146 V142I allele in the Black UK population: V142I allele prevalence in the healthy UK Black population vs Black heart failure patients and dominance of hereditary ATTR cardiomyopathy (vacardi study)

Background Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure (HF). The V142I (valine to isoleucine substitution at position 142 of the transthyretin protein) variant associated with hereditary ATTR-CM is present in 3.9% of Black individuals in the US; however, there is limited data from the UK. There is a broad range of estimates of V122I penetrance, with previous estimates ranging from as low as 7% based on echocardiography to as high as 100% based on autopsy data in Black individuals >65 years of age. Methods The VACardDi study is a prospective study designed to determine the prevalence of the V142I allele in the healthy UK Black population and in Black HF patients from a South London population. N=128 Black patients with a clinical HF diagnosis confirmed by NTpro-BNP and echocardiogram (NYHA class >II, and on HF treatment) were included. At the point of recruitment, a blood sample was collected for genetic testing and baseline data including medical history and echocardiographic parameters were recorded. The patients were further investigated with Cardiac Magnetic Resonance (CMR) and/ or 99 mTc-DPD scans in order to establish the underlying aetiology. In addition, a control population of 252 healthy Black blood donors were prospectively tested from anonymised consecutive samples from the National Blood Transfusion Service to establish the carrier frequency of the V142I in the UK. Results The prevalence of the V142I mutation in the healthy UK Black population from Blood Transfusion Service samples was 3.6%, which is consistent with epidemiological and autopsy studies in African American populations. The median age of the control population was 35 (mean 38, IQR 26–51 in non-carriers vs mean 39, IQR 22–54 in the allele carriers, P=0.79). The prevalence of the V142I allele in the Black HF population was 14% (n=18 carriers). Of the 18 V142I carriers amongst the Black HF population 13 patients have a diagnosis of ATTR V142I cardiomyopathy (72%). We analysed echocardiographic data for the following groups: (1) Black HF patients without the ATTR-CM phenotype (including V142I carriers without imaging evidence of ATTR-CM on CMR or 99 mTc-DPD scans versus) (2) V142I carriers with hereditary ATTR-CM phenotype. The patients diagnosed with wt-ATTR CM have been excluded from both groups. The V142I carriers with hereditary ATTR-CM had increased maximal left ventricular (LV) wall thickness (IQR 1.35–1.9 cm, median 1.6 cm) compared to the Black HF population without ATTR-CM phenotype (IQR 0.9–1.4 cm, median 1.1 cm, P= 0.0004). In contrast, group (1) had increased LV end diastolic dimension (IQR 4.3–5.8 cm, median 5 cm) compared to group (2) (IQR 3.45–45 cm, median 4.1 cm, P=0.001). There was no significant difference in the LV ejection fraction or other echocardiographic parameters between the two groups (44 and 45% respectively) (table 1). Conclusions We have demonstrated an almost 4 times concentration of the V142I allele in the black HF population (14%) versus the healthy black population (3.6%) indicating that V142I carrier status is associated with significantly increased risk for the development of heart failure. We have also demonstrated that the dominant phenotype for 72% of black HF patients was V142I ATTR-CM. These are important findings given the frequency of the allele in the UK Black population (3.6% equivalent to 86,400 people in the UK). This study highlights the increased risk for the development of HF associated with V142I carrier status. Conflict of Interest Received a Pfizer Global ATTR Clinical Research Fellowship to support my OOPR