Author: Kathryn McGurk

Dr Kathryn McGurk is a geneticist and data scientist at Imperial College London. Her research focuses on understanding how genetics affects cardiomyopathies and heart structure and function, and she has a special interest in takotsubo.

What is Takotsubo?

Takotsubo is a sudden and severe heart condition. While under-recognised, it affects 1 in 20 women suspected of a heart attack and men too. It mainly affects women over 65 years old. It is no longer thought to be a cardiomyopathy, but an “acute myocardial ischaemic syndrome”.

The symptoms of a takotsubo episode closely resemble a heart attack: chest pain, breathlessness, ECG reading changes and biomarkers. Patients are rushed into treatment for an emergency heart attack. However, unlike a heart attack, takotsubo is not caused by a blockage in the main blood vessels of the heart. A takotsubo diagnosis is eventually made through the exclusion of other conditions; this is not good enough for patients or clinicians.

Takotsubo is very poorly understood. It is thought to happen to some people when their body is coping with overwhelming physical or emotional stress, but this is not always the case and has not been studied well. The hallmark of takotsubo compared to heart attacks is the “recovery” of heart function within weeks. However, this “recovery” is only partial; recurrence of takotsubo is common, and many people have long-term problems after the first hospital visit.

Why are you interested in studying takotsubo?

A few years ago, I attended Cardiomyopathy UK’s annual patient conference in London. There, I met a group of individuals diagnosed with takotsubo, who noted that they didn’t have an emotional trigger or stress event. They wanted to be involved in more research to better understand their condition.

Once I started studying takotsubo, I was surprised at the lack of understanding and research for this common condition. We do not know why it happens, why it mainly affects women, or which patients are most at risk of complications. There are no specific treatments or preventative measures. No therapies have been shown to reduce recurrences or any other major cardiovascular events. There is no national picture of how this is managed across the NHS.

I think we can better understand what causes takotsubo in our research group with the help of people who are affected.

What research projects are you currently working on?

My current takotsubo research is split into two parts – understanding current NHS care pathways and outcomes, and using genetics as a tool to guide biological understanding. I am also working with a fantastic group of experts, the MINOCA workstream, as part of the NIHR-BHF Cardiovascular Partnership. This UK-wide collaboration will improve our understanding of takotsubo in the near future.

Part one: understanding current NHS care pathways and outcomes

Right now, we are analysing data from the NICOR Myocardial Ischaemia National Audit Project (MINAP), a nationwide NHS database that records every hospital admission for suspected heart attacks in England and Wales. Since many takotsubo patients first appear as suspected heart attack cases, MINAP contains one of the largest collections of real‑world information on this condition (over 5,000 individuals). Uniquely, clinicians were asked to fill in a voluntary discharge questionnaire when the patient was diagnosed with takotsubo. We have access to the data from this questionnaire, and it includes information since 2013 on over 2,000 individuals diagnosed with takotsubo.

Using this unique national dataset, we will examine:

• What kinds of emotional or physical stress triggers are most common, and are they likely a reason for this diagnosis, or are they as common in the population?
• Which patients are most affected (e.g., age, sex, medical history)?
• Symptoms and heart scan findings.
• How patients are treated in hospital, including medications and specialised cardiac support.
• How often do serious complications occur, such as abnormal heart rhythms or blood clots?
• How many patients experience repeat episodes and have a family history of takotsubo?
• How do takotsubo patients differ from other patients admitted with suspected heart attacks?

The results will help clinicians recognise takotsubo more quickly, avoid unnecessary invasive procedures, and provide more personalised care. This will lay the groundwork for our future research into the biological causes of takotsubo, including genetics and imaging studies.

Part two: using genetics as a tool to guide biological understanding

Genetics may help us identify the cause of takotsubo and target therapeutics for this condition if it is similar to other cardiovascular conditions. We know that most of the genes involved in keeping the heart beating are in the left ventricle, and these genes can influence someone’s risk of cardiomyopathy. Do the same genes influence the risk of takotsubo? This understanding will help us find genetic markers to identify people who are at risk of takotsubo much earlier.

The NHS database we are using in “part one” does not include genetic information, so to do this, we are inviting people who have been diagnosed with takotsubo to join “The Heart Hive Cardiomyopathy Study”.

I have takotsubo. How can I get involved?

We are inviting takotsubo-diagnosed individuals and their family members to join the Heart Hive – an online portal where people can sign up to participate in research studies (thehearthive.org).

We will post takotsubo studies, and those who have signed up can get involved if they like. This may include opinions on future research plans, surveys, or participation in genetic studies.

“The Heart Hive Cardiomyopathy Study” is already running on the Heart Hive and will help us better understand takotsubo compared to other cardiomyopathies. Taking part in this study involves providing a saliva sample by post for DNA sequencing. This will help us finally understand takotsubo through better research.

Steps to register and fill out the survey:

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.

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 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.

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.

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.

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.