Hypertrophic cardiomyopathy is a heterogeneous condition that may present with functional limitation due to dyspnea on exertion, angina, or symptoms of heart failure. Although angina is a common symptom, it is thought to be multifactorial, including abnormal microvasculature and epicardial coronary artery disease. The role of stress testing in the detection of coronary artery disease and its limitations are discussed in this review. Stress testing yields additional information beyond the detection of ischemia, which is prognostic independent of the presence of coronary artery disease and can be beneficial in defining the presence of provocable left ventricular outflow tract obstruction, symptoms, response of heart rate and blood pressure to exercise, and functional capacity. Additional noninvasive imaging techniques, including speckle-tracking echocardiography and coronary flow velocity reserve, positron emission tomographic myocardial blood flow, delayed enhancement on cardiac magnetic resonance imaging, and computed tomographic angiography, are also discussed.
Highlights
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Mechanisms of angina in hypertrophic cardiomyopathy are reviewed.
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Ischemia provides prognostic information in hypertrophic cardiomyopathy, even in the absence of coronary artery disease.
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Detection of coronary artery disease in hypertrophic cardiomyopathy utilizing noninvasive testing has limitations.
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Noninvasive stress testing provides additional prognostic information beyond detection of ischemia in patients with hypertrophic cardiomyopathy.
Hypertrophic cardiomyopathy (HCM) is a heterogeneous, inherited cardiomyopathy with an incidence of about 1 in 500 and a wide spectrum of phenotypes ranging from asymptomatic to heart failure. Patients may present with functional limitations due to dyspnea on exertion, angina, syncope, or atrial fibrillation and its complications. Risk for sudden cardiac death (SCD) is low and estimated at about 0.5% per year. On histologic examination, this disorder is characterized by myocyte hypertrophy and disarray, interstitial fibrosis, and intramural coronary artery medial hypertrophy with resultant narrowing. Symptoms have been attributed to the development of left ventricular outflow tract (LVOT) obstruction, diastolic dysfunction, arrhythmias, and mitral regurgitation (MR), due either to a primary valve abnormality, including abnormal papillary muscle attachment, or septal anterior motion. The focus in treating these patients has been on the relief of LVOT obstruction in symptomatic patients using medications or, in those with refractory symptoms despite optimal medical therapy, septal reduction by alcohol septal ablation or surgical septal myectomy. Following septal reduction via surgical myectomy with relief of LVOT obstruction, patients have been shown to have significant improvements in symptoms and mortality similar to the general population when matched for age and gender.
Angina is a common symptom in patients with HCM, affecting approximately 40% of patients, and has been attributed to multiple etiologies. Over the past several decades, our understanding of these mechanisms has been elucidated, and angina is thought to be due to three main processes: subendocardial ischemia related to abnormal intramural coronary arteries, myocardial bridging, and epicardial atherosclerotic coronary artery disease (CAD). Early autopsy studies demonstrated the presence of transmural infarction in the absence of epicardial CAD as well as abnormal intramural coronary arteries characterized by intimal proliferation, media hypertrophy, and/or luminal narrowing. Studies examining the effect of atrial pacing, which effectively increases heart rate and myocardial oxygen demand, resulting in supply-demand mismatch, noted evidence of ischemic symptoms, electrocardiographic (ECG) changes supportive of ischemia, and increased lactate in patients with HCM with normal epicardial coronary arteries, supporting the hypothesis that subendocardial ischemia is a major determinant of angina in some patients. Angiographic studies noted the presence of myocardial bridge segments with systolic compression of epicardial coronary arteries, which was previously thought to be a potential risk factor for SCD ; however, subsequent studies failed to demonstrate a correlation. The exact prevalence of epicardial atherosclerotic CAD in patients with HCM is unknown but is estimated to be approximately 20% from prior case series. The populations in these studies vary. In older studies, patients with symptoms and physical examination findings suggestive of HCM underwent coronary angiography performed for diagnostic purposes, whereas in a more recent series of patients with HCM diagnosed by echocardiography, coronary angiography was performed either to assess symptoms (approximately 75% of patients) or before cardiac surgery (approximately 20%), but the prevalence of CAD was not reported by indication for angiography. Thus it is difficult to ascertain the exact prevalence of epicardial CAD in patients with HCM, and it may be underdiagnosed. Unfortunately, though the majority of patients with HCM have normal coronary arteries, the risks for SCD and subsequent overall mortality are significantly higher in patients with HCM with severe epicardial CAD (2.1% vs <0.5% per year and 6.6% vs <1% per year, respectively) compared with age-, gender-, and comorbidity-matched patients with HCM without severe epicardial CAD. Additionally, patients with HCM and CAD have a higher incidence of angina than patients with HCM without CAD. Therefore, the proper identification of obstructive CAD in patients with symptomatic HCM is of the utmost importance; however, the detection of ischemia in the absence of epicardial CAD is also associated with decreased event-free survival.
There are many limitations of noninvasive testing for distinguishing CAD from ischemia not related to epicardial CAD in the HCM population, and the benefits need to be weighed with the potential risks of radiation exposure from imaging modalities such as single-photon emission computed tomography (SPECT) and positron emission tomographic (PET) myocardial perfusion imaging (MPI) or contrast-enhanced coronary computed tomographic angiography (CTA). In patients with HCM with angina at intermediate to high risk for CAD, the current recommendation is to pursue coronary angiography, either invasive or CTA, for definitive assessment of coronary anatomy. For patients with HCM with angina at low risk for CAD, the use of CTA, SPECT, or PET MPI is reasonable ( Table 1 ). Definitive identification of CAD is not required in asymptomatic patients with HCM, but it is recommended that patients with HCM >40 years of age without angina undergo invasive angiography or CTA before septal reduction therapy so that need for revascularization may be taken into account in procedural planning.
| Exercise electrocardiography |
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| Exercise stress echocardiography |
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| Cardiometabolic stress testing |
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| Single-photon emission computed tomographic/positron emission tomographic myocardial perfusion imaging |
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| Cardiac computed tomographic angiography |
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| Stress perfusion magnetic resonance |
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| Coronary angiography |
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In addition to the detection of CAD, stress testing also provides valuable clinical and prognostic information. This includes the detection of ischemia in the absence of epicardial CAD, aberrations in systolic and diastolic function with stress, symptoms, heart rate and blood pressure response to exercise, and functional capacity. These aspects are discussed in depth, as well as the benefits and shortcomings of various stress methods and imaging modalities.
Stress Testing Protocols
Stress testing relies on methods of stress and detection of ischemia ( Table 2 ). The most physiologic form of stress is exercise; however, pharmacologic methods, including the use of vasodilators (e.g., regadenoson, adenosine, or dipyridamole) or dobutamine, are used in those unable to exercise. During the period of stress, ECG and other information, including heart rate, blood pressure, and symptoms, is recorded. Imaging during stress testing relies on findings characteristic of ischemia, such as limited coronary flow reserve (CFR; decreased tracer uptake on perfusion scintigraphy) resulting in decreased left ventricular (LV) compliance, decreased myocardial contractility (wall motion abnormalities or systolic dysfunction), and increased LV end-diastolic pressure (alterations in transmitral flow patterns on echocardiography). There are limitations to these methods for the detection of CAD in patients with HCM, as discussed below.
| Advantages | Disadvantages | |
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| Method of stress | ||
| Exercise |
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| Vasodilator (e.g., regadenoson, adenosine) |
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| Dobutamine |
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| Detection of obstructive CAD | ||
| Electrocardiography |
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| Cardiometabolic stress testing |
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| Echocardiography |
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| MPI (SPECT, PET imaging) |
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| CFR |
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| CMR |
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| Cardiac CTA |
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Exercise ECG Stress Testing
Normal ECG findings are rare in patients with HCM, particularly if they are symptomatic or if they have LVOT obstruction. The most common abnormal ECG findings in patients with HCM are LV hypertrophy (LVH) with or without strain and abnormal Q waves. Patients with apical HCM often have deep inverted T waves in the anterolateral leads on electrocardiography. Multiple studies in patients with LVH have shown that the majority of patients will have abnormal ECG findings with exercise suggestive of ischemia in the setting of normal results on MPI and coronary angiography. Accordingly, during exercise, patients with HCM frequently have ST-segment and T-wave abnormalities. These resting and stress ECG abnormalities are of limited use in the differentiation of obstructive CAD from other causes of chest pain in patients with HCM. However, as discussed later in this review, exercise stress testing offers additional assessment of functional capacity, provocation of LVOT obstruction, elucidation of symptoms in patients who may have self-imposed restraints on daily activities, and prognostic information regarding heart rate response, cardiac arrhythmias, and blood pressure response.
Cardiopulmonary Exercise Testing
Cardiopulmonary exercise testing (CPET) involves breath-by-breath analysis of respiratory gas exchange during exercise in addition to the information assessed during standard exercise stress testing (ECG changes, blood pressure response, heart rate recovery, symptoms, and functional capacity or metabolic equivalents [METs]). Detection of CAD relies upon ECG or echocardiographic evidence of ischemia and, as discussed in those sections, is of limited utility in patients with HCM. The main variable calculated is peak oxygen consumption (VO 2 ), a correlate of functional capacity, which describes the ability of the cardiovascular system to deliver blood to the periphery for use by skeletal muscles during exercise. Other variables measured are anaerobic threshold (V T ), expiratory ventilation (VE), carbon dioxide output (V co 2 ), ratio of ventilation to carbon dioxide production (VE/V co 2 ), oxygen pulse (O 2 /heart rate), and work efficiency. Insights regarding functional capacity and its determinants are discussed later in this review.
Stress Echocardiography
Stress echocardiography carries two major intrinsic limitations for the detection or exclusion of CAD in patients with HCM: at rest, regions of hypertrophied myocardium may have abnormal wall motion, and up to 75% of patients with HCM can develop LVOT obstruction during exercise. Despite extensive experience with exercise echocardiography in the evaluation of patients with HCM, assessment of epicardial CAD in this population is limited.
Although the diagnosis of ischemia is difficult with stress echocardiography, information regarding functional capacity, symptoms, and heart rate and blood pressure response to exercise can yield information of prognostic utility in patients with HCM. The use of dobutamine as a pharmacologic stress agent is not recommended in patients with HCM, because it is known to induce substantial LVOT gradients in normal individuals. The appearance of a provocable gradient with dobutamine makes the diagnosis of a de novo diagnosis of HCM complicated and results in increased LVOT gradients in patients with HCM. Accordingly, new regional wall motion abnormalities have been found to appear frequently in patients with HCM undergoing dobutamine stress echocardiography. Despite the presence of exercise-induced wall motion abnormalities, these patients often do not have obstructive CAD by coronary angiography. Additional assessment of LV mechanics with stress is discussed later in this review.
Nuclear Scintigraphy Myocardial Perfusion Imaging: SPECT and PET Imaging
Nuclear scintigraphic MPI relies on the differential between rest and stress myocardial perfusion to detect regions of hypoperfusion during stress, which is assessed as relative hypoperfusion on SPECT and absolute hypoperfusion on PET imaging. The ability of PET imaging to define absolute myocardial perfusion distinguishes it from SPECT. Measurement of absolute myocardial perfusion allows CFR to be determined, as discussed later in this review. In the absence of epicardial CAD, patients with HCM have a high prevalence of reversible and/or fixed perfusion defects, with 40% to 60% of patients having abnormal results on single-photon emission computed tomographic MPI studies. The ratio of endocardial to epicardial myocardial blood flow (MBF) decreases significantly during stress in patients with HCM in the absence of epicardial obstructive CAD and suggests that rest-stress perfusion mismatch is due to microvascular ischemia. MBF correlates with extent of delayed enhancement by cardiac magnetic resonance imaging (CMR) and inversely correlates with the severity of LVH. Often, areas of hypertrophy, commonly the interventricular septum or apex, may appear hyperintense and other regions relatively hypoperfused, which must be taken into consideration when interpreting single-photon emission computed tomographic MPI studies ( Figures 1 and 2 ). Septal stress perfusion defects may also be present and have been shown to resolve on repeat testing with administration of verapamil or following septal myectomy, demonstrating that treatment can reduce microvascular ischemia. Given the pervasiveness of abnormal findings with MPI and low prevalence of epicardial CAD, the value of single-photon emission computed tomographic or PET MPI lies in its negative predictive value, not in its ability to detect underlying CAD in patients with HCM.
Stress Perfusion CMR
CMR detects a large number of perfusion abnormalities in patients with HCM, which limits the ability to differentiate obstructive coronary disease from other causes of chest pain. Dobutamine stress CMR and myocardial first-pass perfusion during adenosine stress have been widely used to detect myocardial ischemia in patients without HCM. In addition, CMR assessments of coronary blood flow (CBF) volume and flow pattern, as well as quantitative stress perfusion CMR (sensitivity, 87%; specificity, 93%) have been used for detection of significant stenosis in native coronary arteries and bypass grafts. Although CMR has demonstrated impaired subendocardial myocardial perfusion reserve and increased prevalence of ischemia in regions of severe hypertrophy in HCM, differentiation between epicardial obstructive CAD and microvascular ischemia has not been evaluated and as such is currently not recommended for the detection of CAD in patients with HCM.
Utility of Exercise Stress Testing in HCM beyond Detection of Ischemia
Assessment of Heart Rate, Blood Pressure, and Arrhythmias with Stress and Prognostic Utility
Exercise stress testing allows the discovery of other potential etiologies of decreased functional capacity in patients with HCM, such as chronotropic incompetence and exercise-induced arrhythmias, in addition to worsened LVOT gradients and MR severity. In one study by Bunch et al. , the incidence of exercise-induced arrhythmias was approximately 45% in the 86 patients who underwent exercise stress echocardiography, with 27% experiencing premature atrial contractions, 2% atrial fibrillation, 33% premature ventricular contractions, and 1.2% nonsustained ventricular tachycardia. In the general population, decreased functional capacity, as measured by METs, abnormal blood pressure response, and heart rate recovery, has been shown to predict adverse cardiovascular outcomes. Similarly, in patients with HCM, failure to augment blood pressure by 20 mm Hg or a decline in systolic blood pressure with exercise has been shown to be associated with the development of ventricular arrhythmias and mortality. Overall incidence of abnormal blood pressure response during exercise ranged from 20% to 37%, with a positive predictive value of 14% to 15% and a negative predictive value of 95% to 97% for SCD. Abnormal blood pressure response to exercise has been attributed failure to augment cardiac output during exertion, as detailed previously.
Assessment of LVOT Obstruction
Patients with nonobstructive LVOT gradients at rest may develop obstruction with provocative measures corresponding with symptoms that may not be detected without additional investigation. LVOT obstruction is present in 20% to 25% of patients at rest and, even without the presence of symptoms, has been identified as an important predictor of heart failure, stroke, and cardiovascular death. Multiple studies have demonstrated that the LVOT gradients and degree of MR are dynamic and influenced by LV contractility, loading conditions, and peripheral vascular resistance. Latent LVOT obstruction can be identified in an additional two thirds of symptomatic patients with LVOT gradients <30 mm Hg at rest with the use of provocative measures. Multiple maneuvers have been used to unmask latent LVOT obstruction, including Valsalva maneuvers, standing, exercise, and the administration of medications including amyl nitrite, isoproterenol, and dobutamine. The use of medications is considered nonphysiologic, and as discussed earlier, dobutamine can induce substantial LVOT gradients in normal individuals. Currently, the use of exercise stress echocardiography is the preferred method for the detection of inducible LVOT obstruction, as it most closely mimics physiologic changes resulting in dynamic obstruction ( Figure 3 ).
LVOT obstruction has been shown in multiple studies to be predictive of adverse cardiovascular outcomes though the association between dynamic LVOT obstruction and prognosis is less well-defined. Nistri et al. studied 74 patients with normal resting LVOT gradients who underwent exercise stress echocardiography and found that those with inducible LVOT gradients ≥30 mm Hg at <5 METs had decreased functional capacity compared with those who developed LVOT gradients ≥30 mm Hg after 5 METs. Interestingly, another recent study by Lafitte et al. investigated a subset of patients with a paradoxical response to exercise, meaning that their LVOT gradients decreased with exercise, and found that compared with those with increased LVOT gradients with exercise, these patients had less severe symptoms, better functional capacity, and a trend toward fewer adverse events. Similarly, a more recent analysis by Reant et al. examined 115 patients with HCM and found, using a Cox backward-entry selection model, that an LVOT gradient ≥50 mm Hg with exercise had an additive predictive value for adverse cardiac events when global longitudinal strain was >15%, even if the resting LVOT gradient was ≥30 mm Hg. In addition to the assessment of LVOT gradients with exercise, exercise stress echocardiography allows the assessment of exercise-induced worsening of MR, which was seen in about 18% of patients in a study by Maron et al.
Assessment of Symptoms and Functional Capacity and Prognostic Utility
In patients with symptomatic obstructive HCM, treatment is clearly indicated; however, patients’ perceptions regarding their symptoms may be misleading. In those who are asymptomatic or with equivocal symptoms by history, further investigation is merited to assess both functional capacity and risk for SCD. Decreased functional capacity is a common finding in patients with HCM and may be present even in asymptomatic patients. Decreased functional capacity due to inability to augment cardiac output during exercise has been attributed to a variety of pathophysiologic mechanisms, including increased intracavitary obstruction, small LV cavity size, chronotropic incompetence, exercise-induced LV systolic dysfunction, subendocardial ischemia, exercise-induced worsening of MR, cardiac arrhythmias, and diastolic dysfunction including myocardial stiffness during exercise.
A recently published study from our group examined a cohort of 426 asymptomatic or minimally symptomatic patients with HCM and found that the majority (82%) failed to reach 100% of their age- and gender-predicted METs, and there was a 12% incidence of a composite outcome of appropriate implantable cardioverter-defibrillator shocks, heart failure admissions, and death in those unable to achieve 85% of age- and gender-predicted METs compared with 1% in those achieving ≥100% of age- and gender-predicted METs ( Figure 4 ). On multivariate regression analysis, percentage-predicted age- and gender-predicted METS, heart rate recovery, and atrial fibrillation predicted outcomes, whereas resting and induced LVOT gradients were not predictive. Heart rate recovery in the first minute of recovery has been ascribed to vagal reactivation, and parasympathetic activity has been shown to be blunted in patients with HCM with ventricular tachycardia, suggesting a possible mechanism for the association with SCD seen in this study. Similarly, autonomic dysfunction in patients following myocardial infarction has also been attributed as a cause of sudden death in this population. On the basis of these findings, current recommendations from the American College of Cardiology/American Heart Association and the European Society of Cardiology recommend exercise stress testing in three scenarios: (1) to assess functional capacity or response to treatment, (2) to monitor the electrocardiogram and blood pressure during exercise for SCD risk stratification, and (3) to assess for exercise-induced dynamic LVOT obstruction by echocardiography in patients with resting LVOT gradients <50 mm Hg.
The use of CPET in systolic and diastolic heart failure is well established, and strong correlations exist between peak V o 2 , cardiac output, and mortality, in addition to progression to end-stage heart failure and need for heart transplantation. Additionally, patients with heart failure also have a lower V T , which has been attributed to reduced muscle mass and loss of type I muscle fibers, which are fatigue resistant compared with type IIa and IIb fibers. By the same token, patients with HCM have been shown in multiple studies to exhibit several abnormalities on CPET. In a study by Jones et al. of patients with HCM who underwent CPET, peak V o 2 was <60% predicted in 58% of patients (29 of 50) and >80% predicted in only 4% (two of 50). Additionally in this same study, V T was <60% predicted in 62% of patients (31 of 50), work efficiency was decreased in 32% of patients (16 of 50), and oxygen pulse was reduced. This suggests reduced stroke volume response, ventilation-perfusion mismatch, and abnormal oxygen utilization in the periphery as mechanisms for decreased functional capacity in patients with HCM. Unfortunately, there is significant overlap between the ranges of peak V o 2 among patients with different New York Heart Association classifications, which further underscores the need for quantitative versus qualitative assessment of functional capacity.
Functional capacity as determined by CPET also plays an important role in prognostication for patients with HCM. Finocchiaro et al. studied 156 patients with HCM and evaluated findings on rest and stress echocardiography and CPET and found that decreased functional capacity (peak V o 2 < 80% predicted), ventilatory inefficiency (VE/V co 2 > 34), and left atrial volume index > 40 mL/m 2 were independent predictors of a composite outcome of septal reduction therapy, heart transplantation, and cardiac death. Similarly, in a study from our group examining 1,005 patients with HCM who underwent CPET with echocardiography, lower absolute and percentage predicted V o 2 , abnormal heart rate response, and lower LV ejection fraction were independent predictors of a composite end point of appropriate implantable cardioverter-defibrillator discharges, resuscitated SCD, stroke, heart failure admission, and death ( Figures 5 and 6 ). These studies parallel similar findings in systolic and diastolic heart failure, as noted above.
In addition to improved quantification of functional capacity, the use of CPET in patients with HCM has also allowed improved assessment of the mechanisms limiting functional capacity. As seen in patients with heart failure, peak V o 2 in patients with HCM has also been shown to be associated with cardiac output and determined by the ability to increase stroke volume during exercise. Multiple studies have looked at proposed mechanisms for decreased functional capacity in patients with HCM. No correlation was seen between peak V o 2 and LVH. Peak V o 2 is inversely correlated with resting LVOT gradients and has been shown to improve along with symptom alleviation following septal reduction and abolition of LVOT obstruction. Studies examining the association of peak V o 2 with markers of diastolic dysfunction have been less consistent. With simultaneous cardiac catheterization, a VE/V co 2 ratio of >35.5 was shown to correlate with a pulmonary artery pressure ≥30 mm Hg, mean pulmonary artery pressure ≥20 mm Hg, and pulmonary capillary wedge pressure of ≥15 mm Hg, whereas in other studies, no correlation has been found between functional capacity (peak V o 2 ) and V T and elevated left atrial pressure. Studies investigating the relationship of Doppler echocardiographic assessments of diastolic dysfunction and functional capacity have been equally conflicting. In one study, lateral E′ and left atrial volume index were shown to be inversely correlated with functional capacity (peak V o 2 ), whereas other studies have not confirmed these findings. Compared with other indices of exercise testing, peak V o 2 is decreased in patients with abnormal blood pressure response and chronotropic incompetence during exercise.
Additional studies have been conducted to assess other potential determinants of peak V o 2 in patients with HCM, and more recent studies have found that aortic stiffness determined by CMR is predictive. Aortic stiffness is assessed by the pulse-wave velocity (PWV), or the ratio of aortic path length between the mid and descending aorta to the time delay between the arrival of the foot of the pulse wave between the two points. PWV or aortic stiffness has been shown to be predictive of increased incidence of stoke and death in patients with hypertension and adults age ≥60 years of age and predictive of exercise capacity in patients with heart failure and CAD. Increased aortic stiffness has been hypothesized to result in adverse outcomes by leading to increased systolic blood pressure and LV afterload, resulting in LVH and increased myocardial oxygen demand and subendocardial ischemia. The exact mechanism of increased aortic stiffness in patients with HCM is unknown at this time, but hypotheses include atherosclerotic disease, abnormal vasoconstrictor responses, endothelial dysfunction, and underlying structural abnormalities in the arterial wall related to the underlying myocardial fibril disorganization inherent to HCM. Boonyasirinant et al. found that patients with HCM have significantly higher PWV, or aortic stiffness, compared with a normal control population and that PWV was higher in patients with HCM with myocardial fibrosis compared with those without. The causative nature of this relationship is unknown. In an additional study from our group, aortic stiffness as measured by PWV was shown to be an independent predictor of peak V o 2 , whereas LV wall thickness, LVOT gradients, and diastolic indices were not predictive on multivariate analysis.
On the basis of the studies referenced here, current recommendations from the European Society of Cardiology include a preference for CPET in severely symptomatic patients being evaluated for heart transplantation or mechanical support, to assess the severity and mechanism of exercise limitations, ECG and blood pressure changes in both asymptomatic and symptomatic patients with HCM, and to determine the severity of exercise limitation in symptomatic patients with HCM before alcohol septal ablation or septal myectomy.
LV Mechanics with Stress
Although detection of CAD using exercise stress echocardiography is limited, as discussed earlier, there is a growing body of literature addressing multiple aspects of LV mechanics with stress in patients with HCM. As noted above, assessment of diastolic parameters, including transmitral flow patterns, is often incorporated into stress echocardiography, as LV end-diastolic pressure has been noted to increase with ischemia; however, there is conflicting evidence regarding the association between diastolic parameters (i.e., left atrial volume index, e′) and functional capacity (peak V o 2 ). Patients with HCM have been shown to have lower mitral annular early diastolic velocity (e′) at rest and a diminished increase in e′ with supine exercise bicycle testing compared with normal control subjects. In this same group of 40 patients with HCM, longitudinal diastolic function reserve index, defined as e′ baseline × (e′ 50 watts − e′ baseline ), was lower compared with 41 normal age- and gender-matched control subjects. Longitudinal diastolic function reserve index has also been shown to provide incremental prognostic information for decreased exercise capacity (exercise duration <500 sec) with multivariate regression when controlling for age, gender, body mass index, and left atrial volume index in patients with HCM. Additionally, longitudinal systolic velocity index was similarly noted with a lower mitral annular systolic velocity (s′) at rest and blunted increase with exercise in patients with HCM compared with normal control despite normal LV ejection fraction at rest.
Speckle-tracking echocardiography has been used to examine LV mechanics, including peak longitudinal and circumferential systolic strain, strain rates, twist, dyssynchrony, and systolic functional reserve. Twist and twist rates have been shown to be higher at rest and to increase less with exercise, whereas untwist rates have been shown to be lower at rest and also to increase less with exercise in patients with HCM compared with normal control subjects and patients with hypertension and LVH. This finding is thought to be related to delayed LV filling with exercise, impaired systolic-diastolic coupling, and decreased exercise tolerance in patients with nonobstructive HCM. LV dyssynchrony, defined as the SD of time to peak strain between segments, has been shown to increase in patients with HCM compared with normal control subjects and patients with hypertension and LVH and to correlate with decreased exercise capacity. Additionally, markedly attenuated systolic functional reserve, defined as the difference in rest and stress peak longitudinal strain divided by rest peak longitudinal strain, has been seen in patients with HCM compared with normal control subjects and patients with hypertension and LVH. These findings have increased the depth of understanding of mechanisms of impaired exercise capacity, though much is still left to be discovered in this complex disease.
Additional Noninvasive Assessments of CAD
CFR and Coronary Flow Velocity Reserve
CFR has been used in the assessment of epicardial coronary stenosis and the examination of the microvascular circulation. Validated in multiple studies, CFR is defined as the ratio of maximal hyperemic, or stimulated, CBF to baseline resting CBF and is determined by both epicardial and microvascular resistance. CBF may increase by three to four times at maximal hyperemia, and CFR is generally considered abnormal when less than 2.6, though most studies use 2 as a cutoff. It should be noted that CFR may be abnormal in the setting of obstructive CAD, microvascular disease, or high resting CBF and normal hyperemic CBF, resulting in an abnormal ratio. It can be measured directly by coronary flow wire or indirectly by pulse-wave Doppler echocardiography coronary flow velocity reserve (CFVR), PET MBF reserve, or magnetic resonance imaging MBF reserve. Discussion of these technologies is restricted to their relevance to HCM, and magnetic resonance imaging MBF reserve is not discussed further, because data in HCM are limited, as noted previously.
Both transthoracic and transesophageal echocardiography, especially with the development of contrast enhancement and second-harmonic imaging techniques, can be used to measure CFVR in almost all patients, using coronary flow velocity in the left anterior descending coronary artery at rest and maximal hyperemia. Additionally, CFVR has been shown to be reproducible and to correlate well with Doppler flow wire CFR. Studies suggest that in patients with negative dobutamine stress echocardiographic results, abnormal CFVR in the left anterior descending coronary artery identified by transthoracic pulsed-wave Doppler echocardiography can improve the identification of obstructive CAD within the sampled artery by noninvasive imaging. A small study by Memmola et al. examining 10 symptomatic patients with obstructive HCM noted higher than normal diastolic and lower than normal systolic left anterior descending coronary artery flow velocity at rest, as well as decreased CFVR in the absence of obstructive epicardial CAD. A slightly larger study by Tesic et al. examined 61 patients with HCM (41 nonobstructive) and 20 control subjects and found that diastolic CBF velocity was higher and CFVR lower compared with 20 normal control subjects, and these findings were more pronounced with obstructive HCM compared with nonobstructive HCM. Additionally, CFVR was inversely correlated with septal wall thickness and in the obstructive HCM group inversely correlated with LVOT gradient. It has been hypothesized that the higher diastolic coronary flow velocity is reflective of higher oxygen demand and that in systole there is compression of the microcirculation, impeding flow and exacerbated in situations with increased septal wall thickness and increased LVOT gradients. CFVR < 2 in patients with HCM has been shown to be an independent predictor of adverse cardiac events in multiple studies.
One advantage of PET imaging is the ability to assess regional MBF, which has been shown to be abnormal in patients with HCM even in nonhypertrophied segments and can be regional in nature. As noted earlier in this review, abnormal hyperemic MBF is thought to be due to microvascular disease and has been shown to be associated with areas of delayed enhancement on magnetic resonance imaging and inversely with wall thickness. Impaired hyperemic MBF has also been shown to be related to contractile function independent of the presence of delayed enhancement on magnetic resonance imaging. Similar to CFVR, abnormalities in PET MBF have also been shown to be present in asymptomatic patients with HCM and have been shown to be an independent predictor of adverse cardiac events, including progression to heart failure, development of ventricular arrhythmias, and death. In a more recent analysis Castagnoli et al. followed 100 patients with HCM who underwent PET dipyridamole MBF assessment and found that a threshold of global MBF <1.35 mL/min/g was independently predictive of poor outcomes, including stroke, ventricular arrhythmias, progression to heart failure, and death; however, analysis of regional MBF demonstrated that all four patients who died were within the lowest tertile of lateral wall MBF (≤1.72 mL/min/g), but reduced septal wall MBF was not predictive of death. This suggests that reduced lateral wall MBF may represent more diffuse involvement of the microvascular circulation and more severe disease, but this will need to be further studied.
Delayed Enhancement by CMR
An advantage of CMR is the detection of delayed enhancement, which is a nonspecific finding present in approximately 60% to 80% of patients with HCM and is associated with cardiac death, heart failure death, and all-cause mortality in patients with HCM. First-pass stress perfusion by CMR has shown that the subendocardial zones as well as regions of hypertrophy are reliably the areas of worst inducible hypoperfusion in HCM, whereas fibrosis determined by delayed enhancement predominantly develops within the midwall and subepicardial zones, suggesting that ischemia is not the only determination of delayed enhancement ( Figure 7 ). In contrast, the presence of delayed enhancement in patients with HCM has been found to correlate with larger ischemic burden in comparison with patients with HCM without enhancement. Thus, although the magnitude of delayed enhancement may be an important factor in the assessment of ischemic burden in patients with HCM, it remains difficult to use it as a sole marker of myocardial ischemia, much less as a discriminator between impaired microcirculation and obstructive epicardial CAD.
