Adaya Weissler-Snir

Prevention of sudden death in hypertrophic cardiomyopathy: bridging the gaps in knowledge

Sudden cardiac death (SCD) is the most devastating complication of hypertrophic cardiomyopathy (HCM). Although the annual rate of SCD in the general HCM population is <1% per year according to contemporary series, there is still a small subset of patients who are at increased risk of SCD. The greatest challenge in the management of HCM is identifying those at increased risk as an implantable cardioverter defibrillator is a potentially life-saving therapy. In this review, we sought to summarize the available data on SCD in HCM and provide a clinical perspective on the current differing and somewhat conflicting European and American recommendations on risk stratification, with balanced guidance with regards to rational clinical decision making. Additionally, we sought to learn more on the actual implementation of the guidelines by HCM experts worldwide.

Discrepant Measurements of Maximal Left Ventricular Wall Thickness Between Cardiac Magnetic Resonance Imaging and Echocardiography in Patients With Hypertrophic CardiomyopathyCLINICAL PERSPECTIVE

Background— We sought to compare maximal left ventricular (LV) wall thickness (WT) measurements as obtained by routine clinical practice between echocardiography and cardiac magnetic resonance (CMR) and document causes of discrepancy. Methods and Results— One-hundred and ninety-five patients with hypertrophic cardiomyopathy (median age, 52.8±15.1 years) who underwent echocardiography and CMR imaging within 6 months (median, 41 days; interquartile range, 16–97 days) were included. LVWT was assessed in parasternal long and short axis by 2-dimensional echocardiography and in short axis by CMR. By Bland–Altman plot, mean maximal LVWT difference between echocardiography and CMR was 0.5 mm (95% confidence interval, −6.9, 7.8) with equal distribution of discrepancy along the full range of LVWT. Ninety-seven patients (49.7%) were identified to have intermodal measurement discrepancies ≥10%. In 7 patients (7.2%), reported measurement by CMR was inaccurate because of interpretation error. In 90 patients (92.8%), echocardiography underestimated (n=32; 33.0%) or overestimated (n=58; 59.8%) maximal LVWT. Underestimation was because of focal LV hypertrophy (n=10; 10.3%) or poor acoustic windows (n=22; 22.7%) while overestimation resulted from inclusion of right ventricular myocardium (n=37; 38.1%), LV trabeculations (n=5; 5.2%), papillary muscle (n=3; 3.1%), and apical-septal bundle (n=1; 1.0%), as well as imaging plane obliquity (n=7; 12.5%). In 31 (15.9%) patients, measurement discrepancy occurred at diagnostic or prognostic cut-offs. Conclusions— Although maximal LVWT by echocardiography in general measured similar to CMR, discordance because of limitations in echocardiography technique was present in a significant subset of patients. As measurement of LVWT impacts diagnosis and sudden death management, CMR should be considered as part of routine evaluation of all patients with hypertrophic cardiomyopathy.

Lack of Phenotypic Differences by Cardiovascular Magnetic Resonance Imaging in MYH7 (β-Myosin Heavy Chain)- Versus MYBPC3 (Myosin-Binding Protein C)-Related Hypertrophic CardiomyopathyCLINICAL PERSPECTIVE

Background— The 2 most commonly affected genes in hypertrophic cardiomyopathy (HCM) are MYH7 (&bgr;-myosin heavy chain) and MYBPC3 (&bgr;-myosin-binding protein C). Phenotypic differences between patients with mutations in these 2 genes have been inconsistent. Scarce data exist on the genotype–phenotype association as assessed by tomographic imaging using cardiac magnetic resonance imaging. Methods and Results— Cardiac magnetic resonance imaging was performed on 358 consecutive genotyped hypertrophic cardiomyopathy probands at 5 tertiary hypertrophic cardiomyopathy centers. Genetic testing revealed a pathogenic mutation in 159 patients (44.4%). The most common genes identified were MYH7 (n=53) and MYBPC3 (n=75); 33.1% and 47% of genopositive patients, respectively. Phenotypic characteristics by cardiac magnetic resonance imaging of these 2 groups were similar, including left ventricular volumes, mass, maximal wall thickness, morphology, left atrial volume, and mitral valve leaflet lengths (all P=non-significant). The presence of late gadolinium enhancement (65% versus 64%; P=0.99) and the proportion of total left ventricular mass (%late gadolinium enhancement; 10.4±13.2% versus 8.5±8.5%; P=0.44) were also similar. Conclusions— This multicenter multinational study shows lack of phenotypic differences between MYH7- and MYBPC3-associated hypertrophic cardiomyopathy when assessed by cardiac magnetic resonance imaging. Postmutational mechanisms appear more relevant to thick-filament disease expression and outcome than the disease-causing variant per se.

MV Surgery as Adjunct to Surgical Myectomy for Obstructive HCM: Less Is More Than Enough∗

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained usually asymmetrical cardiac hypertrophy with variable degrees of myocardial fiber disarray and fibrosis. Although there was initial controversy about whether true obstruction to the left ventricular outflow tract (LVOT) existed, it

The role of imaging in the diagnosis and management of hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, affecting approximately 1:500 people. As the yield of genetic testing is only about 35–60%, the diagnosis of HCM is still clinical and based on the demonstration of unexplained and usually asymmetric left ventricular (LV) hypertrophy by imaging modalities. In the past, echocardiography was the sole imaging modality used for the diagnosis and management of HCM. However, in recent years other imaging modalities such as cardiac magnetic resonance have played a major role in the diagnosis, management and risk stratification of HCM, particularly when the location of left ventricular hypertrophy is atypical (apex, lateral wall) and when the echocardiographic imaging is sub-optimal. However, the most unique contribution of cardiac magnetic resonance is the quantification of myocardial fibrosis. Exercise stress echocardiography is the preferred provocative test for the assessment of LV outflow tract obstruction, which is detected only on provocation in one-third of the patients.

Safety of Outpatient Initiation of Disopyramide for Obstructive Hypertrophic Cardiomyopathy Patients

Background Disopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated. Methods and Results All charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted. Disopyramide in our clinic is usually initiated at a dose of 300 mg daily and titrated during follow‐up. A total of 2015 patients were seen in the clinic, including 168 who were started on disopyramide. There were no cardiac events within 3 months of disopyramide initiation. During long‐term follow‐up (255 patient‐years; mean, 447 days; interquartile range, 201–779), only 2 patients developed cardiac events (syncope of unknown cause in both). Thirty‐eight patients (23%) developed side effects of disopyramide and 18 (11%) stopped the drug because of these side effects. Of the patients continuing disopyramide long term, 63% remained free of septal reduction interventions at end of follow‐up. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 ms; however, increasing the dose to 600 mg had no further significant effect. Conclusions Initiation of disopyramide in the outpatient setting is safe and the risk of subsequent sudden cardiac death is low. Because of its QT‐prolonging effect, precautions may be necessary in patients at higher risk of torsades de pointes.

THE RELATIONSHIP BETWEEN THE QUANTITATIVE EXTENT OF MYOCARDIAL FIBROSIS AND BURDEN OF NON-SUSTAINED VENTRICULAR TACHYCARDIA IN HYPERTROPHIC CARDIOMYOPATHY: A DELAYED CONTRAST ENHANCED MRI STUDY

Background: Non-sustained ventricular tachycardia (NSVT) has been shown to be independently associated with sudden death in hypertrophic cardiomyopathy (HCM). Previous studies have found late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) to be independently associated with the

Prevalence and Clinical Implication of Double Mutations in Hypertrophic CardiomyopathyCLINICAL PERSPECTIVE

Background— Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification. Methods and Results— Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in MYBPC3 in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype–phenotype correlations were scarce. Conclusions— Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical MYBPC3 mutations, there is little data to guide clinical decision making in cases with double mutations.

Prevalence and Clinical Implication of Double Mutations in Hypertrophic CardiomyopathyCLINICAL PERSPECTIVE: Revisiting the Gene-Dose Effect

Background— Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification. Methods and Results— Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in MYBPC3 in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype–phenotype correlations were scarce. Conclusions— Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical MYBPC3 mutations, there is little data to guide clinical decision making in cases with double mutations.

Prevalence and Clinical Implication of Double Mutations in Hypertrophic Cardiomyopathy

Background— Available data suggests that double mutations in patients with hypertrophic cardiomyopathy are not rare and are associated with a more severe phenotype. Most of this data, however, is based on noncontemporary variant classification. Methods and Results— Clinical data of all hypertrophic cardiomyopathy patients with 2 rare genetic variants were retrospectively reviewed and compared with a group of patients with a single disease-causing variant. Furthermore, a literature search was performed for all studies with information on prevalence and outcome of patients with double mutations. Classification of genetic variants was reanalyzed according to current guidelines. In our cohort (n=1411), 9% of gene-positive patients had 2 rare variants in sarcomeric genes but only in 1 case (0.4%) were both variants classified as pathogenic. Patients with 2 rare variants had a trend toward younger age at presentation when compared with patients with a single mutation. All other clinical variables were similar. In data pooled from cohort studies in the literature, 8% of gene-positive patients were published to have double mutations. However, after reanalysis of reported variants, this prevalence diminished to 0.4%. All patients with 2 radical mutations in MYBPC3 in the literature had severe disease with death or heart transplant during the first year of life. Data on other specific genotype–phenotype correlations were scarce. Conclusions— Double mutations in patients with hypertrophic cardiomyopathy are much less common than previously estimated. With the exception of double radical MYBPC3 mutations, there is little data to guide clinical decision making in cases with double mutations.