Combining tests of myocardial microstructure and microvascular function could enable earlier detection of hypertrophic cardiomyopathy (HCM) before symptoms and signs appear using conventional tests, according to a new imaging analysis by researchers in the UK.
Inherited HCM affects around 1 in 500 people in the UK, according to Cardiomyopathy UK , and all forms of the condition an estimated 220,000 people. It is a leading cause of heart failure and sudden cardiac death.
Both myocyte disarray and microvascular disease have been implicated in HCM adverse events, and recent evidence suggested that these may occur early in the course of the disease.
Tests Assess Both Cardiac Microstructure and Microvasculature
The research team from University College London (UCL), Barts Heart Centre, and the University of Leeds, tested two advanced cardiac magnetic resonance imaging (CMR) techniques: cardiac diffusion tensor imaging (cDTI) to assess the heart’s microstructure, and quantitative perfusion mapping (perfusion CMR) to detect microvascular disease in the cardiac blood supply.
Participants were aged 18 to 76 and had been prospectively and consecutively recruited from databases of genotyped patients. The researchers used the two tests to assess three groups of patients:
- Patients with overt HCM, diagnosed by increased left ventricular wall thickness not solely explained by abnormal loading conditions (101 patients)
- Patients with subclinical HCM with pathogenic or likely pathogenic HCM genetic variants confirmed on cascade screening, but without hypertrophy (77 patients)
- Healthy volunteers with no relevant medical history or risk factors for coronary disease who were prospectively matched for age, sex, and ethnicity to either the overt HCM or the sub-clinical HCM cohorts (28 controls)
Patients with overt HCM had both very abnormal cDTI scans and a high rate and severity of microvascular disease on perfusion CMR (100% of those who were genotype positive and 82% of those genotype negative).
Scans Could Identify Abnormalities in Gene Carriers Before Symptoms Develop
The study authors said that "crucially", in the group who had "problematic" gene variants without symptoms or hypertrophy, the scans were also able to identify abnormal microstructure compared with healthy volunteers, although to a lesser extent. Almost one in three (28%) of this group had microvascular defects, versus no healthy controls.
Disarray and microvascular disease were independently associated with pathological electrocardiographic abnormalities in both overt and subclinical groups, after adjustment for fibrosis and left ventricular hypertrophy.
The researchers concluded that "measurable changes" in both myocardial microstructure and microvascular function occur in the absence of hypertrophy in sarcomeric mutation carriers, in whom these changes are associated with electrocardiographic abnormalities.
Senior author Dr Luis Lopes, an associate professor at UCL's Institute of Cardiovascular Science, said: "By linking advanced imaging to our cohort of HCM patients (and relatives) with extensive genetic testing, this study detected microstructural abnormalities in vivo in mutation carriers for the first time, and was the first to compare these parameters in HCM patients with and without a causal mutation."
Early Diagnosis a Priority for Era of Disease-Modifying Therapy
The scan changes represent "early phenotype biomarkers", the team said, enabling earlier diagnosis of HCM, which will be a priority "in the emerging era of disease-modifying therapy".
Newly developed therapeutics for the first time provide hope of treatments for HCM that target the disease, rather than just the symptoms. The first drug to slow HCM progression, mavacamten (Camzyos, Bristol-Myers Squibb), was recently approved for use in Europe after it was shown to reduce the severity of the disease even once symptoms were present, although it has yet to be made available in the UK.
The new study, funded by the British Heart Foundation and published in the journal Circulation, opens the prospect of treating HCM at the earliest stages, the researchers said. In addition, earlier detection could assist trials investigating gene therapies currently in development for those with inherited HCM, as well as drug treatments aimed at stopping the disease developing in those at risk.
Dr George Joy, a clinical research fellow at UCL , who led the research, said: "The ability to detect early signs of HCM could be crucial in trials testing treatments aimed at preventing early disease from progressing or correcting genetic mutations. The scans could also enable treatment to start earlier than we previously thought possible."
He said the team now planned to assess whether the scans could identify which patients without overt HCM were most at risk of progressing to severe disease.