Influence of ejection fraction on biomarker expression and response to spironolactone in people at risk of heart failure: findings from the HOMAGE trial.

AIMS: Left ventricular ejection fraction (LVEF) can provide haemodynamic information and may influence the response to spironolactone and other heart failure (HF) therapies. We aimed to study patient characteristics and circulating protein associations with LVEF, and whether LVEF influenced the response to spironolactone. METHODS AND RESULTS: HOMAGE enrolled patients aged >60 years at high risk of developing HF with a LVEF ≥45%. Overall, 527 patients were randomized to either spironolactone or standard of care for ≈9 months, and 276 circulating proteins were measured using Olink® technology. A total of 364 patients had available LVEF determined by the Simpson's biplane method. The respective LVEF tertiles were: tertile 1: 65% (n = 121). Patients with a LVEF >65% had smaller left ventricular chamber size and volumes, and lower natriuretic peptide levels. Compared to patients with a LVEF 65% had higher levels of circulating c-c motif chemokine ligand-23 and interleukin-8, and lower levels of tissue plasminogen activator, brain natriuretic peptide (BNP), S100 calcium binding protein A12, and collagen type I alpha 1 chain (COL1A1). Spironolactone significantly reduced the circulating levels of BNP and COL1A1 without significant treatment-by-LVEF heterogeneity: BNP change β = -0.36 log2 and COL1A1 change β = -0.16 log2 (p  0.1 for both). Spironolactone increased LVEF from baseline to month 9 by 1.1% (p = 0.007). CONCLUSION: Patients with higher LVEF had higher circulating levels of chemokines and inflammatory markers and lower levels of stretch, injury, and fibrosis markers. Spironolactone reduced the circulating levels of natriuretic peptides and type 1 collagen, and increased LVEF

Mutations in PDLIM5 are rare in dilated cardiomyopathy but are emerging as potential disease modifiers

BACKGROUND: A causal genetic mutation is found in 40% of families with dilated cardiomyopathy (DCM), leaving a large percentage of families genetically unsolved. This prevents adequate counseling and clear recommendations in these families. We aim to identify novel genes or modifiers associated with DCM. METHODS: We performed computational ranking of human genes based on coexpression with a predefined set of genes known to be associated with DCM, which allowed us to prioritize gene candidates for their likelihood of being involved in DCM. Top candidates will be checked for variants in the available whole-exome sequencing data of 142 DCM patients. RNA was isolated from cardiac biopsies to investigate gene expression. RESULTS: PDLIM5 was classified as the top candidate. An interesting heterozygous variant (189_190delinsGG) was found in a DCM patient with a known pathogenic truncating TTN-variant. The PDLIM5 loss-of-function (LoF) variant affected all cardiac-specific isoforms of PDLIM5 and no LoF variants were detected in the same region in a control cohort of 26,000 individuals. RNA expression of PDLIM5 and its direct interactors (MYOT, LDB3, and MYOZ2) was increased in cardiac tissue of this patient, indicating a possible compensatory mechanism. The PDLIM5 variant cosegregated with the TTN-variant and the phenotype, leading to a high disease penetrance in this family. A second patient was an infant with a homozygous 10 kb-deletion of exon 2 in PDLIM5 resulting in early-onset cardiac disease, showing the importance of PDLIM5 in cardiac function. CONCLUSIONS: Heterozygous PDLIM5 variants are rare and therefore will not have a major contribution in DCM. Although they likely play a role in disease development as this gene plays a major role in contracting cardiomyocytes and homozygous variants lead to early-onset cardiac disease. Other environmental and/or genetic factors are probably necessary to unveil the cardiac phenotype in PDLIM5 mutation carriers.status: publishe

Natural History of MYH7-related Dilated Cardiomyopathy

Background Variants in MYH7 are responsible for disease in 1-5% of patients with dilated cardiomyopathy (DCM); however, the clinical characteristics and natural history of MYH7-related DCM are poorly described. Objectives We sought to determine the phenotype and prognosis of MYH7-related DCM. We also evaluated the influence of variant location on phenotypic expression. Methods We studied clinical data from 147 individuals with DCM-causing MYH7 variants (47.6% females, 35.6±19.2 years) recruited from 29 international centers. Results At initial evaluation, 106 patients (72.1%) had DCM (LVEF 34.5±11.7%). Median follow-up was 4.5 years (interquartile range: 1.7-8.0) and 23.7% of carriers who were initially phenotype-negative developed DCM. Phenotypic expression by 40 and 60 years was 46% and 88%, respectively, with 18 patients (16%) first diagnosed at <18 years. Thirty-six percent of patients with DCM met imaging criteria for LV non-compaction. During follow-up, 28% showed left ventricular reverse remodeling (LVRR). Incidence of adverse cardiac events among patients with DCM at 5 years was 11.6%, with 5 (4.6%) deaths due to end-stage heart failure (ESHF) and 5 patients (4.6%) requiring heart transplantation. The major ventricular arrhythmia (MVA) rate was low (1.0% and 2.1% at 5 years in patients with DCM and in those with LVEF?35%, respectively). ESHF and MVA were significantly lower compared with LMNA-related DCM and similar than in DCM caused by TTN truncating variants. Conclusions MYH7-related DCM is characterized by early age of onset, high phenotypic expression, low LVRR, and frequent progression to ESHF. Heart failure complications predominate over ventricular arrhythmias, which are rare.Funding: This study has been funded by Instituto de Salud Carlos III (ISCIII) through the projects "PI18/0004, PI20/0320, PT17/0015/0043” (Co-funded by European Regional Development Fund/European Social Fund "A way to make Europe"/"Investing in your future"). The CNIC is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). The Hospital Universitario Puerta de Hierro, the Hospital Sant Joan de Déu and the Hospital Universitario Virgen de la Arrixaca are members of the European Reference Network for Rare and Low Prevalence Complex Diseases of the Heart: ERN GUARD-Heart (http://guardheart.ernnet.eu). Fernando de Frutos receives grant support from ISCIII (CM20/00101). Annette Baas receives funding from CVON2020B005 DOUBLE-DOSE, Dutch Heart Foundation (Dekker 2015T041). Genetic examinations of Polish patients were funded with DETECTIN-HF grant from ERA-CVD framework, NCBiR. Diane Fatkin receives funding from Victor Chang Cardiac Research Institute and NSW Health. Luis R Lopes is funded by an MRC UK Clinical Academic Research Partnership award (MR/T005181/1). Benjamin Meder receives funding from the Deutsches Zentrum für Herz-Kreislauf-Forschung (German Center for Cardiovascular Research, DZHK) and Informatics for Life (Klaus Tschira Foundation). Milos Kubankek receives grant support from the Ministry of Health, Czech Republic (NV19-08-00122) and IPO (Institute for Clinical and Experimental Medicine – IKEM, IN 00023001)

Risk of bias in studies investigating novel diagnostic biomarkers for heart failure with preserved ejection fraction. A systematic review

AIM: Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non-acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB). METHODS AND RESULTS: A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta-analysis was performed. CONCLUSION: The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF.status: publishe

A mutation update for the FLNC gene in myopathies and cardiomyopathies

Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.status: publishe