Limongelli, Giuseppe

Abstract Background In patients with suspected amyloid cardiomyopathy (CM) and a monoclonal protein, tissue biopsy is mandatory to exclude amyloid light-chain CM (AL-CM), the subtype requiring urgent therapy. We aimed to develop a pragmatic approach to estimate the most likely final diagnosis before biopsy. Methods We studied a multicenter cohort of adults referred for biopsy because of suspected amyloid CM. Clinical, laboratory, ECG/echocardiographic and bone-tracer scintigraphy data were collected at initial suspicion. In patients with a monoclonal protein, we derived age cut-offs overall and by carpal tunnel syndrome (CTS), defined an age-based "gray zone" (74–83 years), and evaluated risk modifiers for AL-CM and transthyretin CM (ATTR-CM). We built a points-based algorithm for "gray-zone" patients. Clinical utility was assessed using decision-curve analysis. Results Among 602 patients (median age 76 years; 81% male), 524 (87%) had a monoclonal protein. In the monoclonal-protein subgroup, ATTR-CM accounted for 49%, AL-CM for 30%, and neither ATTR- nor AL-CM for 21%. Age ≤73 years was the Youden-optimal threshold favoring AL-CM (sensitivity 66%, specificity 78%), whereas age >84 years made AL-CM unlikely (sensitivity 98%, negative predictive value 94%), defining a "gray zone" (n=261; ATTR-CM 63%, AL-CM 18%, no amyloid CM 20%). Within the gray zone, abnormal free light-chain ratio, positive urine immunofixation, proteinuria, and higher troponin T and N-terminal pro-B-type natriuretic peptide (NT-proBNP) favored AL-CM, while higher Perugini grade, male sex, greater interventricular septal thickness, and higher NT-proBNP favored ATTR-CM. Penalized models achieved cross-validated area under the curves of 0.87 (AL-CM) and 0.94 (ATTR-CM). A two-score algorithm identified small gray-zone subsets enriched for AL-CM (positive predictive value 81.5%, specificity 98%) or ATTR-CM (positive predictive value 95.2%, specificity 94%). DCA showed higher net benefit for score- and model-based strategies versus treat-all/treat-none across clinically relevant threshold probabilities, with consistent patterns across regions. Conclusions In patients with suspected amyloid CM and a monoclonal protein, age- and CTS-anchored stratification refined by a compact set of routine laboratory and imaging features provides actionable pre-biopsy probabilities and may help prioritize urgent biopsy and AL-directed work-up while definitive tissue typing is pursued.For image description, please refer to the figure legend and surrounding text.

Introduction: The prevalence of bicuspid aortic valves (BAV) is enriched thirty-fold in women with Turner Syndrome (TS) in comparison with the general population. Hypothesis: Common autosomal variants influence the development of BAV in TS women, who may be uniquely sensitized to these variants by the loss of one X chromosome. We sought to identify autosomal BAV susceptibility genes in a cohort of TS women (average age 30 years, 38% BAV, 18% coarctation). Methods: A total of 106 TS women of European ancestry with BAV and 173 TS women with tricuspid aortic valves were genotyped on Illumina Omni-Express arrays. Valve phenotypes were determined by independent review of echocardiograms from the enrolling sites. Tests of association were performed using logistic regression without adjustment for covariates and were summarized in a meta-analysis. Results: Xp dosage was inversely and quantitatively associated with BAV status (P=0.02). Large, recurrent copy number variants in 1p36.13, 3q29, 8p23.1 and 9p24.3 were significantly enriched in BAV cases. After exclusion of 26 outlier samples in multidimensional scaling analysis, there was no significant genomic inflation (lambda= 1.02). The strongest genome-wide association signals were observed in 1p36.23, 3q23, 12q21.2, 18q21 and 22q13.31, and did not overlap with previously reported loci for BAV. A total of 13 SNPs in 18q21 were positively associated with BAV (OR=2.5-4.3) with a minimum P value of 1x10-7. Replication of these regions in independent groups of cases is ongoing. Conclusion: Our results demonstrate that autosomal variants with large magnitudes of effect contribute to BAV in TS women, confirming our hypothesis, and provide evidence for gene-gene interactions in BAV formation.

Turner Syndrome (TS) is a developmental disorder caused by partial or complete loss of one sex chromosome. Bicuspid aortic valve and other left‐sided congenital heart lesions (LSL), including thoracic aortic aneurysms and acute aortic dissections, are 30–50 times more frequent in TS than in the general population. In 454 TS subjects, we found that LSL are significantly associated with reduced dosage of Xp genes and increased dosage of Xq genes. We also showed that genome‐wide copy number variation is increased in TS and identify a common copy number variant (CNV) in chromosome 12p13.31 that is associated with LSL with an odds ratio of 3.7. This CNV contains three protein‐coding genes (SLC2A3, SLC2A14, and NANOGP1) and was previously implicated in congenital heart defects in the 22q11 deletion syndrome. In addition, we identified a subset of rare and recurrent CNVs that are also enriched in non‐syndromic BAV cases. These observations support our hypothesis that X chromosome and autosomal variants affecting cardiac developmental genes may interact to cause the increased prevalence of LSL in TS. © 2016 Wiley Periodicals, Inc.

AbstractBicuspid aortic valve is the most prevalent cardiac valvular malformation. It is associated with a high rate of long‐term morbidity including development of calcific aortic valve disease, aortic regurgitation and concomitant thoracic aortic aneurysm and dissection. Recently, basic and translational studies have identified some key processes involved in the development of bicuspid aortic valve and its morbidity. The development of aortic valve disease and thoracic aortic aneurysm and dissection is the result of complex interactions between genotypes, environmental risk factors and specific haemodynamic conditions created by bicuspid aortic valve anatomy. Herein, we review the pathobiology of bicuspid aortic valve with a special emphasis on translational aspects of these basic findings. Important but unresolved problems in the pathology of bicuspid aortic valve and thoracic aortic aneurysm and dissection are discussed, along with the molecular processes involved.