Ronen Durst

Refinement of Variant Selection for the LDL Cholesterol Genetic Risk Score in the Diagnosis of the Polygenic Form of Clinical Familial Hypercholesterolemia and Replication in Samples from 6 Countries

BACKGROUND Familial hypercholesterolemia (FH) is an autosomal-dominant disorder caused by mutations in 1 of 3 genes. In the 60% of patients who are mutation negative, we have recently shown that the clinical phenotype can be associated with an accumulation of common small-effect LDL cholesterol (LDL-C)-raising alleles by use of a 12-single nucleotide polymorphism (12-SNP) score. The aims of the study were to improve the selection of SNPs and replicate the results in additional samples. METHODS We used ROC curves to determine the optimum number of LDL-C SNPs. For replication analysis, we genotyped patients with a clinical diagnosis of FH from 6 countries for 6 LDL-C-associated alleles. We compared the weighted SNP score among patients with no confirmed mutation (FH/M-), those with a mutation (FH/M+), and controls from a UK population sample (WHII). RESULTS Increasing the number of SNPs to 33 did not improve the ability of the score to discriminate between FH/M- and controls, whereas sequential removal of SNPs with smaller effects/lower frequency showed that a weighted score of 6 SNPs performed as well as the 12-SNP score. Metaanalysis of the weighted 6-SNP score, on the basis of polymorphisms in CELSR2 (cadherin, EGF LAG 7-pass G-type receptor 2), APOB (apolipoprotein B), ABCG5/8 [ATP-binding cassette, sub-family G (WHITE), member 5/8], LDLR (low density lipoprotein receptor), and APOE (apolipoprotein E) loci, in the independent FH/M- cohorts showed a consistently higher score in comparison to the WHII population (P < 2.2 × 10(-16)). Modeling in individuals with a 6-SNP score in the top three-fourths of the score distribution indicated a >95% likelihood of a polygenic explanation of their increased LDL-C. CONCLUSIONS A 6-SNP LDL-C score consistently distinguishes FH/M- patients from healthy individuals. The hypercholesterolemia in 88% of mutation-negative patients is likely to have a polygenic basis.

Mitral valve disease—morphology and mechanisms

Mitral valve disease is a frequent cause of heart failure and death. Emerging evidence indicates that the mitral valve is not a passive structure, but—even in adult life—remains dynamic and accessible for treatment. This concept motivates efforts to reduce the clinical progression of mitral valve disease through early detection and modification of underlying mechanisms. Discoveries of genetic mutations causing mitral valve elongation and prolapse have revealed that growth factor signalling and cell migration pathways are regulated by structural molecules in ways that can be modified to limit progression from developmental defects to valve degeneration with clinical complications. Mitral valve enlargement can determine left ventricular outflow tract obstruction in hypertrophic cardiomyopathy, and might be stimulated by potentially modifiable biological valvular–ventricular interactions. Mitral valve plasticity also allows adaptive growth in response to ventricular remodelling. However, adverse cellular and mechanobiological processes create relative leaflet deficiency in the ischaemic setting, leading to mitral regurgitation with increased heart failure and mortality. Our approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.

Familial hypercholesterolaemia: A global call to arms.

Familial Hypercholesterolaemia (FH) is the commonest autosomal co-dominantly inherited condition affecting man. It is caused by mutation in one of three genes, encoding the low-density lipoprotein (LDL) receptor, or the gene for apolipoprotein B (which is the major protein component of the LDL particle), or in the gene coding for PCSK9 (which is involved in the degradation of the LDL-receptor during its cellular recycling). These mutations result in impaired LDL metabolism, leading to life-long elevations in LDL-cholesterol (LDL-C) and development of premature atherosclerotic cardiovascular disease (ASCVD) [1], [2] and [3]. If left untreated, the relative risk of premature coronary artery disease is significantly higher in heterozygous patients than unaffected individuals, with most untreated homozygotes developing ASCVD before the age of 20 and generally not surviving past 30 years [2], [3], [4] and [5]. Although early detection and treatment with statins and other LDL-C lowering therapies can improve survival, FH remains widely underdiagnosed and undertreated [1], thereby representing a major global public health challenge.

Use of polytetrafluoroethylene-covered stent for treatment of coronary artery aneurysm

Coronary artery aneurysm is an uncommon occurrence, yet it is described more often today than in the past as coronary angiography is now routinely used for diagnosis and treatment of ischemic heart disease. However, there is no therapeutic consensus regarding this finding. We present a case of giant coronary artery aneurysm and review the literature on the use of polytetrafluoroethylene‐covered stents as a therapeutic option for this condition. Combined antiaggregant therapy is needed after the procedure. Randomized controlled trials of surgery versus covered stents are necessary to define the best treatment for large coronary artery aneurysms.

Mutations in DCHS1 cause mitral valve prolapse.

Mitral valve prolapse (MVP) is a common cardiac valve disease that affects nearly 1 in 40 individuals. It can manifest as mitral regurgitation and is the leading indication for mitral valve surgery. Despite a clear heritable component, the genetic aetiology leading to non-syndromic MVP has remained elusive. Four affected individuals from a large multigenerational family segregating non-syndromic MVP underwent capture sequencing of the linked interval on chromosome 11. We report a missense mutation in the DCHS1 gene, the human homologue of the Drosophila cell polarity gene dachsous (ds), that segregates with MVP in the family. Morpholino knockdown of the zebrafish homologue dachsous1b resulted in a cardiac atrioventricular canal defect that could be rescued by wild-type human DCHS1, but not by DCHS1 messenger RNA with the familial mutation. Further genetic studies identified two additional families in which a second deleterious DCHS1 mutation segregates with MVP. Both DCHS1 mutations reduce protein stability as demonstrated in zebrafish, cultured cells and, notably, in mitral valve interstitial cells (MVICs) obtained during mitral valve repair surgery of a proband. Dchs1+/− mice had prolapse of thickened mitral leaflets, which could be traced back to developmental errors in valve morphogenesis. DCHS1 deficiency in MVP patient MVICs, as well as in Dchs1+/− mouse MVICs, result in altered migration and cellular patterning, supporting these processes as aetiological underpinnings for the disease. Understanding the role of DCHS1 in mitral valve development and MVP pathogenesis holds potential for therapeutic insights for this very common disease.

Impact of aortic regurgitation after transcatheter aortic valve implantation: results from the REVIVAL trial.

OBJECTIVES Understanding the severity of aortic regurgitation (AR) after transcatheter aortic valve implantation, its impact on left ventricular (LV) structure and function, and the structural factors associated with worsening AR could lead to improvements in patient selection, implantation technique, and valve design. BACKGROUND Initial studies in patients at high risk of surgical aortic valve replacement have reported both central valvular and paravalvular AR after transcatheter aortic valve implantation. METHODS Transthoracic echocardiograms were quantified from 95 patients in the REVIVAL (TRanscatheter EndoVascular Implantation of VALves) trial. Transthoracic echocardiograms were obtained before implantation of the Edwards-Sapien valve (Edwards Lifesciences, Irvine, California) and thereafter at selected intervals. Measurements included LV internal diameters and volumes, ejection fraction, aortic valve area, and the degree of aortic regurgitation. Measures of degree of native leaflet mobility, thickness, and calcification, as well as left ventricular outflow tract, aortic annulus, and aortic root diameters were also made. RESULTS Eighty-four patients remained after 11 were excluded; 26 (29.8%) died over a period of 3 years. At 24 h post-implantation, 75% had some degree of AR, mostly paravalvular. By 1 year, the mean AR grade increased slightly, but not significantly (1.1 ± 0.8 to 1.3 ± 0.9), and all measures of LV structure and function improved (LV ejection fraction, 50.7 ± 16.1% to 59.4 ± 14.0%). Native aortic leaflet calcification and annulus diameter correlated significantly with the severity of AR at 1 year (p < 0.05). CONCLUSIONS AR after transcatheter aortic valve implantation is frequent but is rarely more than mild. Although AR progresses, it is not associated with a harmful impact on LV structure and function over the first year. Native valve calcification and aortic annulus diameter influence the degree of AR at 6 months.

Echocardiographic Assessment of Percutaneous Patent Foramen Ovale and Atrial Septal Defect Closure Complications

Atrial septal defect (ASD) is a common congenital defect (1 in 1000 live births) and accounts for up to 40% of clinically relevant acyanotic shunts in adults.1 Patent foramen ovale (PFO) is much more common and is present in more than 25% of adults.2,3 The clinical syndromes associated with ASD/PFO represent a significant health burden. Surgical closure is the most common therapy for these defects, and it is associated with low morbidity and mortality. However, it remains a surgical procedure requiring cardiopulmonary bypass, a significant postoperative recovery, and a sternotomy scar that may be undesirable to young patients. Catheter-based techniques for the treatment of ASD/PFO were pioneered by King and Mills in 1975.4 Since then, significant device development and modifications have been made (Table 1). Percutaneous therapy is now the preferred strategy for ASD/PFO closure, by patients and physicians alike, in the absence of complicated anatomy or another indication for traditional cardiac surgery, because it is technically simple and associated with negligible morbidity and mortality.5 Longer-term follow-up, however, remains necessary to more completely evaluate the safety and efficacy of such devices. View this table: Table 1. Summary of Devices Most Frequently Used for Percutaneous Closure of ASD or PFO The role of 2-dimensional (2D) transthoracic echocardiography (TTE) and transesophageal echocardiography (TEE) during the assessment and management of ASD/PFO has been demonstrated.6–8 Although universal practice standards, in the form of consensus committee guidelines or professional society recommendations, still have to be established for the use of echocardiography in this context, it is used by a majority of groups who perform these procedures. In our institution, TTE with color Doppler and/or agitated saline contrast injection is most frequently the method used to diagnose interatrial communication. Once the diagnosis has been made and percutaneous closure is deemed clinically appropriate, a careful …

Recent Origin and Spread of a Common Lithuanian Mutation, G197del LDLR, Causing Familial Hypercholesterolemia: Positive Selection Is Not Always Necessary to Account for Disease Incidence among Ashkenazi Jews

G197del is the most prevalent LDL receptor (LDLR) mutation causing familial hypercholesterolemia (FH) in Ashkenazi Jew (AJ) individuals. The purpose of this study was to determine the origin, age, and population distribution of G197del, as well as to explore environmental and genetic effects on disease expression. Index cases from Israel (n=46), South Africa (n=24), Russia (n=7), The Netherlands (n=1), and the United States (n=1) were enlisted. All trace their ancestry to Lithuania. A highly conserved haplotype (D19S221:104-D19S865:208-D19S413:74) was identified in G197del chromosomes, suggesting the occurrence of a common founder. When two methods were used for analysis of linkage disequilibrium (LD) between flanking polymorphic markers and the disease locus and for the study of the decay of LD over time, the estimated age of the deletion was found to be 20 +/- 7 generations (the 95% confidence interval is 15-26 generations), so that the most recent common ancestor of the mutation-bearing chromosomes would date to the 14th century. This corresponds with the founding of the Jewish community of Lithuania (1338 a.d.), as well as with the great demographic expansion of AJ individuals in eastern Europe, which followed this settlement. The penetrance of mutation-linked severe hypercholesterolemia is high (94% of heterozygotes have a baseline concentration of LDL cholesterol (LDL-C) that is >160 mg/dl), and no significant differences in the mean baseline lipid level of G197del carriers from different countries were found. Polymorphisms of apolipoprotein E and of scavenger-receptor class B type I were observed to have minor effects on the plasma lipid profile. With respect to determinative genetic influences on the biochemical phenotype, there is no evidence that could support the possibility of a selective evolutionary metabolic advantage. Therefore, the founder effect in a rapidly expanding population from a limited number of families remains a simple, parsimonious hypothesis explaining the spread of G197del-LDLR-linked FH in AJ individuals.

Comparison of the Accuracy of Multidetector Computed Tomography Versus Two-Dimensional Echocardiography to Measure Left Atrial Volume

Left atrial (LA) volume is an important prognostic factor in cardiovascular disease. Multidetector computed tomography (MDCT) is an emerging cardiac imaging modality; however, its accuracy in measuring the LA volume has not been well studied. The aim of our study was to determine the accuracy of MDCT in quantifying the LA volume. A total of 48 patients underwent MDCT and 2-dimensional (2D) echocardiography (2DE) on the same day. The area-length and Simpsons methods were used to obtain the 2D echocardiographic LA volume. The LA volume assessment by MDCT was obtained using the modified Simpsons method. Four artificial phantoms were created, and their true volume was assessed by an independent observer using both imaging modalities. The correlation between the LA volume by MDCT and 2DE was significant (r = 0.68). The mean 2D echocardiographic LA volume was lower than the LA volume obtained with MDCT (2DE 79 +/- 37 vs MDCT 103 +/- 32, p <0.05). In the phantom experiment, the volume obtained using MDCT and 2DE correlated significantly with the true volume (r = 0.97, p <0.05 vs r = 0.96, p <0.05, respectively). However, the mean 2D echocardiographic phantom volume was 16% lower than the true volume (2DE, Simpsons method 53 +/- 24 vs the true volume 61 +/- 24, p <0.05). The mean volume calculated using MDCT did not differ from the true volume (MDCT 60 +/- 21 vs true volume 61 +/- 24, p = NS). 2DE appeared to systematically underestimate the LA volume compared to phantom and cardiac MDCT, suggesting that different normal cutoff values should be used for each modality. In conclusion, LA volume quantification using MDCT is an accurate and feasible method.

Genetic association analyses highlight biological pathways underlying mitral valve prolapse

Nonsyndromic mitral valve prolapse (MVP) is a common degenerative cardiac valvulopathy of unknown etiology that predisposes to mitral regurgitation, heart failure and sudden death. Previous family and pathophysiological studies suggest a complex pattern of inheritance. We performed a meta-analysis of 2 genome-wide association studies in 1,412 MVP cases and 2,439 controls. We identified 6 loci, which we replicated in 1,422 cases and 6,779 controls, and provide functional evidence for candidate genes. We highlight LMCD1 (LIM and cysteine-rich domains 1), which encodes a transcription factor and for which morpholino knockdown of the ortholog in zebrafish resulted in atrioventricular valve regurgitation. A similar zebrafish phenotype was obtained with knockdown of the ortholog of TNS1, which encodes tensin 1, a focal adhesion protein involved in cytoskeleton organization. We also showed expression of tensin 1 during valve morphogenesis and describe enlarged posterior mitral leaflets in Tns1−/− mice. This study identifies the first risk loci for MVP and suggests new mechanisms involved in mitral valve regurgitation, the most common indication for mitral valve repair.