Identification of heart failure with preserved ejection fraction helps risk stratification for hypertrophic cardiomyopathy.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is the dominant form of heart failure (HF). We here aimed to investigate the characteristics and prognosis of HFpEF in patients with hypertrophic cardiomyopathy (HCM). METHODS: This was a prospective cohort study and patients with HCM with available NT-proBNP results were enrolled. Patients were categorized into HFpEF [defined as LVEF ≥50%, with symptoms or signs of HF, and N-terminal pro-brain natriuretic peptide ≥800 pg/mL according to American Heart Association (AHA) criteria] and without heart failure (non-HF). The outcomes of interest were all-cause death, cardiovascular death, and sudden cardiac death (SCD). RESULTS: Of 1178 included patients with HCM, 513 (43.5%) were identified as having HFpEF according to AHA criteria. Compared with non-HF patients, patients with HFpEF had significantly larger maximal wall thickness (P < 0.001), higher maximal left ventricular outflow tract gradient (P < 0.001), higher proportion of atrial fibrillation (P < 0.001), higher incidence of all-cause death (log-rank test, P = 0.002), and cardiovascular death (log-rank test, P = 0.005). Multivariable Cox analysis showed that patients with HFpEF had a nearly two-fold higher risk of all-cause death (adjusted HR = 1.80, 95% CI 1.11-2.90; P = 0.017) and cardiovascular death (adjusted HR =1.82, 95% CI 1.05-3.18; P = 0.033) than non-HF patients. CONCLUSIONS: Patients with HCM have a high prevalence of HFpEF and those with HFpEF present greater disease severity and higher mortality than non-HF patients, and thus may require an appropriate and more aggressive treatment for HF management. Identification of patients with HFpEF using AHA criteria can provide guidance on patient risk stratification for patients with HCM.

Deleterious Rare Desmosomal Variants Contribute to Hypertrophic Cardiomyopathy and Are Associated With Distinctive Clinical Features.

BACKGROUND: Deleterious rare variants in genes encoding desmosome proteins have been identified as the essential basis of arrhythmogenic cardiomyopathy (ACM) and detected in dilated cardiomyopathy, but the relationship between deleterious rare desmosomal variants and hypertrophic cardiomyopathy (HCM) remains unknown. METHODS: Whole exome sequencing was performed in 1000 patients with HCM and 761 non-HCM controls to search for deleterious rare variants in genes encoding desmosomal proteins including PKP2, JUP, DSC2, DSG2, and DSP. Clinical phenotypes were assessed in patients with HCM, and patients with deleterious rare desmosomal variants underwent evaluation of ACM revised Task Force Criteria. RESULTS: A total of 27 deleterious rare desmosomal variants were present in 24 (2.4%) patients with HCM and 5 (0.66%) controls. The variants were more prevalent in the patients with HCM than in the controls (P = 0.004). The majority of patients possessing deleterious rare desmosomal variants could not be diagnosed as ACM. Moreover, the patients with deleterious rare desmosomal variants possessed several distinctive clinical features compared with patients without such variants, including a higher incidence of nonsustained ventricular tachycardia (29.2% vs 4.5%, P < 0.001), left bundle branch block (33.3% vs 1.6%, P < 0.001), and right ventricular involvement for an HCM phenotype (29.2% vs 0.30%, P < 0.001). CONCLUSIONS: We screened deleterious rare desmosomal variants in a large HCM case-control cohort and found deleterious rare desmosomal variants can be relevant to HCM. Moreover, our data indicated deleterious rare desmosomal variants were associated with distinctive clinical features of HCM. These findings require validation in other HCM cohorts.

Truncating Variants in OBSCN Gene Associated With Disease-Onset and Outcomes of Hypertrophic Cardiomyopathy.

BACKGROUND: The presence of variants in OBSCN was identified to be linked to hypertrophic cardiomyopathy (HCM), but whether OBSCN truncating variants were associated with HCM remained unknown. METHODS: Whole-exome sequencing was performed in 986 patients with HCM and 761 non-HCM controls to search for OBSCN truncating variants, and the result was tested in a replication cohort consisting of 529 patients with HCM and 307 controls. The association of the OBSCN truncating variants with baseline characteristics and prognosis of patients with HCM were ascertained. RESULTS: There were 28 qualifying truncating variants in the OBSCN gene detected in 26 (2.6%) patients with HCM and 6 (0.8%) controls. The OBSCN truncating variants were more prevalent in patients with HCM than controls (odds ratio, 3.4, P=0.004). This association was confirmed in the replication cohort (odds ratio, 3.8, P=0.024). The combined effects of the two cohorts estimated the odds ratio to be 3.58 (P<0.001). Patients with or without OBSCN truncating variants shared similar demographic and echocardiographic variables at baseline. During 3.3±2.4 years (4795 patient-years) follow-up, the patients with OBSCN truncating variants were more likely to experience cardiovascular death (adjusted hazard ratio, 3.1 [95% CI, 1.40-6.70], P=0.005) and all-cause death (adjusted hazard ratio, 2.63 [95% CI, 1.21-5.71], P=0.015). CONCLUSIONS: Our data indicated that OBSCN truncating variants contributed to the disease-onset of HCM, and increased the risk of malignant events in patients with HCM.

Variant Spectrum of Formin Homology 2 Domain-Containing 3 Gene in Chinese Patients With Hypertrophic Cardiomyopathy.

Background The FHOD3 (formin homology 2 domain-containing 3) gene has recently been identified as a causative gene of hypertrophic cardiomyopathy (HCM). However, the pathogenicity of FHOD3 variants remains to be evaluated. This study analyzed the spectrum of FHOD3 variants in a large HCM and control cohort, and explored its correlation with the disease. Methods and Results The genetic analysis of FHOD3 was performed using the whole exome sequencing data from 1000 patients with HCM and 761 controls without HCM. A total of 37 FHOD3 candidate variants were identified, including 25 missense variants and 2 truncating variants. In detail, there were 27 candidate variants detected in 33 (3.3%) patients with HCM, which was significantly higher than in the 12 controls (3.3% versus 1.6%; odds ratio, 2.13; P<0.05). On the basis of familial segregation, we identified one truncating variant (c.1286+2delT) as a causal variant in 4 patients. Furthermore, the FHOD3 candidate variant experienced significantly more risk of cardiovascular death and all-cause death (adjusted hazard ratio [HR], 3.71; 95%, 1.32-8.59; P=0.016; and adjusted HR, 3.02; 95% CI, 1.09-6.85; P=0.035, respectively). Conclusions Our study suggests that FHOD3 is a causal gene for HCM, and that the presence of FHOD3 candidate variants is an independent risk for cardiovascular death and all-cause death in HCM.

Improvement in sudden cardiac death risk prediction by the enhanced American College of Cardiology/American Heart Association strategy in Chinese patients with hypertrophic cardiomyopathy.

BACKGROUND: The lack of validated and effective sudden cardiac death (SCD) risk prediction methods is the biggest barrier to perform the lifesaving treatment with a prophylactic implantable cardioverter-defibrillator in Chinese patients with hypertrophic cardiomyopathy (HCM). OBJECTIVE: This study aimed to evaluate the efficacy of 3 existing SCD risk prediction methods recommended by the 2011 American College of Cardiology Foundation and American Heart Association (ACCF/AHA) guideline, the 2014 European Society of Cardiology (ESC) guideline, and the 2019 enhanced American College of Cardiology (ACC)/AHA strategy in Chinese patients with HCM. METHODS: The present study consisted of 1369 consecutive adult patients with HCM without a history of SCD events. The primary end point was a composite of SCD and equivalent events, namely, resuscitation from cardiac arrest and appropriate implantable cardioverter-defibrillator shock therapy for ventricular tachycardia or fibrillation. RESULTS: During follow-up of 3.2 ± 2.4 years, 39 patients reached SCD end points, of whom 26 (66.7%) were correctly predicted as those at a high risk of SCD by using methods recommended by the 2019 enhanced ACC/AHA strategy, 20 (51.3%) by the 2011 ACCF/AHA guideline, but only 5 (12.8%) by the 2014 ESC guideline. The 2019 enhanced ACC/AHA strategy showed a higher C-statistic (0.647) for SCD prediction than did the 2011 ACCF/AHA guideline (0.598) and 2014 ESC guideline (0.605) and resulted in the correct reclassification of SCD risk when compared with the 2011 ACCF/AHA guideline (net reclassification index 0.113; P = .074) and 2014 ESC guideline (net reclassification index 0.245; P = .038). CONCLUSION: The 2019 enhanced ACC/AHA strategy showed better predictive performance for SCD risk stratification in Chinese patients with HCM, with a notably high sensitivity.