Big tau aggregation disrupts microtubule tyrosination and causes myocardial diastolic dysfunction: from discovery to therapy.

BACKGROUND: Amyloid plaques and neurofibrillary tangles, the molecular lesions that characterize Alzheimer's disease (AD) and other forms of dementia, are emerging as determinants of proteinopathies 'beyond the brain'. This study aims to establish tau's putative pathophysiological mechanistic roles and potential future therapeutic targeting of tau in heart failure (HF). METHODS AND RESULTS: A mouse model of tauopathy and human myocardial and brain tissue from patients with HF, AD, and controls was employed in this study. Tau protein expression was examined together with its distribution, and in vitro tau-related pathophysiological mechanisms were identified using a variety of biochemical, imaging, and functional approaches. A novel tau-targeting immunotherapy was tested to explore tau-targeted therapeutic potential in HF. Tau is expressed in normal and diseased human hearts, in contradistinction to the current oft-cited observation that tau is expressed specifically in the brain. Notably, the main cardiac isoform is high-molecular-weight (HMW) tau (also known as big tau), and hyperphosphorylated tau segregates in aggregates in HF and AD hearts. As previously described for amyloid-beta, the tauopathy phenotype in human myocardium is of diastolic dysfunction. Perturbation in the tubulin code, specifically a loss of tyrosinated microtubules, emerged as a potential mechanism of myocardial tauopathy. Monoclonal anti-tau antibody therapy improved myocardial function and clearance of toxic aggregates in mice, supporting tau as a potential target for novel HF immunotherapy. CONCLUSION: The study presents new mechanistic evidence and potential treatment for the brain-heart tauopathy axis in myocardial and brain degenerative diseases and ageing.

Effect of Milrinone Infusion on Pulmonary Vasculature and Stroke Work Indices: A Single-Center Retrospective Analysis in 69 Patients Awaiting Cardiac Transplantation.

BACKGROUND: Although milrinone infusion is reported to benefit left ventricular function in chronic left heart failure, few insights exist regarding its effects on pulmonary circulation and right ventricular function. METHODS: We retrospectively reviewed right heart catheterization data at baseline and during continuous infusion of milrinone in 69 patients with advanced heart failure and analyzed the effects on ventricular stroke work indices, pulmonary vascular resistance and pulmonary arterial compliance. RESULTS: Compared to baseline, milrinone infusion after a mean 58 ± 61 days improved mean left ventricular stroke work index (1540 ± 656 vs. 2079 ± 919 mmHg·mL/m2, p = 0.0007) to a much greater extent than right ventricular stroke work index (616 ± 346 vs. 654 ± 332, p = 0.053); however, patients with below median stroke work indices experienced a significant improvement in both left and right ventricular stroke work performance. Overall, milrinone reduced left and right ventricular filling pressures and pulmonary and systemic vascular resistance by approximately 20%. Despite an increase in pulmonary artery capacitance (2.3 ± 1.6 to 3.0 ± 2.0, p = 0.013) and a reduction in pulmonary vascular resistance (3.8 ± 2.3 to 3.0 ± 1.7 Wood units), milrinone did not reduce the transpulmonary gradient (13 ± 7 vs. 12 ± 6 mmHg, p = 0.252), the pulmonary artery pulse pressure (25 ± 10 vs. 24 ± 10, p = 0.64) or the pulmonary artery diastolic to pulmonary capillary wedge gradient (2.0 ± 6.5 vs. 2.4 ± 6.0, p = 0.353). CONCLUSION: Milrinone improved left ventricular stroke work indices to a greater extent than right ventricular stroke work indices and had beneficial effects on right ventricular net input impedance, predominantly via augmentation of left ventricular stroke volume and passive unloading of the pulmonary circuit. Patients who had the worst biventricular performance benefited the most from chronic milrinone infusion.

Right ventricular protein expression profile in end-stage heart failure.

Little is known about the right ventricular (RV) proteome in human heart failure (HF), including possible differences compared to the left ventricular (LV) proteome. We used 2-dimensional differential in-gel electrophoresis (pH: 4-7, 10-150 kDa), followed by liquid chromatography tandem mass spectrometry, to compare the RV and LV proteomes in 12 explanted human hearts. We used Western blotting and multiple-reaction monitoring for protein verification and RNA sequencing for messenger RNA and protein expression correlation. In all 12 hearts, the right ventricles (RVs) demonstrated differential expression of 11 proteins relative to the left ventricles (LVs), including lesser expression of CRYM, TPM1, CLU, TXNL1, and COQ9 and greater expression of TNNI3, SAAI, ERP29, ACTN2, HSPB2, and NDUFS3. Principal-components analysis did not suggest RV-versus-LV proteome partitioning. In the nonischemic RVs (n = 6), 7 proteins were differentially expressed relative to the ischemic RVs (n = 6), including increased expression of CRYM, B7Z964, desmin, ANXA5, and MIME and decreased expression of SERPINA1 and ANT3. Principal-components analysis demonstrated partitioning of the nonischemic and ischemic RV proteomes, and gene ontology analysis identified differences in hemostasis and atherosclerosis-associated networks. There were no proteomic differences between RVs with echocardiographic dysfunction (n = 8) and those with normal function (n = 4). Messenger RNA and protein expression did not correlate consistently, suggesting a major role for RV posttranscriptional protein expression regulation. Differences in contractile, cytoskeletal, metabolic, signaling, and survival pathways exist between the RV and the LV in HF and may be related to the underlying HF etiology and differential posttranscriptional regulation.

Evolving targeted therapies for right ventricular failure.

INTRODUCTION: Although right and left ventricular embryological origins, morphology and cardiodynamics differ, the notion of selectively targeted right ventricular therapies remains controversial. AREAS COVERED: This review focuses on both the currently evolving pharmacologic agents targeting right ventricular failure (metabolic modulators, phosphodiesterase type V inhibitors) and future therapeutic approaches including epigenetic modulation by miRNAs, chromatin binding complexes, long non-coding RNAs, genomic editing, adoptive gene transfer and gene therapy, cell regeneration via cell transplantation and cell reprogramming and cardiac tissue engineering. EXPERT OPINION: Strategies for adult right ventricular regeneration will require a more holistic approach than strategies for adult left ventricular failure. Instances of right ventricular failure requiring global reconstitution of right ventricular myocardium, attractive approaches include: i) myocardial patches seeded with cardiac fibroblasts reprogrammed into cardiomyocytes in vivo by small molecules, miRNAs or other epigenetic modifiers; and ii) administration of miRNAs, lncRNAs or small molecules by non-viral vector delivery systems targeted to fibroblasts (e.g., episomes) to stimulate in vivo reprogramming of fibroblasts into cardiomyocytes. For selected heritable genetic myocardial diseases, genomic editing affords exciting opportunities for allele-specific silencing by site-specific directed silencing, mutagenesis or gene excision. Genomic editing by adoptive gene transfer affords similarly exciting opportunities for restoration of myocardial gene expression.

Right ventricular long noncoding RNA expression in human heart failure.

The expression of long noncoding RNAs (lncRNAs) in human heart failure (HF) has not been widely studied. Using RNA sequencing (RNA-Seq), we compared lncRNA expression in 22 explanted human HF hearts with lncRNA expression in 5 unused donor human hearts. We used Cufflinks to identify isoforms and DESeq to identify differentially expressed genes. We identified the noncoding RNAs by cross-reference to Ensembl release 73 (Genome Reference Consortium human genome build 37) and explored possible functional roles using a variety of online tools. In HF hearts, RNA-Seq identified 84,793 total messenger RNA coding and noncoding different transcripts, including 13,019 protein-coding genes, 2,085 total lncRNA genes, and 1,064 pseudogenes. By Ensembl noncoding RNA categories, there were 48 lncRNAs, 27 pseudogenes, and 30 antisense RNAs for a total of 105 differentially expressed lncRNAs in HF hearts. Compared with donor hearts, HF hearts exhibited differential expression of 7.7% of protein-coding genes, 3.7% of lncRNAs (including pseudogenes), and 2.5% of pseudogenes. There were not consistent correlations between antisense lncRNAs and parent genes and between pseudogenes and parent genes, implying differential regulation of expression. Exploratory in silico functional analyses using online tools suggested a variety of possible lncRNA regulatory roles. By providing a comprehensive profile of right ventricular polyadenylated messenger RNA transcriptome in HF, RNA-Seq provides an inventory of differentially expressed lncRNAs, including antisense transcripts and pseudogenes, for future mechanistic study.

Epigenetic Regulation in Heart Failure: Part I RNA.

Epigenetic regulatory mechanisms play key roles in cardiac development, differentiation, homeostasis, response to stress and injury and disease. Human heart failure epigenetic regulatory mechanisms have not been deciphered to date. This 2-part review distills the rapidly evolving research focused on human heart failure epigenetic regulatory mechanisms. Part I focuses on epigenetic regulatory mechanisms involving RNA, specifically the role of short, intermediate and long noncoding RNAs and endogenous competing RNA regulatory networks. Part II focuses on the epigenetic regulatory mechanisms involving DNA, including DNA methylation, histone modifications, and chromatin conformational changes. Part II concludes with 2 examples of well-studied integrated epigenetic regulatory mechanisms, the structural and functional roles of the mediator complex in regulating transcription, and the epigenetic networked "cross-talk" regulating atrial natriuretic peptide and brain natriuretic peptide promoter activation.

Right ventricular myocardial biomarkers in human heart failure.

BACKGROUND: Right ventricular (RV) dysfunction contributes to mortality in chronic heart failure (HF). However, the molecular mechanisms of RV failure remain poorly understood, and RV myocardial biomarkers have yet to be developed. METHODS AND RESULTS: We performed RNA sequencing (RNA-seq) on 22 explanted human HF RVs and 5 unused donor human heart RVs (DON RV) and compared results to those recently reported from 16 explanted human LVs We used Bowtie-Tophat for transcript alignment and transcriptome assembly, DESeq for identification of differentially expressed genes (DEGs) and Ingenuity for exploration of gene ontologies. In the HF RV, RNA-seq identified 130,790 total RNA transcripts including 13,272 protein coding genes, 10,831 long non-coding RNA genes and 8,605 pseudogenes. There were 800-1000 DEGs between DON and HF RV comparison groups with differences concentrated in cytoskeletal, basement membrane, extracellular matrix (ECM), inflammatory mediator, hemostasis, membrane transport and transcription factor genes, lncRNAs and pseudogenes. In an unbiased approach, the top 10 DEGs SERPINA3, SERPINA5, LCN6, LCN10, STEAP4, AKR1C1, STAC2, SPARCL1, VSIG4 and F8 exhibited no overlap in read counts between DON and HF RVs, high sensitivities, specificities, predictive values and areas under the receiver operating characteristic curves. STEAP4, SPARCL1 and VSIG4 were differentially expressed between RVs and LVs, supporting their roles as RV-specific myocardial biomarkers. CONCLUSIONS: Unbiased, comprehensive profiling of the RV transcriptome by RNA-seq suggests structural changes and abnormalities in inflammatory processes and yields specific, novel HF RV vs HF LV myocardial biomarkers not previously identified by more limited transcriptome profiling approaches.

Pulmonary hypertension and right ventricular failure in left ventricular systolic dysfunction.

PURPOSE OF REVIEW: Pulmonary hypertension and right ventricular failure (RVF) in left ventricular systolic dysfunction (LVSD) is associated with high morbidity and mortality. This review presents an overview of the classification, pathophysiology, natural history, clinical features, prevention and treatment of this common clinical problem with a focus on the most recent studies. Many of the current evidence-based therapeutic agents for pulmonary hypertension in the absence of systolic or diastolic heart failure (e.g. prostaglandins, endothelin antagonists) are not efficacious in pulmonary hypertension with LVSD. RECENT FINDINGS: Recent clinical evidence strongly supports an evolving role for phosphodiesterase type 5 (PDE5) inhibition in patients with pulmonary hypertension and LVSD. Chronic PDE5 inhibition in the short-to-intermediate duration studies to date significantly reduces pulmonary pressures and pulmonary vascular resistance (PVR), effects reverse right ventricle and left ventricle remodeling, improves ventilator efficiency, improves peak exercise capacity and improves quality of life in selected patients with stable, moderately symptomatic LVSD and pulmonary hypertension. SUMMARY: Although long-term outcome studies are currently lacking, chronic PDE5 inhibition should be considered in carefully selected LVSD patients who manifest persistent significant elevation of pulmonary hypertension or PVR or uncontrolled RVF after aggressive management with all standard current evidence-based LVSD therapies (neurohormonal antagonists, diuretics and cardiac resynchronization in appropriate candidates).

Mitral valve surgery in advanced heart failure.

The appropriateness and timing of mitral valve surgery in patients with advanced heart failure and severe mitral regurgitation remains controversial. Recent surgical results provide evidence for beneficial effects on left ventricular remodeling and functional capacity. Given the absence of randomized trials comparing the outcomes of mitral valve surgery to medical therapy, however, clinical decision making regarding surgery for these fragile patients poses a dilemma to thoughtful clinicians. This paper reviews the pathophysiology of mitral regurgitation in heart failure and proposes an integrated approach to management.

Impact of dose reductions on efficacy outcome in heart transplant patients receiving enteric-coated mycophenolate sodium or mycophenolate mofetil at 12 months post-transplantation.

Mycophenolic acid (MPA) dose reduction is associated with increased risk of rejection and graft loss in renal transplantation. This analysis investigated the impact of MPA dose changes with enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) in de novo heart transplant recipients. In a 12-month, single-blind trial, 154 patients (EC-MPS, 78; MMF, 76) were randomized to either EC-MPS (1080 mg bid) or MMF (1500 mg bid) in combination with cyclosporine and steroids. The primary efficacy variable was the incidence of treatment failure, comprising a composite of biopsy-proven (BPAR) and treated acute rejection, graft loss or death. Significantly fewer patients receiving EC-MPS required > or =2 dose reductions than patients on MMF (26.9% vs. 42.1% of patients, p = 0.048). Accordingly, the average daily dose of EC-MPS as a percentage of the recommended dose was significantly higher than for MMF (88.4% vs. 79.0%, p = 0.016). Among patients requiring > or =1 dose reduction, the incidence of treated BPAR grade > or =3A was significantly lower with EC-MPS compared with MMF (23.4% vs. 44.0%, p = 0.032). These data suggest that EC-MPS-treated heart transplant patients are less likely to require multiple dose reductions than those on MMF which may be associated with a significantly lower risk of treated BPAR > or =3A.