Dynamic Changes in the Molecular Signature of Adverse Left Ventricular Remodeling in Patients With Compensated and Decompensated Chronic Primary Mitral Regurgitation.

BACKGROUND There is no proven medical therapy that attenuates adverse left ventricular remodeling in patients with chronic primary mitral regurgitation (CPMR). Identification of molecular pathways important in the progression of left ventricular remodeling in patients with CPMR may lead to development of new therapeutic strategies. METHODS AND RESULTS We performed baseline echocardiographic, cardiac catheterization, and serum NT-pro-BNP analysis in patients with severe CPMR awaiting mitral valve surgery and stratified the study population into compensated or decompensated CPMR. We obtained left ventricular endomyocardial biopsies (n=12) for mRNA expression analysis, and compared baseline transcript levels of 109 genes important in volume-overload left ventricular remodeling with levels in normal hearts (n=5) and between patients with compensated (n=6) versus decompensated (n=6) CPMR. Patients were then randomized to treatment with and without carvedilol and followed until the time of surgery (mean follow-up 8.3 months) when repeat endomyocardial biopsies were obtained to correlate transcriptional dynamics with indices of adverse remodeling. CPMR was associated with increased NPPA expression levels (21.6-fold, P=0.004), decreased transcripts of genes important in cell survival, and enrichment of extracellular matrix genes. Decompensated CPMR was associated with downregulation of SERCA2 (0.77-fold, P=0.009) and mitochondrial gene expression levels and upregulation of genes related to inflammation, the extracellular matrix, and apoptosis, which were refractory to carvedilol therapy. CONCLUSIONS Transition to decompensated CPMR is associated with calcium dysregulation, increased expression of inflammatory, extracellular matrix and apoptotic genes, and downregulation of genes important in bioenergetics. These changes are not attenuated by carvedilol therapy and highlight the need for development of specific combinatorial therapies, targeting myocardial inflammation and apoptosis, together with urgent surgical or percutaneous valve interventions.

[1]  D. Atar,et al.  Baseline Characteristics of Patients With Heart Failure and Preserved Ejection Fraction in the PARAGON-HF Trial , 2018, Circulation. Heart failure.

[2]  Daniel C. Lee,et al.  Plasminogen Activator Inhibitor Type I Controls Cardiomyocyte Transforming Growth Factor-&bgr; and Cardiac Fibrosis , 2017, Circulation.

[3]  L. Fleisher,et al.  2017 AHA/ACC Focused Update of the 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. , 2017, Journal of the American College of Cardiology.

[4]  T. Denney,et al.  Increased Sarcolipin Expression and Adrenergic Drive in Humans With Preserved Left Ventricular Ejection Fraction and Chronic Isolated Mitral Regurgitation , 2014, Circulation. Heart failure.

[5]  W. Davidson,et al.  Effects of Early, Late, and Long-term Nonselective &bgr;-Blockade on Left Ventricular Remodeling, Function, and Survival in Chronic Organic Mitral Regurgitation , 2013, Circulation. Heart failure.

[6]  Dexter T. Duncan,et al.  GLAD4U: deriving and prioritizing gene lists from PubMed literature , 2012, BMC Genomics.

[7]  T. Denney,et al.  A randomized controlled phase IIb trial of beta(1)-receptor blockade for chronic degenerative mitral regurgitation. , 2012, Journal of the American College of Cardiology.

[8]  J. Häggström,et al.  Evaluation of plasma activity of matrix metalloproteinase-2 and -9 in dogs with myxomatous mitral valve disease. , 2011, American journal of veterinary research.

[9]  X. Cui,et al.  Dynamic molecular and histopathological changes in the extracellular matrix and inflammation in the transition to heart failure in isolated volume overload. , 2011, American journal of physiology. Heart and circulatory physiology.

[10]  E. Foster.  Clinical practice. Mitral regurgitation due to degenerative mitral-valve disease. , 2010, The New England journal of medicine.

[11]  P. Lucchesi,et al.  Extracellular matrix remodeling during the progression of volume overload-induced heart failure. , 2010, Journal of molecular and cellular cardiology.

[12]  K. Sliwa,et al.  Forgotten cardiovascular diseases in Africa , 2010, Clinical Research in Cardiology.

[13]  T. Denney,et al.  Profibrotic Growth Factor Genes in Chronic Isolated Mitral Regurgitation in the Dog Microarray Identifies Extensive Downregulation of Noncollagen Extracellular Matrix and , 2009 .

[14]  T. Denney,et al.  Dissociation between cardiomyocyte function and remodeling with beta-adrenergic receptor blockade in isolated canine mitral regurgitation. , 2008, American journal of physiology. Heart and circulatory physiology.

[15]  B. Cowan,et al.  Pilot Study to Assess the Influence of &bgr;-Blockade on Mitral Regurgitant Volume and Left Ventricular Work in Degenerative Mitral Valve Disease , 2008, Circulation.

[16]  P. Varadarajan,et al.  Effect of Beta-blocker therapy on survival in patients with severe mitral regurgitation and normal left ventricular ejection fraction. , 2008, The American journal of cardiology.

[17]  L. Dell’Italia,et al.  Sympathetic Activation Causes Focal Adhesion Signaling Alteration in Early Compensated Volume Overload Attributable to Isolated Mitral Regurgitation in the Dog , 2008, Circulation research.

[18]  Jennifer L. Osborn,et al.  Direct multiplexed measurement of gene expression with color-coded probe pairs , 2008, Nature Biotechnology.

[19]  D. Meyers,et al.  Afterload Reduction May Halt and Beta-Adrenergic Blockade May Worsen Progression of Left Ventricular Dysfunction in Patients With Chronic Compensated Mitral Regurgitation: A Retrospective Cohort Study , 2007, Angiology.

[20]  J. Korewicki,et al.  Reduced myocardial expression of calcium handling protein in patients with severe chronic mitral regurgitation. , 2006, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[21]  R. Cardinal,et al.  Beta1-adrenoceptor blockade mitigates excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog. , 2006, American journal of physiology. Heart and circulatory physiology.

[22]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[23]  L. Dell’Italia,et al.  &bgr;1-Adrenergic Receptor Blockade Attenuates Angiotensin II–Mediated Catecholamine Release Into the Cardiac Interstitium in Mitral Regurgitation , 2003, Circulation.

[24]  S. Bolling,et al.  Myocardial Proinflammatory Cytokine Expression and Left Ventricular Remodeling in Patients With Chronic Mitral Regurgitation , 2003, Circulation.

[25]  D. DeMets,et al.  Effect of Carvedilol on the Morbidity of Patients With Severe Chronic Heart Failure: Results of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) Study , 2002, Circulation.

[26]  B. Carabello,et al.  Differential effects of the angiotensin-converting enzyme inhibitor lisinopril versus the beta-adrenergic receptor blocker atenolol on hemodynamics and left ventricular contractile function in experimental mitral regurgitation. , 2002, Journal of the American College of Cardiology.

[27]  S. Oparil,et al.  Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs. , 1997, The American journal of physiology.

[28]  M. Takemura,et al.  Plasma Fas ligand, an inducer of apoptosis, and plasma soluble Fas, an inhibitor of apoptosis, in patients with chronic congestive heart failure. , 1997, Journal of the American College of Cardiology.

[29]  S. Oparil,et al.  Increased ACE and chymase-like activity in cardiac tissue of dogs with chronic mitral regurgitation. , 1995, The American journal of physiology.

[30]  B. Carabello,et al.  Effects of chronic beta-adrenergic blockade on the left ventricular and cardiocyte abnormalities of chronic canine mitral regurgitation. , 1994, The Journal of clinical investigation.

[31]  P. Chomczyński,et al.  Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. , 1987, Analytical biochemistry.

[32]  C. McCarthy,et al.  Soluble ST2 in Heart Failure. , 2018, Heart failure clinics.

[33]  P. Manga,et al.  Left ventricular remodelling in chronic primary mitral regurgitation: implications for medical therapy. , 2018, Cardiovascular journal of Africa.

[34]  Victor Mor-Avi,et al.  Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. , 2015, Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography.

[35]  Brad T. Sherman,et al.  DAVID: Database for Annotation, Visualization, and Integrated Discovery , 2003, Genome Biology.

[36]  W. Likoff,et al.  Valvular Heart Disease , 2018, The Perioperative Medicine Consult Handbook.

[37]  D. Mann,et al.  Cellular and ventricular contractile dysfunction in experimental canine mitral regurgitation. , 1992, Circulation research.