Titin Gene Mutations and Cardiomyopathies
Aim Peripartum cardiomyopathy (PPCM) can be an initial manifestation of familial dilated cardiomyopathy (DCM). We aimed to identify mutations in families that could underlie their PPCM and DCM.
Methods and results We collected 18 families with PPCM and DCM cases from various countries. We studied the clinical characteristics of the PPCM patients and affected relatives, and applied a targeted next-generation sequencing (NGS) approach to detect mutations in 48 genes known to be involved in inherited cardiomyopathies. We identified 4 pathogenic mutations in 4 of 18 families (22%): 3 in TTN and 1 in BAG3. In addition, we identified 6 variants of unknown clinical significance that may be pathogenic in 6 other families (33%): 4 in TTN, 1 in TNNC1, and 1 in MYH7. Measurements of passive force in single cardiomyocytes and titin isoform composition potentially support an upgrade of one of the variants of unknown clinical significance in TTN to a pathogenic mutation. Only 2 of 20 PPCM cases in these families showed the recovery of left ventricular function.
Conclusion Targeted NGS shows that potentially causal mutations in cardiomyopathy-related genes are common in families with both PPCM and DCM. This supports the earlier finding that PPCM can be part of familial DCM. Our cohort is particularly characterized by a high proportion of TTN mutations and a low recovery rate in PPCM cases.
Peripartum cardiomyopathy (PPCM) is an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the first months following delivery, where no other cause of heart failure is found. The left ventricle may not be dilated but the ejection fraction is nearly always reduced <45%. According to this recent definition, the time frame is not strictly defined, in contrast to previous definitions. The severity of PPCM is highly variable, ranging from complete recovery to rapid progression to end-stage heart failure. Peripartum cardiomyopathy affects 1:300 to ~1:3000 pregnancies, with geographic hot spots of high incidence such as in Haiti and Nigeria.
The precise mechanisms that lead to PPCM are not fully known. Several risk factors and possible underlying pathological processes have received attention, such as abnormal autoimmune responses, apoptosis, and impaired cardiovascular microvasculature. Recent work into the pathogenesis of PPCM has shown involvement of a cascade with oxidative stress, the prolactin-cleaving protease cathepsin D, and the nursing hormone prolactin, which may lead to a target for a disease-specific therapy, namely pharmacological blockade of prolactin by bromocriptine. In addition, involvement of cardiac angiogenic imbalance may explain why PPCM is a disease seen in late pregnancy and why pre-eclampsia and multiple gestation are important risk factors. Peripartum cardiomyopathy is probably caused by a complex interaction of more than one pathogenic mechanism. The large variation in incidence and clinical characteristics may reflect the involvement of specific mechanisms, or combinations thereof, in certain subgroups of PPCM.
We and others recently reported that PPCM can be an initial manifestation of familial dilated cardiomyopathy (DCM), indicating that, at least in a subset of cases, genetic predisposition plays a role in the pathophysiology of pregnancy-associated heart failure. Accordingly, Haghikia et al. reported a positive family history for cardiomyopathy in 16.5% (19 of 115) of PPCM cases from a German PPCM cohort. So far, eight cases with underlying mutations in DCM-related genes have been published and several other cases with familial occurrences of PPCM and DCM, as well as familial clustering of PPCM, have been reported. Here, we describe our extensive genetic analysis using next-generation sequencing (NGS) technology to identify potentially causal mutations in families with both PPCM and DCM from various parts of the world.
Abstract and Introduction
Abstract
Aim Peripartum cardiomyopathy (PPCM) can be an initial manifestation of familial dilated cardiomyopathy (DCM). We aimed to identify mutations in families that could underlie their PPCM and DCM.
Methods and results We collected 18 families with PPCM and DCM cases from various countries. We studied the clinical characteristics of the PPCM patients and affected relatives, and applied a targeted next-generation sequencing (NGS) approach to detect mutations in 48 genes known to be involved in inherited cardiomyopathies. We identified 4 pathogenic mutations in 4 of 18 families (22%): 3 in TTN and 1 in BAG3. In addition, we identified 6 variants of unknown clinical significance that may be pathogenic in 6 other families (33%): 4 in TTN, 1 in TNNC1, and 1 in MYH7. Measurements of passive force in single cardiomyocytes and titin isoform composition potentially support an upgrade of one of the variants of unknown clinical significance in TTN to a pathogenic mutation. Only 2 of 20 PPCM cases in these families showed the recovery of left ventricular function.
Conclusion Targeted NGS shows that potentially causal mutations in cardiomyopathy-related genes are common in families with both PPCM and DCM. This supports the earlier finding that PPCM can be part of familial DCM. Our cohort is particularly characterized by a high proportion of TTN mutations and a low recovery rate in PPCM cases.
Introduction
Peripartum cardiomyopathy (PPCM) is an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the first months following delivery, where no other cause of heart failure is found. The left ventricle may not be dilated but the ejection fraction is nearly always reduced <45%. According to this recent definition, the time frame is not strictly defined, in contrast to previous definitions. The severity of PPCM is highly variable, ranging from complete recovery to rapid progression to end-stage heart failure. Peripartum cardiomyopathy affects 1:300 to ~1:3000 pregnancies, with geographic hot spots of high incidence such as in Haiti and Nigeria.
The precise mechanisms that lead to PPCM are not fully known. Several risk factors and possible underlying pathological processes have received attention, such as abnormal autoimmune responses, apoptosis, and impaired cardiovascular microvasculature. Recent work into the pathogenesis of PPCM has shown involvement of a cascade with oxidative stress, the prolactin-cleaving protease cathepsin D, and the nursing hormone prolactin, which may lead to a target for a disease-specific therapy, namely pharmacological blockade of prolactin by bromocriptine. In addition, involvement of cardiac angiogenic imbalance may explain why PPCM is a disease seen in late pregnancy and why pre-eclampsia and multiple gestation are important risk factors. Peripartum cardiomyopathy is probably caused by a complex interaction of more than one pathogenic mechanism. The large variation in incidence and clinical characteristics may reflect the involvement of specific mechanisms, or combinations thereof, in certain subgroups of PPCM.
We and others recently reported that PPCM can be an initial manifestation of familial dilated cardiomyopathy (DCM), indicating that, at least in a subset of cases, genetic predisposition plays a role in the pathophysiology of pregnancy-associated heart failure. Accordingly, Haghikia et al. reported a positive family history for cardiomyopathy in 16.5% (19 of 115) of PPCM cases from a German PPCM cohort. So far, eight cases with underlying mutations in DCM-related genes have been published and several other cases with familial occurrences of PPCM and DCM, as well as familial clustering of PPCM, have been reported. Here, we describe our extensive genetic analysis using next-generation sequencing (NGS) technology to identify potentially causal mutations in families with both PPCM and DCM from various parts of the world.