BACKGROUND:A better understanding of the factors that contribute to heterogeneous outcomes and lifetime disease burden in hypertrophic cardiomyopathy (HCM) is critically needed to improve patient ...management and outcomes. The SHaRe registry (Sarcomeric Human Cardiomyopathy Registry) was established to provide the scale of data required to address these issues, aggregating longitudinal data sets curated by 8 international HCM specialty centers.
METHODS:Data on 4591 patients with HCM (2763 genotyped) followed up for a mean of 5.4±6.9 years (24 791 patient-years; median, 2.9 years; interquartile range, 0.3–7.9 years) were analyzed for cardiac arrest, cardiac transplantation, appropriate implantable cardioverter-defibrillator therapy, all-cause death, atrial fibrillation, stroke, New York Heart Association functional class III/IV symptoms (all making up the overall composite end point), and left ventricular ejection fraction <35%. Outcomes were analyzed individually and as composite end points.
RESULTS:Median age at diagnosis was 45.8 (interquartile range, 30.9–58.1) years, and 37% of patients were female. Age at diagnosis and sarcomere mutation status were predictive of outcomes. Patients <40 years old at diagnosis had a 77% (95% CI, 72–80) cumulative incidence of the overall composite outcome by 60 years of age compared with 32% (95% CI, 29–36) by 70 years of age for patients diagnosed at >60 years old. Young patients with HCM (age, 20–29 years) had 4-fold higher mortality than the general US population at a similar age. Patients with pathogenic/likely pathogenic sarcomere mutations had a 2-fold greater risk for adverse outcomes compared with patients without mutations; sarcomere variants of uncertain significance were associated with intermediate risk. Heart failure and atrial fibrillation were the most prevalent adverse events, although typically not emerging for several years after diagnosis. Ventricular arrhythmias occurred in 32% (95% CI, 23–40) of patients <40 years of age at diagnosis but in 1% (95% CI, 1–2) of those >60 years old at diagnosis.
CONCLUSIONS:The cumulative burden of HCM is substantial and dominated by heart failure and atrial fibrillation occurring many years after diagnosis. Young age at diagnosis and the presence of a sarcomere mutation are powerful predictors of adverse outcomes. These findings highlight the need for close surveillance throughout life and the need to develop disease-modifying therapies.
This study shows that myocardial fibrosis is an early characteristic of hypertrophic cardiomyopathy caused by sarcomere mutations. The C-terminal propeptide of procollagen type I was shown to be a ...serum biomarker of early myocardial fibrosis.
Hypertrophic cardiomyopathy is caused by mutations in genes encoding sarcomere proteins.
1
,
2
With a prevalence of approximately 1 case per 500 persons in the general population, hypertrophic cardiomyopathy is the most common monogenic cardiac disorder.
3
The clinical diagnosis depends on the identification of unexplained left ventricular hypertrophy, but this finding is present only in persons with established disease and is typically absent in childhood.
4
In contrast, genetic diagnosis identifies pathogenic sarcomere mutations in persons at any age, including mutation carriers with overt hypertrophic cardiomyopathy and mutation carriers without hypertrophy who are at high risk for the development of disease. Studying . . .
Purpose of Review
Preimplantation genetic testing for monogenic conditions (PGT-M) is an increasingly utilized reproductive technology for patients with inherited heart disease (IHD). In this ...article, we provide an overview of the PGT-M process, including current guidance about its use, and review recent data about the perspectives and experiences of patients considering the use of PGT-M.
Recent Findings
PGT-M is used for a variety of IHDs; however, there is evidence that providers do not consistently raise this topic with patients, which may be due to a lack of knowledge about PGT-M. Regardless of the condition, patients report similar motivations for using PGT-M, such as the desire for a healthy child and the wish to save offspring from suffering. Patients make individualized decisions that are influenced by their lived experience with the diagnosis, a sense of responsibility to prevent disease transmission and other personal and logistical considerations. The PGT-M process can be challenging and each patient requires comprehensive information and support throughout.
Summary
PGT-M is a complex multi-step process whereby individual decision-making is influenced by various intrinsic and extrinsic factors. Adequate information and support are necessary for individual decision-making and expectation-setting. This is best accomplished by a multidisciplinary collaboration including cardiology, genetics, reproductive endocrinologists, and obstetric providers.
Preimplantation genetic testing for monogenic disorders (PGT‐M) is a reproductive technology used in conjunction with in‐vitro fertilization (IVF) to reduce the risk of passing on a known genetic ...condition from parent to child. There is limited research describing the experience and emotional impact of PGT‐M among individuals with inherited aortic or vascular disease (IAVD). Our qualitative study aims to explore the factors that influence reproductive decision‐making and the uptake of PGT‐M within this population. Individuals diagnosed with IAVD who have considered PGT‐M, and/or their reproductive partner, were recruited using internal clinical databases and advocacy organizations. Virtual semi‐structured interviews were conducted using an interview guide that included questions related to participants' lived experience of their condition, risk perception, reproductive history, familiarity with PGT‐M/IVF, and financial/psychosocial considerations. A total of 17 interviews were completed (13 affected individuals, 4 unaffected partners) and analyzed using thematic analysis. Emergent themes included: (1) the lived experience and perceived severity of disease; (2) need for comprehensive, balanced, and timely information; (3) and impact of personal values and circumstances. When discussing the impact of lived experience on reproductive decision‐making, participants identified the physical and emotional impact of disease and variability of disease as factors influencing the uptake of PGT‐M. Many described PGT‐M as the only reproductive option presented to them by providers. Even so, participants expressed gaps in their understanding of PGT‐M, particularly regarding cost/insurance coverage and the experience of IVF. Finally, participants recognized that the decision to pursue PGT‐M primarily requires introspection and evaluation of one's values, but that cost remains a significant consideration. The findings from our study highlight the complexity of reproductive decision‐making for individuals with IAVD and provide insight into their psychological and informational needs when engaging in this process. Providers can use these findings to tailor their discussions about reproductive decision‐making with this patient cohort.
Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy (HCM) and a potential substrate for arrhythmias and heart failure. Sarcomere mutations seem to induce profibrotic changes before left ...ventricular hypertrophy (LVH) develops. To further evaluate these processes, we used cardiac magnetic resonance with T1 measurements on a genotyped HCM population to quantify myocardial extracellular volume (ECV).
Sarcomere mutation carriers with LVH (G+/LVH+, n=37) and without LVH (G+/LVH-, n=29), patients with HCM without mutations (sarcomere-negative HCM, n=11), and healthy controls (n=11) underwent contrast cardiac magnetic resonance, measuring T1 times pre- and postgadolinium infusion. Concurrent echocardiography and serum biomarkers of collagen synthesis, hemodynamic stress, and myocardial injury were also available in a subset. Compared with controls, ECV was increased in patients with overt HCM, as well as G+/LVH- mutation carriers (ECV=0.36±0.01, 0.33±0.01, 0.27±0.01 in G+/LVH+, G+/LVH-, controls, respectively; P≤0.001 for all comparisons). ECV correlated with N-terminal probrain natriuretic peptide levels (r=0.58; P<0.001) and global E' velocity (r=-0.48; P<0.001). Late gadolinium enhancement was present in >60% of overt patients with HCM but absent from G+/LVH- subjects. Both ECV and late gadolinium enhancement were more extensive in sarcomeric HCM than sarcomere-negative HCM.
Myocardial ECV is increased in HCM sarcomere mutation carriers even in the absence of LVH. These data provide additional support that fibrotic remodeling is triggered early in disease pathogenesis. Quantifying ECV may help characterize the development of myocardial fibrosis in HCM and ultimately assist in developing novel disease-modifying therapy, targeting interstitial fibrosis.
Abstract Background Familial involvement is common in dilated cardiomyopathy (DCM) and >40 genes have been implicated in causing disease. However, the role of genetic testing in clinical practice is ...not well defined. We examined the experience of clinical genetic testing in a diverse DCM population to characterize the prevalence and predictors of gene mutations. Methods and Results We studied 264 unrelated adult and pediatric DCM index patients referred to 1 reference lab for clinical genetic testing. Up to 10 genes were analyzed ( MYH7 , TNNT2 , TNNI3 , TPM1 , MYBPC3 , ACTC , LMNA , PLN , TAZ , and LDB3 ), and 70% of patients were tested for all genes. The mean age was 26.6 ± 21.3 years, and 52% had a family history of DCM. Rigorous criteria were used to classify DNA variants as clinically relevant (mutations), variants of unknown clinical significance (VUS), or presumed benign. Mutations were found in 17.4% of patients, commonly involving MYH7 , LMNA , or TNNT2 (78%). An additional 10.6% of patients had VUS. Genetic testing was rarely positive in older patients without a family history of DCM. Conversely in pediatric patients, family history did not increase the sensitivity of genetic testing. Conclusions Using rigorous criteria for classifying DNA variants, mutations were identified in 17% of a diverse group of DCM index patients referred for clinical genetic testing. The low sensitivity of genetic testing in DCM reflects limitations in both current methodology and knowledge of DCM-associated genes. However, if mutations are identified, genetic testing can help guide family management.
Genetic testing has become more accessible and is increasingly being incorporated into the care of patients with hypertrophic cardiomyopathy. Genetic test results can help to refine diagnosis and ...distinguish at-risk relatives from those who are not at risk.
Recent genetic research has explored how genetic variants may contribute to gender dysphoria and transgender and gender-diverse (TGD) identities. When investigating communities that have been ...marginalized, it is important for researchers to incorporate perspectives of the communities the research is targeting. Therefore, investigators should incorporate the TGD community’s opinions into this research to mitigate potential ethical issues, given the history of pathologization of TGD identities and utilization of genetics for eugenics. The aim of this study was to understand the perspectives of TGD individuals about trans-associated genetic research (TAGR). Eighteen semi-structured interviews were conducted with members of the TGD community to explore how TGD individuals view TAGR. Through inductive content analysis, five major themes were emergent: (1) TAGR could affect self-perception of identity; (2) TAGR could affect external views of TGD people; (3) TAGR could affect access to gender-affirming services; (4) TAGR could contribute to the pathologization and elimination of TGD identities; and (5) researchers should consult TGD community members and consider ethical concerns before conducting research. Participants highlighted concerns about TAGR being used as a tool for discrimination. Those who identified potential advantages of TAGR gave warning that TAGR would be unlikely to solely have positive effects. It is important for genetic researchers to prioritize the perspectives and concerns of TGD people highlighted in this study. Research about the TGD community needs to include TGD individuals as core members of the research team. Moreover, due to the serious ethical issues outlined in this study, TAGR should be reconsidered altogether.
Genetic testing and genetic counseling are routinely indicated for patients with hypertrophic cardiomyopathy (HCM); however, the uptake and utility of these services is not entirely understood. This ...systematic review and meta‐analysis summarizes the uptake and utility of genetic counseling and genetic testing for patients with HCM and their at‐risk family members, as well as the impact of genetic counseling/testing on patient‐reported outcomes (PROs). A systematic search was performed through March 12, 2021. Meta‐analyses were performed whenever possible; other findings were qualitatively summarized. Forty‐eight studies met inclusion criteria (47 observational, 1 randomized). Uptake of genetic testing in probands was 57% (95% confidence interval CI: 40, 73). Uptake of cascade screening for at‐risk relatives were as follows: 61% for cascade genetic testing (95% CI: 45, 75), 58% for cardiac screening (e.g. echocardiography) (95% CI: 40, 73), and 69% for either/both approaches (95% CI: 43, 87). In addition, relatives of probands with a positive genetic test result were significantly more likely to undergo cascade screening compared to relatives of probands with a negative result (odds ratio = 3.17, 95% CI: 2.12, 4.76). Overall, uptake of genetic counseling in both probands and relatives ranged from 37% to 84%. Multiple studies found little difference in PROs between individuals receiving positive versus negative genetic test results; however, other studies found that individuals with positive genetic test results experienced worse psychological outcomes. Genetic testing may also inform life choices, particularly decisions related to reproduction and insurance. Genetic counseling was associated with high satisfaction, increased perceived personal control and empowerment, and decreased anxiety. Approximately half to three‐quarters of patients with HCM and their relatives undergo genetic testing or cascade screening. PROs after genetic testing varied and genetic counseling was associated with high satisfaction and improved PROs.
PDF
