Unveiling Clinical and Genetic Distinctions in Pure‐Apical Versus Distal‐Dominant Apical Hypertrophic Cardiomyopathy

Abstract

Background

Original apical hypertrophic cardiomyopathy was characterized by left ventricular hypertrophy confined to the apex below the papillary muscle level. In contrast, apical hypertrophic cardiomyopathy in Western countries often includes hypertrophy extending to the midventricular septum. Recognizing these phenotypic differences is essential as they may influence the clinical prognosis. The aim of this study was to delineate the clinical and genetic disparities between the pure‐apical form, according to the original definition, and the distal‐dominant form, in which hypertrophy extends to the ventricular septum without basal septal hypertrophy.

Methods

A retrospective analysis was conducted for 111 consecutive patients with apical hypertrophic cardiomyopathy with assessment of hypertrophic cardiomyopathy–related adverse events including hypertrophic cardiomyopathy–related death, heart failure admission, embolic stroke admission, and sustained ventricular tachycardia with hemodynamic instability or appropriate implantable cardioverter‐defibrillator discharge. Genetic testing for hypertrophic cardiomyopathy‐associated genes was performed in 72 patients.

Results

Among the patients, 60 were classified as pure‐apical form, and 51 were classified as distal‐dominant form. The median age at diagnosis was 63 years, with a predominance of men in both groups. Over a follow‐up period of 11.0 years, the incidence of hypertrophic cardiomyopathy–related adverse events was significantly higher in the distal‐dominant group than in the pure‐apical group (log‐rank, P<0.001). The detection rate of pathogenic or likely pathogenic variants was also significantly higher in the distal‐dominant group than in the pure‐apical group (26% versus 3%; P=0.005).

Conclusions

Distinct clinical and genetic profiles of the 2 apical hypertrophic cardiomyopathy phenotypes warrant their recognition and differentiation in clinical practice due to distinct prognoses and genetic backgrounds.

Nonstandard Abbreviations and Acronyms

ApHCM

apical hypertrophic cardiomyopathy

DD

distal‐dominant

HCM

hypertrophic cardiomyopathy

LP

likely pathogenic

PA

pure‐apical

SCD

sudden cardiac death

Clinical Perspectives.

What Is New?

• Apical hypertrophic cardiomyopathy can be categorized into 2 distinct phenotypes based on the extent of hypertrophy: pure‐apical and distal‐dominant forms.

• These 2 phenotypes exhibit markedly different genetic backgrounds and clinical prognoses.

What Are the Clinical Implications?

• Recognition of these morphological distinctions is crucial, as the distal‐dominant form, characterized by more extensive hypertrophy, is associated with a poorer prognosis compared with the pure‐apical form.

Apical hypertrophic cardiomyopathy (ApHCM) is a variant of hypertrophic cardiomyopathy (HCM) characterized by hypertrophy localized to the left ventricular (LV) apex. Hypertrophy is confined to the apical level in the original definition. ¹ , ² ApHCM constitutes 15% of HCM cases in Asian populations; however, its prevalence in non‐Asian populations is significantly lower, ranging from 1% to 10%. ³ Additionally, although the original ApHCM was reported to have a favorable prognosis, ApHCM patients in Western countries might have a more malignant prognosis. ⁴ , ⁵ However, the specific characteristics of this condition among these populations remain poorly understood. The literature on ApHCM often presents definitions that deviate from the original, creating inconsistencies. As noted in studies, definitions of ApHCM have included not only cases with hypertrophy confined to the apex but also cases in which the apex is the most thickened part of the ventricle. ⁶ , ⁷ , ⁸ Thus, it is anticipated that in clinical settings, the definition of ApHCM is being used in a manner different from the original definition, leading to confusion. This definitional variability can result in diagnostic and treatment inconsistencies in clinical practice and may influence the variations in reported prognoses.

We previously proposed 2 ApHCM phenotypes: a pure‐apical (PA) form characterized by hypertrophy confined solely to the apex and a distal‐dominant (DD) form in which hypertrophy extends from the apex to the midventricular septum. ⁹ Our study suggested that these phenotypes have different clinical prognoses. Specifically, the PA phenotype, corresponding to the original definition, reportedly has a favorable prognosis compared with that of DD, with few occurrences of fatal arrhythmias and heart failure (HF) events associated with HCM. Distinguishing between these phenotypes might be crucial because their differences significantly influence treatment strategies and prognosis evaluation. However, since our report, ⁹ there have been few studies conducted on the 2 phenotypes, ⁵ , ⁸ and it therefore remains unclear whether there is a difference in long‐term prognosis and morphological changes between these 2 phenotypic expressions. Furthermore, familial PA cases have been reported to be less common than DD cases, indicating potential differences between genetic backgrounds of the 2 subtypes.

In this study, next‐generation sequencing was used to elucidate the genetic variations distinguishing the PA and DD phenotypes. The genetic analysis was complemented by a longitudinal cohort study in which clinical outcomes were assessed. The aim of this approach was to facilitate the development of more personalized treatment strategies and improved patient outcomes by providing insights into the molecular underpinnings of ApHCM.

Methods

The study was approved by the Ethics Committee on Medical Research of Kochi Medical School (Approval No. ERB‐002555) and followed the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation. Written informed consent was obtained from all participants.

The data, analytic methods, and materials used to conduct this research and support these findings are available from the corresponding author upon reasonable request.

Study Population and Clinical Evaluation

We retrospectively analyzed 111 consecutive patients with ApHCM who were diagnosed at Kochi Medical School Hospital. The subjects in this study were first evaluated between 1982 and 2018. The time of initial diagnosis was determined on the basis of clinical evaluation and echocardiographic confirmation. The diagnosis of HCM was established by a 2‐dimensional echocardiographic demonstration of unexplained LV hypertrophy with maximum LV wall thickness exceeding 15 mm. ApHCM is defined as predominant hypertrophy at the apex of the left ventricle without significant hypertrophy at the base. Moreover, according to the definitions provided by Kubo et al, ⁹ ApHCM is categorized into 2 phenotypes: PA and DD. PA is defined as hypertrophy (≥15 mm) that is confined to the LV apex, below the level of the papillary muscles. The DD phenotype, on the other hand, is characterized by apical hypertrophy extending to the interventricular septum, without basal septal hypertrophy.

As in our previous study on HCM, ¹⁰ evaluation of patients included medical history, clinical examination, 12‐lead electrocardiography, and echocardiography. LV wall thickness was measured at the mitral valve, papillary muscles, and apical levels at end diastole using parasternal short‐axis views (either 2‐dimensional or M‐mode). LV end‐diastolic diameter and end‐systolic diameter were obtained from M‐mode and 2‐dimensional images from parasternal long‐axis views, calculating fractional shortening (% fractional shortening = [LV end‐diastolic diameter−LV end‐systolic diameter]/LV end‐diastolic diameter ×100). Intraventricular gradients were derived from continuous‐wave Doppler using the simplified Bernoulli equation. End‐stage HCM was defined as LV systolic dysfunction with a global ejection fraction <50% ascertained from apical 2‐ and 4‐chamber views, ensuring the exclusion of concomitant coronary artery disease through coronary artery angiography or myocardial scintigraphy.

HCM‐related deaths were categorized into 3 types: (1) sudden cardiac death (SCD), characterized by an unexpected sudden collapse in patients with a stable or uneventful clinical course; (2) HF death, occurring in the context of progressive cardiac decompensation; and (3) embolic death, resulting from a probable or proven embolic stroke. HCM‐related adverse events were defined as (1) SCD‐relevant events including SCD and spontaneous sustained ventricular tachycardia with hemodynamic instability or appropriate implantable cardioverter‐defibrillator (ICD) discharge; (2) composite HF events, encompassing HF death and hospitalization for HF; and (3) composite embolic events, including deaths from embolic stroke and hospitalization for embolic stroke. The event time for HCM‐related deaths and HCM‐related events was defined as the period from the initial diagnosis of HCM to occurrence of the events.

Genetic Analysis

Genomic DNA from all available individuals was extracted from whole blood samples by standard techniques. We designed a panel consisting of 145 genes (Table S1) associated with cardiomyopathies using SureDesign for HaloPlex technology (Agilent Technologies Inc., Santa Clara, CA). Sequence library preparation for all subjects was performed according to the HaloPlex target enrichment system protocol for Illumina paired‐end sequencing. Sequencing was performed on an Illumina HiSeq (Illumina Inc., San Diego, CA).

The sequence reads were aligned to the human reference genome GRCh37/hg19 using BWA‐MEM. ¹¹ Variant calling was performed with Genome Analysis Toolkit (Broad Institute, Cambridge, MA). ¹²

We excluded variants with an alternative allele frequency >0.1% in any freely accessible population database in the National Heart, Lung, and Blood Institute Exome Sequencing Project with 6500 exomes, ¹³ gnomAD exome collection version 2.1.1, 1000 Genomes Project ¹⁴ version 5b, and ToMMo 38K (https://jmorp.megabank.tohoku.ac.jp). ¹⁵

Filtered variants were classified according to American College of Medical Genomics and Genomics/Association for Molecular Pathology guidelines ¹⁶ as pathogenic, likely pathogenic (LP), variant of uncertain significance, likely benign, and benign. Genes associated with HCM that were included in the analysis were MYBPC3, MYH7, TNNI3, TNNT2, TPM1, ACTC1, MYL2, MYL3, ACTN2, PLN, JPH2, FHOD3, CSRP3, TNNC1, CACNA1C, DES, FHL1, FLNC, GLA, LAMP2, PRKAG2, RAF1, RIT1, TTR, and ALPK3, with reference to an expert consensus statement on the state of genetic testing for cardiac diseases. ¹⁷

Statistical Analysis

Statistical analysis was performed using R statistical software version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria; URL:https://www.R‐project.org/). Continuous variables are presented as medians (interquartile ranges). Differences in significance between the 2 groups were assessed using the Mann–Whitney U test for continuous variables and Fisher's exact test for categorical variables. For HCM‐related death, cumulative incidence probability curves and Gray's K‐sample test were used to account for competing risks (eg, non–HCM‐related deaths), providing a more comprehensive analysis. Gray's K‐sample test was used for HCM‐related death analysis due to the presence of competing risks, such as non–HCM‐related deaths, which the Kaplan–Meier method cannot account for. The Kaplan–Meier method and log‐rank test were used for HCM‐related event‐free survival analysis, as they are appropriate for evaluating the time to the first event. Statistical significance was set at P<0.05.

For the variant detection analysis:

The analysis was performed to compare the overall detection rates of pathogenic or LP variants across the panel of genes and the detection rate of variant of uncertain significance among the HCM‐associated genes described above between the PA and DD groups. The focus was on whether a variant was detected in any of the panel genes, and no separate statistical tests were conducted for individual genes. This approach focuses on aggregate detection rates rather than gene‐specific associations, which eliminates the need for adjustments for multiple comparisons.

Results

Clinical Characteristics

Among the 111 consecutive patients with ApHCM, we identified 60 patients with the PA and 51 patients with the DD. Their clinical characteristics are shown in Table 1.

Table 1.

Patient Characteristics at the Initial Evaluation

Variable	Total cohort (N=111)	Pure‐apical (N=60)	Distal‐dominant (N=51)	P value
Age at diagnosis, y	63 (55–69)	62 (54–68)	64 (55–70)	0.711
Male sex, n (%)	89 (80)	49 (82)	40 (78)	0.812
Reason for diagnosis
ECG abnormality	70 (63)	43 (72)	27 (53)	0.050
Family screening	2 (2)	0 (0)	2 (4)	1.000
Symptoms	39 (35)	16 (27)	23 (45)	0.049
Family history of SCD, n (%)	16 (14)	6 (10)	10 (20)	0.244
Family history of HCM, n (%)	17 (15)	3 (5)	14 (27)	0.001
NYHA II, n (%)	39 (35)	21 (35)	18 (35)	1.000
NYHA III or IV, n (%)	3 (3)	0 (0)	3 (6)	0.094
Hypertension, n (%)	55 (50)	30 (50)	25 (49)	1.000
AF, n (%)	17 (15)	8 (13)	9 (18)	0.602
Syncope, n (%)	4 (4)	2 (3)	2 (4)	1.000
Medications (n=89)		n=48	n=41
Anticoagulant drugs, n (%)	10 (11)	5 (10)	5 (12)	1.000
β blockers, n (%)	7 (8)	3 (6)	4 (10)	0.699
Antiarrhythmic drugs, n (%)	6 (7)	2 (4)	4 (10)	0.408
Calcium blockers, n (%)	10 (11)	7 (15)	3 (7)	0.331

AF indicates atrial fibrillation; HCM, hypertrophic cardiomyopathy; NYHA, New York Heart Association; and SCD, sudden cardiac death.

In the baseline data, the average age of the patients in both groups was ≈60 years, and men constituted about 80% of the study population. There was no significant difference between the 2 groups in age, sex, family history of sudden death, or history of hypertension. No patients had an ICD implanted by the time of the initial evaluation. Diagnosis from ECG abnormalities detected during medical checkups was significantly more frequent in the PA group (72% versus 53%; P=0.050), whereas the rate of diagnosis based on symptoms such as palpitations or dyspnea was lower in the PA group than in the DD group (27% versus 45%; P=0.049).

Echocardiographic findings revealed that the DD group exhibited significantly greater LV maximum wall thickness (17 mm [15–18] versus 19 mm [16–21]; P<0.001), intraventricular septal wall thickness (11 mm [10–12] versus 12 mm [11–13]; P=0.005), and left atrial diameter (40 mm [37–42] versus 43 mm [39–48]; P=0.006). No significant differences were observed between the groups regarding fractional shortening or the presence of intraventricular pressure gradients exceeding 30 mm Hg (Table 2). One patient in the PA group had a significant intraventricular pressure gradient (38 mm Hg). In the DD group, 4 patients had significant pressure gradients ranging from 36 to 49 mm Hg.

Table 2.

Findings of Echocardiogram and ECG at the Initial Evaluation

Variable	Total cohort (N=111)	Pure‐apical (N=60)	Distal‐dominant (N=51)	P value
Maximum left ventricular wall thickness, mm	17 (16–20)	17 (15–18)	19 (16–21)	<0.001
Intraventricular septal wall thickness, mm	12 (10–13)	11 (10–12)	12 (11–13)	0.005
Posterior wall thickness, mm	11 (10–12)	11 (10–12)	11 (10–12)	0.069
Left ventricular end‐diastolic diameter, mm	48 (45–51)	47 (45–49)	49 (45–51)	0.073
Fractional shortening, %	42 (38–47)	41 (39–46)	42 (38–47)	0.671
Left atrial diameter, mm	40 (38–44)	40 (37–42)	43 (39–48)	0.006
Intraventricular obstruction, (%)	5 (5)	1 (2)	4 (8)	0.178
ECG findings (n=80)		n=49	n=31
Abnormal Q, n (%)	3 (4)	1 (2)	2 (6)	0.556
ST‐T change, n (%)	76 (95)	46 (94)	30 (97)	1.000
Giant negative T wave, n (%)	40 (50)	23 (47)	17 (55)	0.647
Holter ECG finding n=62 NSVT, n (%)	8 (13)	5 (13)	3 (13)	1.000

NSVT indicates nonsustained ventricular tachycardia.

Clinical Outcomes

The median follow‐up period was 11.0 (5.3–15.2) years. During the follow‐up period, HCM‐related deaths occurred in 5 patients (5%), all of whom were in the DD group. These HCM‐related deaths included SCD in 1 patient, HF deaths in 3 patients, and embolic death in 1 patient. Additionally, HCM‐related adverse events were noted in 24 patients (22%): SCD‐relevant events in 3 patients, composite HF events in 15 patients, and composite embolic stroke events in 9 patients. Regarding ICD implantation during the follow‐up period, 2 patients with the DD experienced pulseless ventricular tachycardia and subsequently underwent ICD implantation for secondary prevention. One of these patients received an appropriate ICD discharge. Additionally, 2 other patients with the DD underwent ICD implantation for primary prevention. Multiple types of events occurred in 3 patients.

HCM‐Related and Non–HCM‐Related Deaths

The cumulative incidence of HCM‐related and non–HCM‐related deaths was compared between the PA and DD groups of HCM (Figure 1). For HCM‐related deaths, the cumulative incidence was significantly higher in the DD group compared with the PA group (Gray's K‐sample test; P=0.007). In contrast, no significant difference was observed for non–HCM‐related deaths between the 2 groups (Gray's K‐sample test; P=0.798). The cumulative incidence rates at 5, 10, 15, 20, and 25 years for each group and event type are summarized in the table below the graph in Figure 1. Furthermore, there were no HCM‐related deaths in the PA group during the follow‐up period.

Figure 1. Cumulative incidence for HCM‐related and non–HCM‐related deaths.

This figure illustrates the cumulative incidence of HCM‐related deaths and non–HCM‐related deaths in patients with PA and DD subtypes of HCM. Solid lines represent HCM‐related deaths, while dashed lines represent non–HCM‐related deaths. Blue lines indicate the PA subtype, and red lines indicate the DD subtype. The P values for Gray's K‐sample test are displayed in the figure. The table below the graph provides the cumulative incidence rates at 5, 10, 15, 20, and 25 y for each group and event type. Additionally, Gray's K‐sample test statistics and P values are summarized in the lower table. DD indicates distal‐dominant; HCM, hypertrophic cardiomyopathy; and PA, pure‐apical.

HCM‐Related Events

Regarding HCM‐related events (Figure 2A through Figure 2D), a composite analysis revealed that the DD group had a significantly higher event rate (log‐rank, P<0.001) than that in the PA group. Specifically, both SCD‐relevant events (P=0.040) and HF‐related events (P=0.001) occurred with greater frequency in the DD group. In contrast, there was no significant difference in the incidence of embolic events between the DD and PA groups (P=0.720).

Figure 2. Comparison of incidence of HCM‐related events between the PA and DD groups.

Kaplan–Meier curves for the incidence of HCM‐related events. A, Composite events, which included HCM‐related deaths, SCD relevant events, heart failure events, and embolic events. B, SCD relevant events, including SCD, successful resuscitation from VT or VF, and appropriate ICD discharge. C, Heart failure events including heart failure death and heart failure hospitalization. D, Embolic events, including embolic stroke and systemic embolism. DD indicates distal‐dominant; HCM, hypertrophic cardiomyopathy; HF, heart failure; PA, pure‐apical; SCD, sudden cardiac death; VF, ventricular fibrillation; and VT, ventricular tachycardia.

Time‐Dependent Changes in Phenotype and Number of Events

Figure 3 shows the changes in phenotypes up to the final assessment and event rates associated with each phenotype. In 11 individuals (18%) initially identified as belonging to the PA group, the DD phenotype evolved by the final evaluation. Within this subgroup transitioning to the DD phenotype, 2 individuals developed apical aneurysms and both of them subsequently experienced an embolic event. By the final evaluation, 2 individuals remaining in the PA group had developed apical aneurysms, and 1 of them experienced an embolic event. There was no individual initially categorized as the PA group in whom the end‐stage HCM evolved by the final evaluation.

Figure 3. Time‐dependent morphological changes, left ventricular remodeling, and incidence of adverse events.

This figure illustrates the morphological changes and LV remodeling observed in the PA and DD groups over the course of the follow‐up period. It also shows the incidence of adverse events in each group. The numbers in parentheses inside the colored squares indicate the sample sizes (N). DD indicates distal‐dominant; HF, heart failure; PA, pure‐apical; and SCD, sudden cardiac death.

For patients diagnosed with DD phenotype at baseline, 4 patients (8%) progressed to end‐stage HCM. Additionally, 6 patients (12%) in this group developed apical aneurysms.

Detection of Genetic Variants and Their Association With Phenotype

The results of genetic analysis are presented in Figure 4. Targeted sequencing was performed for the patients (PA group: n=37; DD group: n=35). In the PA group, only 1 patient was found to have a heterozygous pathogenic variant. In contrast, in the DD group, variants identified as either heterozygous LP or pathogenic variants were found in 9 patients. The prevalence of LP and pathogenic variants in the DD group was significantly higher than that in the PA group (26% versus 3%; P=0.005). Moreover, there was a notable increase in the occurrence rate of variant of uncertain significance, as well as LP and pathogenic variants, in genes associated with HCM in the DD group as compared with the PA group (46% versus 16%; P=0.013) (see Table S2 for details on genetic variants).

Figure 4. Variant detection rates in the pure‐apical and distal‐dominant groups.

This figure shows the detection rates of likely pathogenic and pathogenic variants in the pure‐apical and distal‐dominant groups, the rate being significantly higher in the latter group. The detection rates of variants of uncertain significance, likely pathogenic and pathogenic variants within genes associated with HCM were also higher in the distal‐dominant group. HCM indicates hypertrophic cardiomyopathy; and VUS, variant of uncertain significance.

Analysis of the incidence of HCM‐related events in patients undergoing genetic analysis showed that those carrying LP, pathogenic, or variant of uncertain significance variants had a significantly higher risk of composite events (log‐rank, P=0.036); however, no significant difference was found between the 2 groups regarding HCM‐related deaths (Figure 5).

Figure 5. Incidences of HCM‐related deaths and events in the variant‐positive and variant‐negative groups.

This figure shows Kaplan–Meier curves depicting the incidence of HCM‐related deaths and events in 72 patients with ApHCM who underwent genetic testing. A, Occurrence of HCM‐related deaths. B, Composite events including HCM‐related deaths, events relevant to SCD, HF events, and embolic events. ApHCM indicates apical hypertrophic cardiomyopathy; HCM, hypertrophic cardiomyopathy; HF, heart failure; and SCD, sudden cardiac death.

Discussion

In this study, we classified cases of ApHCM into 2 groups on the basis of the distribution and expanse of their hypertrophy: a PA group, with hypertrophy confined to the apex, and a DD group, with hypertrophy extending beyond the apex. We investigated the long‐term prognosis over a period of >10 years for a cohort of Japanese patients diagnosed with these phenotypes. Additionally, we analyzed the genetic backgrounds of these groups using results from targeted sequencing.

The principal findings of our study are as follows: (1) The incidence of HCM‐related events was significantly lower in the PA group than in the DD group; and (2) in the PA group, only 1 case harbored a pathogenic variant in HCM‐related genes. The DD group exhibited a significantly higher detection rate of pathogenic or LP variants in HCM‐related genes.

These findings clearly indicate that the PA group and the DD group, which are usually grouped together in clinical practice, differ significantly in terms of clinical significance and genetic background.

Clinical Outcomes in ApHCM

The annual mortality rate for patients with HCM is generally reported to be 0.5% to 1%. ¹⁰ , ¹⁸ , ¹⁹ Originally, ApHCM was perceived to have a better prognosis than other forms of HCM. ³ , ⁶ However, according to Klarich et al, the annual mortality rate for patients with ApHCM is ≈0.5% to 4%, which is similar to the 1% observed for general HCM. ⁴ , ²⁰ In our study, patients were divided into PA and DD groups to analyze outcomes over a follow‐up period of 11 years. The results showed that HCM‐related deaths occurred in the DD group but not in the PA group.

Regarding HCM‐related events in general HCM, a 20% incidence rate over 5 years has been reported previously. ¹⁸ , ²¹ In our study, the PA group had significantly fewer HCM‐related events than those in the DD group. However, the incidence rate of HCM‐related events in the DD group was similar to the incidence rates in previous reports on general HCM. Although patients in the PA group had a favorable prognosis, the clinical outcomes for patients in the DD group should be considered comparable to those of general HCM.

The observed differences in prognoses from previous ApHCM studies were speculated to stem from analyses that included mixed cohorts of PA and DD phenotypes. It is essential to emphasize that the PA group, representing the classical form of ApHCM, consistently exhibits a favorable prognosis. Accurate identification of the morphological distinctions between PA and DD is crucial for precise prognosis estimation.

Time‐Dependent Morphological Changes and LV Remodeling

In this study, we found that 4% of patients with ApHCM progressed to the end‐stage HCM within a 10‐year period, and all of those patients were in the DD group. No cases in the PA group progressed to end‐stage HCM. To the best of our knowledge, this study is the first showing the percentage of patients with ApHCM who progress to end‐stage HCM, notably emphasizing that this transition does not occur in the PA. Among those who progressed to end‐stage HCM, three quarters experienced HF‐related events or SCD‐relevant event, indicating a poor prognosis in line with findings from previous studies. ²² , ²³

Additionally, even in patients with PA phenotype, which typically has a favorable prognosis, the formation of aneurysms increases the likelihood of embolic events. Apical aneurysms represent a significant complication in ApHCM and can affect management strategies. ²⁴ , ²⁵ , ²⁶ According to the literature, aneurysm formation occurs in ≈13% to 15% of ApHCM cases. ²⁵ , ²⁷ In this study, 9% of the patients developed apical aneurysms, with a correspondingly high incidence of subsequent embolic events. Notably, even among patients in the PA group, known for their generally good prognosis, 4 patients (7%) developed aneurysms, and 3 of those patients experienced embolic events. Consequently, it is prudent to closely monitor aneurysm formation in patients with the PA phenotype as well. The relatively low incidence of embolic events in patients with the DD phenotype with aneurysms might be attributed to more consistent follow‐up, which allows for earlier detection of aneurysms and earlier initiation of anticoagulation therapy.

Risk factors associated with aneurysm formation in patients with the PA phenotype should be investigated in detail in future research.

Differences in Genetic Background and Causes of the PA

Early small‐scale studies indicated a predilection for ACTC1 or TPM1 variants in ApHCM. ⁷ However, recent studies have revealed variants in genes that are commonly associated with classical HCM, including MYBPC3 and MYH7 among others, in ApHCM cases. MYBPC3 and MYH7 are the primary genes involved, as is the case with classical HCM. ApHCM is thought to exhibit an autosomal dominant pattern of inheritance, akin to that observed in classical HCM. Towe et al reported that only 25% of patients with ApHCM harbor a variant in genes associated with HCM, a rate slightly lower than the detection frequency typically observed in the broader HCM population. ²⁰ , ²⁸

Although this study revealed trends in the DD group that are consistent with previous reports, it showed a distinctly different genetic profile in the PA group. Consistent with the findings reported by Kubo et al, ⁹ the PA group had fewer family histories of HCM. Additionally, only 1 patient in the PA group was found to have a pathogenic variant in genes related to HCM. These results suggest that, unlike classical HCM, the PA phenotype may not be primarily caused by sarcomeric gene abnormalities.

In the patient with the PA phenotype in whom a pathogenic variant in the MYBPC3 gene was detected, the follow‐up period lasted for only 1 year; thus, subsequent morphological changes are yet to be determined.

In this study, genetic factors attributable to the PA phenotype were not determined; however, the genetic factors might be elucidated by using whole exome sequencing or whole genome sequencing. Furthermore, the prevalence of sporadic cases in this population suggests that the condition might not be attributable solely to a single gene disorder. Recent studies have highlighted polygenic risk scores in HCM ²⁹ , ³⁰ ; thus, analyzing these scores in ApHCM might offer valuable insights into its genetic underpinnings.

Detection of Variants and Prognostic Implications

In classical HCM, some studies have demonstrated that detecting variants in sarcomere genes facilitates prognosis prediction. ³¹ , ³² On the other hand, according to Towe's study, ²⁰ among patients with ApHCM, there is no significant difference in prognosis between genotype‐positive and genotype‐negative patients. It is possible that these findings were influenced by the inclusion of non–cardiac‐related deaths as adverse events in that report.

In our study focusing on the entire ApHCM cohort, when we confined the analysis to nonfatal HCM‐related events, the incidence was significantly higher in the variant‐positive group than in the variant‐negative group, suggesting that genotype‐positive serves as a potential predicter for worse prognosis even in patients with ApHCM.

Limitations

This study has several limitations. First, this study was conducted at a single center, involved a relatively small cohort, and used a retrospective design. Nevertheless, this study is, to the best of our knowledge, the most extensive and longest‐duration study to categorize ApHCM into PA and DD groups. Second, the subjects in this study were first evaluated between 1982 and 2018. Regarding medication, some patients diagnosed with ApHCM in earlier years were treated with calcium channel blockers instead of β blockers. Additionally, there was limited availability of certain data at initial evaluation, such as cardiac magnetic resonance imaging data and diastolic function parameters such as E/e′ ratio, left atrial volume index, in patients diagnosed in earlier years. Therefore, future studies including these data are needed to further clarify the pathogenesis of ApHCM. Third, the genetic analysis was confined to targeted sequencing, as neither whole exome nor whole genome sequencing was conducted. As a result, the possibility of unidentifiable pathogenic variants in genes not included in our analysis cannot be discounted. Nonetheless, the genes related to HCM were comprehensively covered in our analysis. Furthermore, the percentage of patients with a family history of HCM was notably lower in the PA group, suggesting a lower likelihood of the condition being a monogenic disorder in this subgroup. In future studies, polygenic risk scores should be evaluated to further elucidate this aspect.

Conclusions

Patients with the distal‐dominant form of ApHCM had a significantly higher incidence of HCM‐related events and a higher detection rate of pathogenic and LP variants in genes associated with HCM. Therefore, the 2 phenotypes of ApHCM should be recognized and distinguished clinically. Additionally, even for patients with ApHCM, genetic testing may be useful for risk stratification of the prognosis.

Sources of Funding

This work was supported by grants from Japan Agency for Medical Research and Development (JP18km0405209, JP21ek0109543, JP24ek0109755) to Drs Nomura and Komuro, and the Kochi Medical School Hospital President's Discretionary Grant to Dr Sugiura.

Disclosures

None.

Supporting information

Tables S1–S2