Declaration of conflict of interest. I have nothing to disclose.

Transcription

1 Declaration of conflict of interest I have nothing to disclose.

2 Left Bundle branch block in HF: DO GENETICS MATTER? Silvia Giuliana Priori Cardiovascular Genetics, Langone Medical Center, New York University School of Medicine, New York, USA and Molecular Cardiology, IRCCS Fondazione Maugeri Dept of Cardiology, University of Pavia. Italy

3 QRS AND HEART FAILURE Nearly 5 million Americans suffer from heart failure (HF), and more than die annually for the disease. Intraventricular conduction delay caused by asymmetrical contraction is present in 1/3 of HF patients and it may be an independent risk factor for death. LBB decreases regional loading, contractile work, myocardial blood flow, and oxygen consumption in the early-activated anterior myocardium, whereas these parameters are increased in the late-activated lateral LV. CRT improves contractile synchrony, systolic function and rehomogenizes regional workload.

4 Genetics and LBBB in HF The question whether genetic abnormalities are part of the interaction between conduction delay/dyssynchrony and increased mortality is an important one. Two aspects need to be discussed: 1) Role of the genome: is there a genetic predisposition to develop LBBB? 2) Changes in the trascriptome: Do genetic factors account for the effect of LBBB on prognosis?

5 Is there a genetic predisposition to develop LBBB? Data from inherited diseases.

6 Inherited Cardiac Conduction Diseases (1) Progressive cardiac conduction defect (PCCD) is a frequent disease attributed to degeneration and fibrosis of the His bundle. Over the past years, gene defects have been identified demonstrating that PCCD could be a genetic disease as mutations in SCN5A, SCN1B and TRPM4 have been identified as the causal genes of inherited progressive cardiac conduction disease.

7 Inherited Cardiac Conduction Diseases (2) In a recent French study in families with CCD, progressive hemiblocks and RBBB were the most frequent conduction defects (44% and 33%, respectively). whereas LBBB was unfrequent (5%). Genetic predisposition to CCD seems to cause predominantly RBBB. Gourraud J B et al. Heart 2012;98:

8 Inherited DCM + CCD caused by LAMIN A/C mutations The cardiac phenotype associated with LMNA mutations is characterized by atrial fibrillation, conduction disturbances, ventricular arrhythmias, and dilated cardiomyopathy In a meta-analysis of 299 carriers of a lamin A/C mutation (van Berlo et al J Mol Med 2005), 18% of patients less than 10 years of age had evidence of delayed intracardiac conduction. In patients over 30 years of age, 92% had conduction system disease, with 44% requiring pacemaker placement At variant with the genes implicated in CCD, Lamin A/C ia linked to LBBB.

9 Heritability of human electrocardiogram Heritability represents a relevant component of the human electrocardiogram In the general population, ECG intervals duration have on average 25-40% of their variability attributable to genetic factors. Single SNPs are usually associated with small effect. This implies the evaluation of large cohorts of patients in order to detect significant signals and differentiate them from noise. Genetics: Meta-analysis identifies variants in 22 loci associated with QRS duration. Osório J.Nat Rev Cardiol Feb;8(2):

10 Pleiotropic associations of ECG variables Sotoodehnia N et al Nature Genetics 2010

11 GWAS of QRS complex duration in 40,407 healthy subjects Sotoodehnia N et al Nature Genetics 2010

12 SNPs that modulates the ECG predict SCD? ECG parameters like QRS duration and QTc duration influence the risk of SCD. Solid evidence from GWAS studies has shown that QRS and QT duration are modulated by common genetic variants CAN WE ASSUME THAT SCD IS INFLUENCED BY SNPs THAT MODULATE THE ECG?

13 WHEN SIZE MATTERS! Arking et al performed a genome-wide association metaanalysis in 1,283 SCD cases and >20,000 control individuals tested the role of 49 SNPs previously implicated in modulating electrocardiographic traits (QRS, QT, and RR intervals). Consistent with epidemiological studies showing increased risk of SCD with prolonged QRS/QT intervals, the interval-prolonging alleles are in aggregate associated with increased risk for SCD (P=0.006).

14 ECG modifiers and SCD: more complexity PLN (QT/QRS, p = 0.013) NOS1AP (QT, p = 0.010) KCNQ1 (QT, p =0.014) TKT/CACNA1D/PRKCD (QRS, p = ) SURPRISINGLY HOWEVER In TKT/CACNA1D/PRKCD and the QRS/QT interval prolonging allele is associated with decreased risk for SCD.

15 From QRS prolongation to SCD It is clear that SNPs do not act individualluy to modify a complex trait. SNPs are COMMON but their EFFECT is SMALL More modifiers occur at the same time and they may have opposite effects A summation of the influence of different SPNs will have to be taken in consideration

16 Is the combination of LBB and dyssynchrony able to modulate the trascriptome?

17 What is remodeling? Cardiac myocytes are able to react to biomechanical stress caused by pressure or volume load, reactive oxygen species, cytokines, circulating neurohormones. Biomechanical stress activates signalling pathways converging on transcription factors, co-regulators mrna that alter gene expression and induce hypertrophy and dysfunction.

18 The Molecular Signature of HF Gene expression changes create a Molecular Signature for HF that includes among several other changes decreased expression of alpha-myosin heavy chain sarcoplasmic-endoplasmic reticulum (αmhc), calcium ATPase 2-a (SERCA2a), phospholamban (PLB) and increased expression of brain natriuretic peptide (BNP). Therapeutic interventions such as beta-blockers and ACE inhibitors reverse the remodeling associated with HF. IS THERE A REMODELING ASSOCIATED WITH DYSSYNCHRONY IN HF?

19 Increase in SERCA during CRT Twenty heart failure patients were evaluted before and after CRT. Biopsy samples were obtained to assess the effect of CRT on gene expression profile (CANDIDATE GENES). CRT was associated with a significant upregulation of SERCA2alpha P =.01), PLN (P =.01), their ratio (P =.01), ratio of SERCA/NCX (P =.02), beta1-ar (P =.03), and APL (P =.01) mrna levels. Mullens W Heart Rhythm 2008

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21 Remodeling and CRT 24 Pts NYHA Class III and IV receiving CRT were divided into 2 groups according to their response to CRT. (Responders= increase in EF of 25% & NYHA class >1) LV mrna levels of α-mhc, β-mhc and BNP, SERCA, and PLN were analyzed. RESPONDERS SHOWED SIGNIFCANT NORMALIZATION OF EXPRESSION PROFILES Vanderheyden M et al JACC 2008

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23 LBB and the trascriptome In a canine model of LBBB ( ablation) and pacing leading to HF it has been possible to demonstrate the change in the expression profile of 1050 transcripts. Energy-deriving processes, including oxidative phosphorylation, tricarboxylic acid cycle, fatty acid and amino acid metabolism, were concomitantly downregulated in failing myocardium, whereas various cell signaling pathways and extracellular matrix components were upregulated.

24 Figure 1. KEGG pathway analysis in tachycardia pacing-induced heart failure. Barth A S et al. Circ Cardiovasc Genet 2009;2:

25 Dyssynchrony increases heterogeneity in gene expression in the LV that is partially reduced by CRT. Barth A S et al. Circ Cardiovasc Genet 2009 Copyright American Heart Association

26 CONCLUSION 1: THE GENOME Genomic variants that influence QRS duration have also been associated with risk of SCD Some of them derive from GENES that cause Cardiac Conduction diseases, some others have been identified through GWAS studies HOWEVER interactions between SNPs has not been assessed carefully As far as the genetic basis of QRS in HF no studies have been conducted that allow to extrapolate findings obtained in the general population to HF patients.

27 CONCLUSION 2: THE TRANSCRIPTOME Animal studies showed that the PRE-SELECTION of genes that are likely to be differentially expressed provides a limited view on genetic remodeling. The same approach needs to be extended to human studies even if the inhertent difficultis make these studies complex. The major hurdle is represented by expression variations in genes that are still a functional mistery LOT OF WORK TO BE DONE BUT POTENTIALLY VERY REWARDING!