Author: Kathryn McGurk

Refocusing clinical care for young people with cardiomyopathies

We are excited to share our publication (Jennings et al. 2025) in Cardiology in the Young describing discussion needs and potential research avenues for young people with dilated cardiomyopathy (DCM). We hope it is a valuable insight for clinicians and researchers, particularly for the ongoing development of clinical care specifically for the young with DCM.

DCM is a heart condition characterised by an enlarged left ventricle that can lead to heart failure. It is most often diagnosed in adult males, however, when diagnosed in childhood, it can present unique challenges to patients and clinicians. As children move from the paediatric hospital services to the adult services (“transition”), they need unique support when taking responsibility for their health and living with DCM.

Using a patient-scientist’s perspective to inform a literature review, we identified areas that could form the basis of the information provided during transition clinical services. This could aid the further standardisation of clinical care for young people and ensure that the correct support is in place to equip young people to make informed decisions and provide an opportunity for discussion about topics that may be experienced when living with a chronic condition. The key areas identified as requiring additional support from clinical teams are: mental health, exercise, alcohol consumption, cigarettes, recreational drugs, and sexual health.

Young people with DCM and their families require specialised mental health support to equip them for lifelong clinical care. For patients, it is important to support them as they come to terms with their limitations amongst healthy peers. Family members may have experienced traumatic events such as sudden death or feel the empathetic burden of being the “well” sibling. Medical trauma during childhood can impact stress tolerance in later life and young people may be more susceptible to poor mental health outcomes without intervention. Repeated signposting to mental health services is recommended for both the patient and their families.

Genetic testing is often undertaken for diagnostic support in cardiomyopathies. If carried out during childhood, results should be revisited with the young person in the transition to adulthood. This would ensure the patient has a full understanding of the downstream effects of a given result and the impact on access to family planning measures, etc.

Current exercise guidelines suggest it is safe to exercise to perspiration with the ability to hold a conversation and avoid exercising when feeling unwell or tired. The advice however is generally non-specific regarding varying exercise types and duration, with little research available on DCM in the young.

Alcohol and caffeine are regularly consumed in adults, but the evidence surrounding their negative impacts is non-specific, and the advice is to avoid them in excess, hydrate more before and after consumption, and avoid taking them in combination. They may oppose the effects of therapeutic drugs used for DCM treatment.

Smoking, vaping, cannabis, cocaine, MDMA, and ketamine, negatively influence the cardiovascular system, with cocaine described as the most cardiotoxic. There is little specific evidence for patients with cardiomyopathy, and it is recommended by medical professionals to avoid consumption. When advocating abstinence to teenagers, it is important to discuss the reasoning for this.

Pregnancy can be contraindicated in some people with DCM, and progesterone-only or barrier methods of contraception are recommended to avoid the risks associated with oestrogen-based alternatives. During the transition to adult services, the implications and planning of pregnancy should be discussed to ensure that patients are well-informed about the importance of avoiding unplanned pregnancies.

Further research is needed to address the many uncertainties in these areas with respect to young age, particularly for physical activity, and such guidance would be welcomed by the young with DCM who must come to terms with being different and more limited amongst healthy peers.

Could mavacamten be a key player in implementing pharmacogenetics in cardiovascular prescribing?

We are pleased to share our publication (McGurk et al. 2024) in Circulation on the pharmacogenetic influences over mavacamten pharmacokinetics.

Mavacamten is a first-in-class, orally administered, cardiac-specific, small-molecule allosteric modulator of β-cardiac myosin. Mavacamten reversibly inhibits the binding of β-cardiac myosin to actin to reduce hypercontractility in an exposure-dependent manner.

DNA variants can alter the therapeutic and adverse effects of drugs at recommended dosages. Variants in genes encoding cytochrome P450 enzymes, expressed in the liver and small intestine, are associated with variable drug metabolism. Individuals can be categorized into 5 metabolizer phenotypes: poor, intermediate, extensive (sometimes described as normal), rapid, and ultrarapid. CYP2C19 is the dominant metabolizer of mavacamten and poor metabolizers, attributable to diplotypes of 2 CYP2C19 alleles [the CYP2C19*2 (p.Pro227Pro;c.681G>A; rs4244285) and CYP2C19*3 (p.Trp212Ter;c.636G>A; rs4986893) alleles], are at increased risk of systolic dysfunction from mavacamten treatment at the recommended dose. Individual metabolizer status is further complicated by additional variation across other common alleles within this gene, other CYP450 genes, and other relevant pathways.

The prevalence of poor metabolizers (PMs) is common and varies by population (below). The half-life is extended to 23 days in PMs from 9 days in normal metabolisers (NMs). In NMs, it takes ~4 weeks (five half-lives) to eliminate mavacamten from the body after treatment discontinuation.

The EMA and UK Medicines and Healthcare Products Regulatory Agency recommend genotyping for CYP2C19 to determine the appropriate dose. If treatment is initiated without metabolizer status determination, dosage should follow as described for poor metabolizers (starting at 2.5 mg once daily and a maximum dose of 5 mg once daily). The recommended starting dose for all other metabolizers is 5 mg once daily and a maximum dose of 15 mg once daily. Dose modifications are provided for concomitant medicinal products, including CYP2C19 and CYP3A4 inhibitors and inducers. The EMA and Australian Therapeutic Goods Administration suggest a simulated 5 mg dose in a poor metabolizer is similar to the maximum dose (15 mg) in a normal metabolizer.

It remains unclear how the EMA genotyping recommendation will be implemented across diverse European health care systems. Genetic testing for variants in sarcomere-encoding genes is used for individuals with HCM to establish the molecular etiology; pharmacogenetic analysis could be incorporated for individuals who have not already undergone testing and allow for the EMA recommended dosage stratification.

The NICE guidelines note uncertainty surrounding the impact of sarcomeric variants on treatment effect (section 3.7): the relationship between treatment response and genotype has not been fully characterised, with the possibility of differences between individuals with and without sarcomere variants and/or with variants in thick vs thin filament genes.

Providing the appropriate mavacamten dosage to each individual with oHCM from treatment initiation should allow for improved quality of life at the lowest risk of adverse events, cost, and burden to health care systems. Prescribers must be aware of the potential for metabolic variability across and within different ancestries and clinical vigilance with close monitoring will be required to avoid adverse events. Successful treatment requires improving symptoms of oHCM in rapid metabolizers and minimizing the risk of drug-induced systolic dysfunction in poor metabolizers. Treatment without genotyping risks reduced ejection fraction in poor metabolizers or increased time to therapeutic dose in normal metabolizers. With limited medications for the management of oHCM, or where there is limited access to septal reduction therapy, effective titration of cardiac myosin inhibitors is vital to the success of treatment. Whereas future clinical trials with improved metabolizer and ancestral representation will aid our understanding in this area, CYP2C19 genotyping may allow for less frequent clinical monitoring and reduced costs.

We also discuss i) only NICE recommends mavacamten as an add-on to standard care and notes long waiting times for echo; ii) Tian et al 2023 which studied 7 PMs; iii) the potential for predose mavacamten plasma concentration measurement (based on 21 individuals of phase 1 trial).

The NHS England National Genomics Education Programme has also released some guidance and an example clinical scenario

This is just one example of how common DNA variants influence cardiovascular treatment. Pharmacogenetic influences are known and reported for drugs during trials, but to date are used clinically only in a few areas. Further implementation in a cardiovascular setting would allow for reduced adverse events, time to therapeutic dose, and titration, of drug interventions.

What is the penetrance of the variants most likely to be identified as secondary findings in cardiomyopathy-associated genes?

We are pleased to share our publication (McGurk et al. 2023) in the American Journal of Human Genetics on the penetrance of  rare variants in cardiomyopathy-associated genes: a cross-sectional approach to estimate penetrance for secondary findings.

The penetrance of cardiomyopathies (CMs) is incomplete and age-related, and expressivity is highly variable. These features present huge challenges for disease management. In particular, the penetrance of individual variants in CM-associated genes is incompletely characterised and poorly understood, especially when identified in asymptomatic individuals without family history.

With the growing availability of whole exome sequencing in wider clinical settings and consumer-initiated elective genomic testing, the importance of estimating the penetrance of individual variants identified as secondary findings (SFs) to guide intervention is ever-increasing. Genes associated with inherited CMs make up one-fifth of the 78 genes recommended by the American College of Medical Genetics and Genomics (ACMG SF v3.1) for reporting SFs during clinical sequencing. Variant-specific estimates of penetrance are required to appropriately inform clinical practice and to fully utilise genetics as a tool to individualise the risk of developing disease in asymptomatic carriers.

We apply a cross-sectional approach, using a method that compares the allele frequency of individual rare variants in large cohorts of cases and reference populations to estimate penetrance. Sequencing data for 10,400 individuals referred for HCM genetic panel sequencing and 2,564 individuals referred for DCM genetic panel sequencing were included in the analysis. To estimate the prevalence of CMs, a literature review and meta-analysis were undertaken, resulting in prevalence estimates for HCM (1:543; 1:1,300 women, 1:360 men) and DCM (1:220; 1:340 women, 1:160 men).

In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant CM. Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes.

We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (51% HCM and 17% DCM cases). 49 variants were observed at least ten times (14% of cases) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry, and simulate the impact of including future cohorts.

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This dataset is the first to report the penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some carriers of highly penetrant variants may benefit from SFs.

Identification of an increased lifetime risk of major adverse cardiovascular events in UK Biobank participants with scoliosis

We are pleased to share a new article by Valentina Santofimio on research she completed during her masters programme with us.

The abnormal curvature of the spine in scoliosis patients can impact organs within the ribcage including the heart. Most cardiac studies of scoliosis patients to date surround investigations into congenital heart disease. The relationship between scoliosis and non-congenital cardiac manifestations in adults is not well characterised.

Our study focused on investigating the impact of scoliosis on the heart through assessment of cardiac MRI (CMR) traits in the UK Biobank (UKB) adult population cohort. A total of 4,095 (0.8%, 1 in 120) UKB participants were identified to have all-cause scoliosis.

Significant associations were found between scoliosis and older age, female sex, heart failure, valve disease, hypercholesterolemia, diagnosis of hypertension, and decreased enrolment for CMR. We identified altered radial and longitudinal peak diastolic strain rates (PDSR) in participants with scoliosis with CMR available compared to participants without diagnosis of scoliosis. 3D cardiac modelling also showed altered cardiac strain.

A significantly increased lifetime risk of MACE was observed for UKB participants with scoliosis (HR=1.45, P<0.001), mainly driven by heart failure (HR=1.58, P<0.001) and atrial fibrillation (HR=1.54, P<0.001). The probability of MACE doubled in males into older age (from 60 years of age). This may be caused through the altered cardiac diastolic strain rates observed in participants with scoliosis.

The abnormal curvature of the spine can increase mechanical constraint on the heart which may result in diastolic dysfunction and the severity of the spinal deformity has been shown to aggravate ventricular and right atrial pressure.

Scoliosis may be an important modifier of cardiac strain in the adult population. This has clinical implications for the consideration of undertaking scoliosis treatment surgery. However, further research is required to follow up the role of scoliosis in cardiac manifestations in a clinical setting, alongside genetic analyses to assess causality.