and patients more often complained of prolonged episodes of atypical chest pain. . Myocardial ischemia is responsible for some of the lethal complications of HCM including ventricular arrhythmias, sudden death, progressive left ventricular remodeling and systolic dysfunction. In some cases ventricular arrhythmias and sudden death may represent the first clinical manifestation of ischemia . Although the genesis of ischemia in HCM is still poorly understood, several pathophysiological features have been identified, including reduced arteriolar density, fibrosis, myocyte disarray and elevated left ventricular end-diastolic pressure. Moreover, structural abnormalities of small vessels have been described in patients with HCM and are thought to represent a primary abnormality, although its pathogenesis remains unclear .

In the past decade, a number of studies in HCM patients have demonstrated marked impairment of the coronary vasodilator reserve and in absence of significant coronary lesions is attributed to impairment of the coronary microcirculation .

Microvascular dysfunction is a common feature of HCM and is not confined to the hypertrophied regions of the myocardium, but is rather a widespread feature of HCM hearts, pointing to a primary involvement of the small vessels in the disease process .

It has been suggested that the reduced capillarity density that accompanies increased left ventricular mass in HCM is responsible for the microvascular dysfunction, but in addition to capillary density, Knaapen et al. suggest that increased hemodynamic loading conditions, as reflected by the outflow tract gradient, left atrium dimensions, and the levels of the biochemical marker NT-pro BNP, are additional important factors of microvascular dysfunction in HCM .

Microvascular dysfunction, in turn, represents a predisposing factor for myocardial ischemia, which may lead to cardiac dysfunction and fibrosis . In patients with HCM, the severity of microvascular dysfunction represents a strong predictor of unfavorable outcome and cardiovascular mortality .

Thus, the hypothesis that microvascular dysfunction may represent a common substrate of progression for several diseases appears plausible, and may have implications for the treatment of different cardiomyopathies, including HCM, dilated cardiomyopathy, aortic stenosis and others .

Accurate quantitative assessment of microvascular dysfunction and myocardial ischemia is not easily feasible in clinical practice. Although signs of inducible ischemia may be detected by electrocardiogram, echocardiogram or myocardial scintigraphy, the vasodilator response to dipyridamol by positron emission tomography (PET) and cardiac magnetic resonance (MRI) is considered more accurate methods but the availability for PET and MRI is limited in clinical practice .

Coronary flow reserve (CFR) is another available method to asses coronary microvascular function. CFR in left anterior descending coronary artery is markedly lower in patients with HCM than in healthy subjects and it has proven to be a strong prognostic predictor in patients with HCM .

While CFR is a useful marker of the status of the microcirculation it is also affected by epicardial disease and is load dependent . Thus in patients with some degree of atherosclerosis CFR may not be as useful for identifying abnormalities specific to the microcirculation given this limitation. Fearon et al. described the index of microcirculatory resistance (IMR), which specifically interrogates the status of the microcirculation and is independent of the presence of an epicardial stenosis . The IMR is a new simple and reproducible method for invasively assessing the state of the coronary microcirculation independently of the state of the epicardial artery using a single pressure-temperature sensor-tipped coronary wire .

The IMR has demonstrated less intrinsic variability and better reproducibility than CFR, and whereas CFR is very sensitive to hemodynamic changes, IMR is largely independent of variations in hemodynamic state. The IMR is more specific than CFR, by the fact that CFR interrogates the entire coronary system, including the epicardial artery and the microcirculation while the IMR specifically quantifies the microcirculation; therefore the IMR appears to be superior to CFR for assessing the coronary microcirculation .

The IMR can be used to predict and identify patients with periprocedural myocardial infarction related to percutaneous coronary interventions (PCI). A pre-PCI IMR ≥ 27 has shown to be independently associated with high risk of developing periprocedural myocardial infarction ; An IMR ≥ 32 has also been identified as a predictor of microvascular dysfunction in patients with ST-segment elevation myocardial infarction ; It has been reported that IMR is an independent predictor of left ventricular functional recovery and viability after acute myocardial infarction and even it has been shown that an IMR ≥ 40 in patients whose suffer an ST-segment elevation myocardial infarction is an independent predictor of long-term clinical outcome, including death alone and death or rehospitalization because of congestive heart failure, whereas other common invasive methods for assessing microvascular function are not ; it has been demonstrated a reversible elevation in microcirculatory resistances (IMR) in Takotsubo cardiomyopathy too .

In our case IMR showed a value of 39 with normal IMR in healthy humans being < 27.2 U (median value of 12.6) .

The coronary microcirculation dysfunction found in our study is consistent with previous researches, however the use of IMR to assess the coronary microcirculation in HCM has not been previously reported to our knowledge.

This objective, easily derived index that is specific to the microcirculation may be useful in future investigations of HCM and may help better understand pathophysiology of HCM. Additionally, the ability to simultaneously assess FFR is useful in ruling out an occult epicardial obstruction.