Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC), with higher morbidity and mortality. These diseases are genetically diverse and associated with rare mutations in a large number of genes, many of which overlap among the phenotypes. To better investigate the genetic overlap between these three phenotypes and to identify new genotype–phenotype correlations, we designed a custom gene panel consisting of 115 genes known to be associated with cardiomyopathic phenotypes and channelopathies. A cohort of 38 unrelated patients, 16 affected by DCM, 14 by HCM and 8 by ARVC, was recruited for the study on the basis of more severe phenotypes and family history of cardiomyopathy and/or sudden death. We detected a total of 142 rare variants in 40 genes, and all patients were found to be carriers of at least one rare variant. Twenty-eight of the 142 rare variants were also predicted as potentially pathogenic variants and found in 26 patients. In 23 out of 38 patients, we found at least one novel potential gene–phenotype association. In particular, we detected three variants in OBSCN gene in ARVC patients, four variants in ANK2 gene and two variants in DLG1, TRPM4, and AKAP9 genes in DCM patients, two variants in PSEN2 gene and four variants in AKAP9 gene in HCM patients. Overall, our results confirmed that cardiomyopathic patients could carry multiple rare gene variants; in addition, our investigation of the genetic overlap among cardiomyopathies revealed new gene–phenotype associations. Furthermore, as our study confirms, data obtained using targeted next-generation sequencing could provide a remarkable contribution to the molecular diagnosis of cardiomyopathies, early identification of patients at risk for arrhythmia development, and better clinical management of cardiomyopathic patients.
Background
Right heart catheterization (RHC) is recommended by guidelines for the diagnosis of pulmonary hypertension, the definition of hemodynamic impairment and responsiveness to drug therapy. However, RHC is an invasive test with associated risk of complications. Noninvasive echocardiographic tools, possibly predictive of pulmonary hypertension at RHC, could be therefore extremely useful.
Methods
Sixty-four consecutive patients with suspected pulmonary hypertension were enrolled in the study and assessed by echocardiography and RHC. Diagnosis of pulmonary hypertension was based on mean pulmonary artery pressure (≥25 mmHg) at RHC.
Results
Of 64 consecutive patients enrolled, 77% were diagnosed as having pulmonary hypertension after RHC. On the basis of significant differences between patients with pulmonary hypertension at RHC and those without on echocardiographic assessment, a multiple logistic regression model was constructed to predict the presence of pulmonary hypertension at RHC. The score was calculated using right atrium and ventricular diastolic area, tricuspid regurgitation V
max, tricuspid regurgitation severity degree and left ventricular ejection fraction. The score area under the curve was therefore 0.786 (P = 0.0001), higher than for tricuspid regurgitation V
max (P = 0.06). A score value more than 57 was associated with a 93% sensitivity, a 67% specificity, a 91% positive predictive power, a 73% negative predictive power, and an odds ratio 27 (P < 0.001) of pulmonary hypertension at RHC, significant even after correction at multivariable analysis. Accuracy of the prediction model was assessed in a validation cohort with comparable results (P = n.s.).
Conclusion
A simple noninvasive echocardiographic score can be useful in predicting the diagnosis of pulmonary hypertension at RHC and may be considered for the selection of patients who should undergo or could avoid RHC.
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