Structural Coronary Microvascular Dysfunction in Asymptomatic Patients With Apical Hypertrophic Cardiomyopathy

Microvascular dysfunction, reflected by an inadequate increase in myocardial blood flow in response to dipyridamole infusion, is a recognized feature of hypertrophic cardiomyopathy. Its long-term effect on the prognosis is unknown. We prospectively evaluated a cohort of patients with hypertrophic cardiomyopathy after they had undergone quantitative assessment of myocardial blood flow by positron-emission tomography (PET). Fifty-one patients (New York Heart Association class I or II) were followed for a mean (+/-SD) of 8.1+/-2.1 years after PET. Twelve subjects with atypical chest pain served as controls. Measurement of flow was performed at base line and after the infusion of the coronary vasodilator dipyridamole, with the use of nitrogen-13-labeled ammonia. Patients were then divided into three equal groups with increasing values of myocardial blood flow. The response of myocardial blood flow to dipyridamole was severely blunted in the patients, as compared with the controls (1.50+/-0.69 vs. 2.71+/-0.94 ml per minute per gram of tissue, P<0.001). Sixteen patients (31 percent) had an unfavorable outcome (death from cardiovascular causes, progression to New York Heart Association class III or IV, or sustained ventricular arrhythmias requiring the implantation of a cardioverter-defibrillator) 2.2 to 9.1 years after PET. Reduced blood flow in response to dipyridamole was strongly associated with an unfavorable outcome. Multivariate analysis showed that among patients in the lowest of the three flow groups the age-adjusted relative hazard of death from cardiovascular causes was 9.6 (P=0.02) and the relative hazard of an unfavorable outcome (a combined end point) was 20.1 (P=0.003), as compared with patients in the two other flow groups. Specifically, all four patients who died from heart failure and three of five who died suddenly were in this subgroup. In patients with hypertrophic cardiomyopathy, the degree of microvascular dysfunction is a strong, independent predictor of clinical deterioration and death. Severe microvascular dysfunction is often present in patients with mild or no symptoms and may precede clinical deterioration by years. Copyright 2003 Massachusetts Medical Society

A relatively simple, invasive method for quantitatively assessing the status of the coronary microcirculation independent of the epicardial artery is lacking. By using a coronary pressure wire and modified software, it is possible to calculate the mean transit time of room-temperature saline injected down a coronary artery. The inverse of the hyperemic mean transit time has been shown to correlate with absolute flow. We hypothesize that distal coronary pressure divided by the inverse of the hyperemic mean transit time provides an index of microcirculatory resistance (IMR) that will correlate with true microcirculatory resistance (TMR), defined as the distal left anterior descending (LAD) pressure divided by hyperemic flow, measured with an external ultrasonic flow probe. A total of 61 measurements were made in 9 Yorkshire swine at baseline and after disruption of the coronary microcirculation, both with and without an epicardial LAD stenosis. The mean IMR (16.9+/-6.5 U to 25.9+/-14.4 U, P=0.002) and TMR (0.51+/-0.14 to 0.79+/-0.32 mm Hg x mL(-1) x min(-1), P=0.0001), as well as the % change in IMR (147+/-66%) and TMR (159+/-105%, P=NS versus IMR % change), increased significantly and to a similar degree after disruption of the microcirculation. These changes were independent of the status of the epicardial artery. There was a significant correlation between mean IMR and TMR values, as well as between the % change in IMR and % change in TMR. Measuring IMR may provide a simple, quantitative, invasive assessment of the coronary microcirculation.

Hypertrophic cardiomyopathy (HCM) is an umbrella term for a heterogeneous heart muscle disease that was historically (and still is) defined by the detection of left ventricular (LV) hypertrophy (LVH) in the absence of abnormal cardiac loading conditions. Long after this morphological definition was established, the genetic basis of HCM was discovered, and we now know it is predominantly caused by autosomal dominant mutations in sarcomeric protein genes.1 Several patterns of LVH have been described in HCM: asymmetric septal (here referred to as “classic” HCM), concentric, reverse septal, neutral, and apical (ApHCM),2 as well as other, rarer LVH variants such as isolated lateral LVH and isolated inferoseptal LVH. Distinguishing between morphological HCM subtypes has conferred little in terms of personalized management strategies, with one distinctive exception: ApHCM. Compared with classic HCM, ApHCM is more sporadic, sarcomere mutations are detected less frequently, there is more atrial fibrillation (AF) and sudden cardiac death (SCD) risk factors differ. No authoritative ApHCM‐specific recommendations to guide diagnosis, family screening, and patient risk stratification currently exist. First described in Japan in 1976,2 ApHCM is exemplified by “giant” negative precordial T‐waves on electrocardiography and by “spadelike” configuration of its LV cavity in end diastole.3 This review summarizes the epidemiology, clinical expression, genetics, and prognosis of ApHCM, while also highlighting knowledge gaps. Pathophysiology and Clinical Characteristics Epidemiology ApHCM is not as rare as first thought, accounting for up to 25% of HCM in Asian populations and 1% to 10% in non‐Asians.4 Ethnic variation influences prevalence, natural history, and prognosis, and Western sufferers may exhibit a more malignant form.1 Genetics Fewer ApHCM patients report a positive family history compared with classic HCM,5 potentially suggesting differences in ascertainment screening and/or different etiological (genetic, environmental) factors. In this context, the applicability of conventional HCM risk stratification can be challenged given that family history of SCD is heavily weighted6, 7 (Table 1).1, 2, 4, 8, 9, 10, 11 Table 1 Genetic and Phenotypic Differences and Similarities Between Classic HCM and ApHCM Classic (ASH) HCM ApHCM % Of all HCM cases 462 82 Mean age at diagnosis, y 46 (all subtypes) 41.41 ECG Voltage criteria for LVH Nonspecific ST‐segment and T‐wave abnormalities Deep, narrow Q‐waves in the lateral and inferior leads Giant negative T‐waves characteristic Voltage criteria for LVH, T‐wave inversion AF relatively common; NSVT Genetics Autosomal dominant sarcomere protein gene mutations Identifiable pathogenic gene mutations in 34%–40% Majority of gene mutations in MYBPC3 and MYH7 Autosomal dominant sarcomere protein gene mutations Identifiable pathogenic gene mutations in 13%–25% Majority of gene mutations in MYBPC3 and MYH711 Associated morbidity Atrial fibrillation8 LVOTO Diastolic dysfunction Chest pain Pulmonary hypertension9 Ventricular arrhythmias Atrial fibrillation Diastolic dysfunction Chest pain Pulmonary hypertension Ventricular arrhythmias All‐cause mortality rate 1.3% (all subgroups combined)10 0.5%–4% (but much lower patient numbers)—likely equivalent4 ApHCM indicates apical hypertrophic cardiomyopathy; ASH, asymmetrical septal hypertrophy; HCM, hypertrophic cardiomyopathy; LVH, left ventricular hypertrophy; LVOTO, left ventricular outflow tract obstruction; MYBPC3, myosin‐binding protein C; MYH7, β‐myosin heavy chain; NSVT, nonsustained ventricular tachycardia. John Wiley & Sons, Ltd In terms of identifiable sarcomere gene mutations, one study that used a 9‐gene panel, 25% of 71 ApHCM versus 34% of 1053 all‐cause HCM patients had detectable genetic defects11: ACTC1 (cardiac α‐actin 1), MYBPC3 (myosin‐binding protein C), MYH7 (β‐myosin heavy chain), MYL2 (myosin regulatory light chain), MYL3 (myosin essential light chain), TNNT2 (cardiac troponin T2), TNNI3 (cardiac troponin I3), TNNC1 (troponin C1, slow skeletal and cardiac type), and TPM1 (α‐tropomyosin 1). The phenotype and clinical outcomes of these ApHCM patients did not differ between genotype‐positive or ‐negative subjects.11 Other studies confirm reduced mutation rates in ApHCM versus all‐cause HCM (13% versus 40% with an 8‐gene panel, plus 3 metabolic cardiomyopathy genes: GLA (α‐galactosidase A) for Fabry disease; LAMP2 (lysosomal associated membrane protein‐2) for Danon disease; and PRKAG2 (protein kinase, AMP‐activated, noncatalytic, gamma‐2) for PRKAG2 cardiomyopathy.12 As with classic HCM, identified genetic mutations in ApHCM are mainly sarcomeric, autosomal dominant, and influenced by environmental and ethnic/demographic factors including sex.5 Specific data regarding genetic profiling in the different ApHCM morphologies or ethnicities are lacking. In a study looking at genotype‐phenotype correlations in ApHCM, those that carried a pathogenic sarcomere gene mutation had a stronger family history of HCM (39% versus 26%; P=0.4) but no phenotypic features were not significantly different.11 European Society of Cardiology (ESC) and American College of Cardiology Foundation/American Heart Association HCM guidelines provide no ApHCM‐specific genotyping or family screening recommendations. Histopathology Myocardial biopsies from the LV apex in ApHCM have been compared with those from the septum in classic HCM and show less myocyte disorganization (10% versus 86%, P 0.5 is associated with increased incidence of AF, stroke, heart failure, and cardiovascular death.24 Degree of obliteration rather than apical wall thickness influences prognosis.23 MVOCO may occur as a consequence of midapical lateral and septal hypertrophy15 and therefore a complication of mixed rather than pure ApHCM. In severe cases, midventricular cavity obliteration persists in diastole and is often associated with a paradoxical midcavity diastolic flow jet, which indicates the associated presence of an apical aneurysm.16 In contrast, the pathophysiology behind midventricular obstruction in classic HCM is attributable to the basal‐to‐midseptal hypertrophy coming into contact with a hypercontractile but nonhypertrophied LV free wall, often with the interposition of hypertrophied papillary muscle. Apical Aneurysms Apical aneurysms are defined as a discrete, thin‐walled, dyskinetic/akinetic segment of the most distal portion of the LV with a relatively wide communication to the main cavity in diastole.16 They occur in 2% of patients with HCM and 13% to 15% with ApHCM16, 25 (Figure 3). A cue to their presence is the persistence of apical blood pooling distal to the point of apical systolic cavity obliteration17 and/or a paradoxical diastolic jet. Small aneurysms are often overlooked on echocardiography and may be difficult to delineate without advanced imaging.15 In ApHCM, it is hypothesized that apical aneurysms and obstructive physiology arise from regional myocardial scarring caused by repeatedly exposing the apical myocardium to increased LV wall stress and high systolic pressures, leading to pressure overload, increased oxygen demand, impaired coronary perfusion, and ischemia.25 The dyskinetic/akinetic aneurysm confers risk of apical thrombus formation and thromboembolic stroke.25 Apical aneurysms have been associated with LVH severity, SCD, monomorphic VT,24 LV systolic dysfunction, and heart failure.25 Figure 3 CMR comparison of mixed ApHCM (A through C) and pure ApHCM (D through F), both with apical aneurysm formation. Long‐axis views of a patient with mixed ApHCM in diastole in 2‐chamber (Ai) and 4‐chamber (Aii), which in systole demonstrate midventricular obstruction but not total cavity obliteration due to persistence of apical chamber (Bi; Bii). The apical aneurysm contains LGE (Ci; Cii). A different patient with pure ApHCM has a thinned aneurysmal apex demonstrated in diastole on 2‐ (Di) and 4‐chamber views (Dii). In systole, the apical aneurysm becomes apparent (Ei; Eii) and contains LGE (Fi; Fii). ApHCM indicates apical hypertrophic cardiomyopathy; LGE, late gadolinium enhancement. It is important to distinguish apical aneurysms arising from ApHCM from those arising from midcavity obstruction in classic HCM. One study investigating outcomes in patients with apical aneurysms irrespective of the HCM morphological subtype, identified aneurysms in 4.8%.26 Authors identified 2 distinct patterns of LVH in those with aneurysms: segmental thickening confined to the distal LV in 51%, and in the remaining 49% diffuse thickening of the septum and free wall, resulting in an “hourglass” configuration with midventricular muscular narrowing, creating discrete proximal and distal chambers.26 Thromboembolic events were 2‐fold more common (P=0.06) in those with apical aneurysms compared with those without, and this subgroup also experienced a 3‐fold greater adverse event rate, at 6.4%/year. Phenotypic Mimics Fabry disease causes progressive LVH that potentially mimics ApHCM. Up to 23% of patients with Fabry disease with LVH have ApHCM pattern by CMR.27 Long‐term athletic training produces cardiac structural changes, namely, increased diastolic dimensions of the LV cavity, LVH, and increased LV mass.28 In athletes with LVH, distinguishing the physiological “athlete's heart” from HCM may be challenging. An overlapping “gray zone” is described when absolute LV wall thickness is between 13 and 15 mm, observed in 2% of highly trained male athletes.29 Highly trained female athletes rarely show >11 mm of LVH, suggesting that athletic females presenting within the “gray zone” are more likely to have HCM.29 In one athletes study exploring LVH ≥13 mm on echocardiography, 3 had pure apical LVH (range 15–18 mm), and 2 had LVH basally, as well as in the apex.28 Native T1 and extracellular volume values using CMR are lower in athletes than in HCM, which is a useful differentiator.30 Furthermore, as LVH increases in athletes, extracellular volume continues to decrease, whereas in HCM it continues to increase. Athletes with pure apical LVH had normal ECGs (no T‐wave inversion28), and the phenotype was postulated to reflect athletic training, rather than true HCM. Another study demonstrated that athletes with HCM were 3 times likelier to exhibit ApHCM than their sedentary HCM counterparts (35.8% versus 11.9%).31 It is difficult to distinguish apical LVH attributable to athletic remodeling from ApHCM; however, an ApHCM‐pattern ECG is regarded as unequivocally abnormal.31 The increased frequency of ApHCM in athletes may itself reflect an ascertainment bias resulting from screening programs, but as mentioned above, the difficulty in assessing SCD risk remains. Imaging Echocardiography Transthoracic echocardiography can reveal apical hypertrophy, differentiate between pure and mixed forms, and identify additional prognostic features that could influence outcome such as the presence of diastolic dysfunction, MVOCO, or apical aneurysms.23, 32, 33 However, imaging the apex remains a potential challenge, particularly for subtle prognostic features such as apical akinesis or sequestration caused by massive hypertrophy.16 Early phenotypes and relative ApHCM could be missed by echocardiography; thus, those with deep T‐wave inversion and noncontributory echocardiography should undergo additional imaging.34 Although global LV systolic function may appear normal or supranormal in ApHCM, LV peak systolic mitral annular velocity (S’) is commonly reduced, more so in the mixed rather than in the pure form.32 Interstitial fibrosis of the subendocardium (where muscle bundles aligned along the LV driving long‐axis function), commonly seen in ApHCM, may partly account for this impairment. Furthermore, end‐systolic MVOCO and paradoxical diastolic flow jets predict apical asynergy and apical aneurysms, and are associated with increased morbidity16 (Figure 4). Figure 4 Transthoracic echocardiography in ApHCM. ApHCM with a small discrete apical chamber visible in the apical 3‐chamber view (A) and corresponding polar plot showing loss of longitudinal strain apically (B). At rest, continuous wave Doppler across the point of distal ventricular obstruction demonstrates a midsystolic peaking jet, followed by a drop in velocity prior to second peak representing paradoxical early diastolic jet flow, with gradients of 54 and 39 mm Hg, respectively (Ci). During Valsalva, systolic and diastolic jets merge, with a systolic intracavity gradient of 127 mm Hg, and a lengthening of the diastolic “tail” toward late diastole (Cii). By contrast, (D) demonstrates continuous wave Doppler traces from a patient with ApHCM and midcavity obstruction. At rest, there is midsystolic loss of Doppler alignment due to cavity obliteration, with corresponding Doppler dropout before paradoxical diastolic jet (Di). During Valsalva, the measured systolic gradient is unchanged, but the paradoxical diastolic jet gradient now exceeds 100 mm Hg with extension in duration to the end of diastole (Dii). ApHCM indicates apical hypertrophic cardiomyopathy. Two‐dimensional strain or speckle tracking demonstrate regional apical dyskinesis and reduced LV “twist,” which can be attributable to cavity obliteration negating the effect of apical twist in systolic contraction. Cardiovascular Magnetic Resonance CMR may detect early ApHCM phenotypes better than echocardiography. Apical hypertrophy was missed by echocardiography in 40% of cases, later detected by CMR.35 CMR is more sensitive at detecting apical aneurysms and can identify 25% to 43% of those missed by echocardiography.25, 36 CMR has advantages in confounding patient populations, such as athletes. Late gadolinium enhancement (LGE) is common in HCM; the presence and amount of LGE may be associated with the severity of hypertrophy as well as increased risk of heart failure and SCD.37 LGE patterns in ApHCM are characteristically apical and subendocardial37, 38, 39–patterns that are uncommon in other HCM variants in the absence of coexisting coronary disease. This “MI pattern” of LGE adds credence to the hypothesis that apical myocardial ischemia is key in ApHCM. HCM registry data showed LGE in ApHCM in 45.8% of subjects.40 Aneurysms are considered the arrhythmogenic substrate, but it may be the intra‐aneurysm scar that matters most. Of note, extent/presence of (apical or any) LGE does not feature in the ESC HCM risk‐stratification algorithm. Despite heterogeneity in reported native T1 values (indicating diffuse myocardial fibrosis) in classic and ApHCM versus healthy controls, values consistently correlate with wall thickness and LGE and can also be elevated in LGE‐negative apical segments.41 Areas of T2 elevation (indicating myocardial edema) are also seen in HCM. Rest and stress perfusion data are missing for ApHCM (Figure 5). Rest perfusion abnormalities have been well described in classic HCM, correlating with severity of LGE, degree of hypertrophy and myocardial fibrosis.42 The clinical significance of perfusion abnormalities is not yet explored. Figure 5 Quantitative perfusion mapping in ApHCM. CMR pixelwise inline perfusion maps at rest (A), stress (B) in (i) basal, (ii) mid, (iii) apical short axis and (iv) 2‐chamber views in a patient with ApHCM and MVOCO. Stress perfusion defects are seen in the hypertrophied apex. Bull's‐eye plots are shown (rest C, stress D). There is 37% MBF reduction at stress (D) apically (1.47 mL/g per minute) vs 2.35 mL/g per minute in remote, non‐hypertrophied segments. Rest MBF(C) is 0.74 and 0.85 mL/g per minute, respectively. MPR is 1.99 in the apex and 2.76 in remote myocardium, indicating microvascular disease in the hypertrophied apex. Healthy volunteer stress MBF is 2 to 4 mL/g per minute. ApHCM indicates apical hypertrophic cardiomyopathy; CMR, cardiovascular magnetic resonance; MBF, myocardial blood flow; MPR, myocardial perfusion reserve; MVOCO, midventricular obstruction and cavity obliteration. Cardiac Computerized Tomography Computerized tomography (CT) using iodine‐based contrast detects late enhancement consistent with the presence of myocardial fibrosis. While the segment‐based sensitivity of computerized tomography for HCM fibrosis detection is lower than for CMR, patient‐based sensitivity is similar43 offering a viable alternative for those unable to undergo CMR. As it is not uncommon for ApHCM to open clinically with chest pain and T‐wave inversion, computerized tomography reporters should be alert to the possibility of discovering ApHCM in such referrals. Nuclear Scintigraphy Perfusion imaging using single photon emission computed tomography (SPECT) unveils the characteristic (but not pathognomonic) “solar polar” perfusion map of ApHCM: an intensely bright apical spot of counts surrounded by a circumferential ring of decreasing counts.44 Other findings include increased apical tracer uptake at rest and the spadelike configuration of the LV.45 Fixed and reversible stress perfusion defects are reported in the context of unobstructed epicardial coronary arteries,45 but again, the significance of these findings is unexplored. Single photon emission computed tomography can miss ApHCM because dense apical fibrosis normalizes apical tracer counts so single photon emission computed tomography and other findings (ECG, wall thickness) do not correlate.1, 45 Angiography Left ventriculography identifies the characteristic “ace of spades” LV cavity configuration in end diastole in 69% of cases1 and aids the detection of apical aneurysms.16 Management Strategies Management in HCM involves symptom assessment and determination of likely mechanisms of symptoms, risk assessment and its mitigation, family screening, and chronic symptom/risk management. Treatment options for ApHCM are based on classic HCM approaches aiming to minimize any heart failure, AF, or MVOCO symptoms and reduce/mitigate ventricular arrhythmias and sudden death. Therapy is medical or electrophysiological (device/ablation), but as LV outflow tract obstruction is typically absent in ApHCM, therapeutic benefits may be lower than in classic HCM, and myectomy‐type approaches are exploratory rather than routine (Table 2). Table 2 Management Differences and Similarities Between Classic HCM and ApHCM Classical (ASH) HCM ApHCM Medical β‐Blockers–first line treatment (aim to reduce LVOTO and burden of ventricular arrhythmias) Nondihydropyridine calcium channel blockers–second line Atrial fibrillation and thromboembolism less common than in ApHCM but if present, anticoagulant indicated β‐blockers also first line (symptom improvement in MVOCO and reduce burden of ventricular arrhythmias) Nondihydropyridine calcium channel blockers also second line Anticoagulants in the case of atrial fibrillation or thromboembolism Ablation Alcohol septal ablation of hypertrophied basal septum in symptomatic LVOTO VT ablation considered Potential role of alcohol ablation in symptomatic ApHCM with MVOCO (no randomized control data) No role for alcohol septal ablation VT ablation in rare cases Devices ICD implantation (ESC 5‐y HCM SCD risk score tailored more specifically to ASH risk factors than other morphological variants) AHA guidance on ICD implantation broader ICDs may be underutilized because of current scoring criteria if using ESC algorithm Current prospective trial of distal ventricular pacing for ApHCM with drug refractory symptoms and MVOCO Surgical Septal myectomy (reduces symptoms and risks associated with LVOTO) Few case reports detailing symptomatic improvement following apical myectomy. No randomized control data AHA indicates American Heart Association; ApHCM, apical hypertrophic cardiomyopathy; ESC, European Society of Cardiology; ICD, implantable cardiac defibrillator; LVOTO, left ventricular outflow tract obstruction; MVOCO, midventricular obstruction and cavity obliteration; SCD, sudden cardiac death; VT, ventricular tachycardia. John Wiley & Sons, Ltd Medical β‐Blockers reduce rest and exercise‐induced LV outflow tract obstruction in classic HCM,46 and the negative inotropic and chronotropic effects of nondihydropiridine calcium channel blockers prolong LV filling, reduce gradients, and improve subendocardial blood flow in classic HCM,46 but data for ApHCM are missing. Catheter Ablation Although sustained monomorphic VT is uncommon in classic HCM, a case series reported monomorphic VT in ApHCM from reentry in a region of apical scar. Circuits were varied (endocardial, epicardial, intramural) and successfully ablated using endocardial/epicardial/transcoronary approaches.47 Devices There are currently no trials or predictive models to guide implantable cardiac defibrillator (ICD) insertion specifically for ApHCM. The ESC 5‐year HCM SCD risk score6, 7 was based on all HCM morphological subtypes without breakdown for ApHCM.6 Potential risk markers for SCD in ApHCM (apical aneurysm, MVOCO, midcavity gradient, paradoxical diastolic flow jet) were not shortlisted predictors. ApHCM patients tend to score negative for family history of SCD, and there is concern that risk may be underestimated. For intermediate‐risk patients, the ESC guideline suggests that the presence of “other” potentially relevant associated adverse markers like apical aneurysms (alluding to ApHCM) may also be taken into account when planning implantable cardiac defibrillators.48 In contrast, Maron's group have recently sought to evolve the American Heart Association guidance for implanting cardiac defibrillators by proposing new criteria for HCM patients fulfilling one or more major risk factors for SCD. These include novel high‐risk markers such as CMR LGE demonstration of extensive fibrosis comprising ≥15% of LV mass by quantification or “extensive and diffuse” by visual estimation, and also the presence of LV apical aneurysm, independent of size, with associated regional scarring.10 This risk stratification is more sensitive at predicting those at risk of SCD than the ESC guidance10, 40 and demonstrates progression toward understanding more individualized risk factors. Dual‐chamber pacing with short atrioventricular delay has been proposed as a treatment for symptomatic HCM with apical LVH where there are detectable midapical LV obstructive gradients.49 This is thought to work by reducing the extent of regional LV cavity obliteration through the introduction of contractile dyssynchrony. Our group is currently conducting a randomized placebo‐controlled trial of distal ventricular pacing in patients with drug‐refractory symptoms and MVOCO (http://Clinicaltrials.gov NCT03450252). Alcohol Septal Ablation and Apical Myectomy The absence of overt septal hypertrophy causing LV outflow tract obstruction may render septal ablation/myectomy in ApHCM unwarranted, but single case studies have highlighted a potential role in those with symptomatic MVOCO, as it may reduce gradients and improve heart failure symptoms. Additionally, apical myectomy has been reported to increase end‐diastolic dimensions and improve symptoms. Conclusions ApHCM poses specific etiological, diagnostic, prognostic, and therapeutic challenges compared with more commonly detected and better understood morphological HCM variants. The phenotypic spectrum and natural history of ApHCM (“pure,” “mixed,” and “relative”) is being clarified, as is the impact of sarcomere gene mutations, sex, and other clinical and environmental factors on phenotype expression. Further research is needed to understand why some patients develop mixed ApHCM with a higher risk of arrhythmias, heart failure, and SCD, while others go on to manifest the pure form with a relatively more benign course. ApHCM‐specific treatments are needed to halt or regress the LV mid‐to‐apical hypertrophy and its ensuing complications and multicenter longitudinal outcome data needed to robustly inform on an SCD risk stratification tool appropriate for ApHCM. Sources of Funding Dr Hughes is supported by the British Heart Foundation (grant number FS/17/82/33222). Dr Captur and Professor Moon are supported by the Barts Charity HeartOME1000 grant MGU0427. Dr Captur is supported by the National Institute for Health Research Rare Diseases Translational Research Collaboration (NIHR RD‐TRC, #171603) and by NIHR University College London Hospitals Biomedical Research Center. Professor Moon is directly and indirectly supported by the University College London Hospitals NIHR Biomedical Research Center and Biomedical Research Unit at Barts Hospital, respectively. Disclosures None.