Rationale: Cyclic nucleotide phosphodiesterases (PDEs) through the degradation of cGMP play critical roles in maintaining cardiomyocyte homeostasis. Ca 2؉ /calmodulin (CaM)-activated cGMP-hydrolyzing PDE1 family may play a pivotal role in balancing intracellular Ca 2؉ /CaM and cGMP signaling; however, its function in cardiomyocytes is unknown. Objective: Herein, we investigate the role of Ca 2؉ /CaM-stimulated PDE1 in regulating pathological cardiomyocyte hypertrophy in neonatal and adult rat ventricular myocytes and in the heart in vivo. Methods and Results: Inhibition of PDE1 activity using a PDE1-selective inhibitor, IC86340, or downregulation of PDE1A using siRNA prevented phenylephrine induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal and adult rat ventricular myocytes. Importantly, administration of the PDE1 inhibitor IC86340 attenuated cardiac hypertrophy induced by chronic isoproterenol infusion in vivo. Both PDE1A and PDE1C mRNA and protein were detected in human hearts; however, PDE1A expression was conserved in rodent hearts. Moreover, PDE1A expression was significantly upregulated in vivo in the heart and myocytes from various pathological hypertrophy animal models and in vitro in isolated neonatal and adult rat ventricular myocytes treated with neurohumoral stimuli such as angiotensin II (Ang II) and isoproterenol. Key Words: phosphodiesterase Ⅲ cGMP Ⅲ cardiomyocyte Ⅲ cardiac hypertrophy C a 2ϩ /calmodulin (CaM)-dependent signaling has been implicated in promoting pathological gene expression involved in hypertrophy and heart failure through the activation of Ca 2ϩ /CaM-dependent kinases, phosphatases, and ion channels. 1 Recently, a number of intrinsic negative regulators of cardiac growth have been identified which activate cGMPdependent signaling. 2 Stimulation of cGMP synthesis through genetic upregulation of natriuretic peptide receptor (guanylyl cyclase-A) prevents neurohumoral or pressure overload induced hypertrophy, 3 whereas disruption of cGMP synthesis results in enhanced hypertrophy and deteriorated cardiac function. 4 Likewise, chronic inhibition of cGMP metabolism by a cyclic nucleotide phosphodiesterase (PDE)5 inhibitor prevents and reverses pressure overload induced cardiac hypertrophy. 5 PDEs, by degrading cAMP and/or cGMP, regulate the amplitude, duration, and compartmentation of intracellular cyclic nucleotide signaling. PDEs constitute a superfamily of enzymes grouped into 11 broad families based on their distinct kinetic, regulatory, and inhibitory properties. PDE family members are also differentially expressed in various tissues and present within distinct subcellular domains. Together, these properties enable PDE enzymes to regulate the spatiotemporal, intracellular cAMP and cGMP gradients in response to various external stimuli. At least 5 PDE families, PDE1 to -5, have been reported in the heart, of which PDE1 and PDE5 are most likely responsible for cGMP hydrolysis. Logically, alteration of cGMP-hydrolyzing PDE expression/ activity...

BackgroundMalnutrition is a common condition that is associated with adverse prognosis in patients with heart failure (HF). The Prognostic Nutritional Index (PNI), Geriatric Nutritional Risk Index (GNRI) and controlling nutritional status (CONUT) have all been used as objective indices for evaluating nutritional status. We aimed to clarify the relationship between these nutritional indices and the parameters of inflammatory markers, cardiac function and exercise capacity, as well as to compare the ability of these indexes for predicting mortality.MethodsWe evaluated PNI, GNRI and CONUT in consecutive 1307 patients with HF.ResultsFirst, there were significant correlations between nutritional indices and the following: C reactive protein; tumour necrosis factor-α; adiponectin; B-type natriuretic peptide; troponin I; inferior vena cava diameter and peak VO2 (P<0.05, respectively). Second, in the Kaplan-Meier analysis (follow-up 1146 days), all-cause mortality progressively increased from normal to mild, moderate and severe disturbance groups in the indices (log-rank, P<0.01, respectively). In the Cox proportional hazard analysis, each index was an independent predictor of all-cause mortality in patients with HF (P<0.001, respectively). Third, receiver operating curve demonstrated that the areas under the curve of PNI and GNRI were larger than that of CONUT score (P<0.05, respectively).ConclusionPatients with HF being malnourished had higher mortality accompanied by higher levels of C reactive protein, tumour necrosis factor-α, adiponectin, B-type natriuretic peptide, troponin I, right-sided volume overload and impaired exercise capacity, rather than left ventricular systolic function. Additionally, PNI and GNRI were superior to CONUT score in predicting mortality in patients with HF.

Cardiac fibroblasts become activated and differentiate to smooth muscle-like myofibroblasts in response to hypertension and myocardial infarction (MI), resulting in extracellular matrix (ECM) remodeling, scar formation and impaired cardiac function. cAMP and cGMP-dependent signaling have been implicated in cardiac fibroblast activation and ECM synthesis. Dysregulation of cyclic nucleotide phosphodiesterase (PDE) activity/expression is also associated with various diseases and several PDE inhibitors are currently available or in development for treating these pathological conditions. The objective of this study is to define and characterize the specific PDE isoform that is altered during cardiac fibroblast activation and functionally important for regulating myofibroblast activation and ECM synthesis. We have found that Ca2+/calmodulin-stimulated PDE1A isoform is specifically induced in activated cardiac myofibroblasts stimulated by Ang II and TGF-β in vitro as well as in vivo within fibrotic regions of mouse, rat, and human diseased hearts. Inhibition of PDE1A function via PDE1-selective inhibitor or PDE1A shRNA significantly reduced Ang II or TGF-β-induced myofibroblast activation, ECM synthesis, and pro-fibrotic gene expression in rat cardiac fibroblasts. Moreover, the PDE1 inhibitor attenuated isoproterenol-induced interstitial fibrosis in mice. Mechanistic studies revealed that PDE1A modulates unique pools of cAMP and cGMP, predominantly in perinuclear and nuclear regions of cardiac fibroblasts. Further, both cAMP-Epac-Rap1 and cGMP-PKG signaling was involved in PDE1A-mediated regulation of collagen synthesis. These results suggest that induction of PDE1A plays a critical role in cardiac fibroblast activation and cardiac fibrosis, and targeting PDE1A may lead to regression of the adverse cardiac remodeling associated with various cardiac diseases.

AimsHeart failure with preserved ejection fraction (HFpEF) has several pathophysiological aspects, including stiffness and/or congestion of multiple organs. Poor prognosis is expected in heart failure patients with liver stiffness, which has recently been assessed by non‐alcoholic fatty liver disease fibrosis score (NFS; based on aspartate aminotransferase to alanine aminotransferase ratio, platelet counts, and albumin). We aimed to investigate the impact of NFS on prognosis of HFpEF patients, with consideration for the peripheral collagen markers such as procollagen type III peptide (PIIIP), type IV collagen 7S, and hyaluronic acid.Methods and resultsWe performed a prospective observational study. Consecutive 492 hospitalized HFpEF patients were divided into four groups based on their NFS: first–fourth quartiles (n = 123). The fourth quartile group had the highest levels of PIIIP, type IV collagen 7S, hyaluronic acid, and B‐type natriuretic peptide (P<0.001 each). In addition, there were significant positive correlations between PIIIP, type IV collagen 7S, hyaluronic acid, B‐type natriuretic peptide, and NFS (P < 0.001 each). In the follow‐up period (mean 1107 days), 93 deaths occurred. All‐cause mortality increased in all four quartiles (8.1%, 12.2%, 23.6%, and 31.7%, P < 0.001). In the multivariable Cox proportional hazard analysis, NFS was an independent predictor of all‐cause mortality in the HFpEF patients.ConclusionsNFS, a novel indicator of liver fibrosis, correlates with circulating systemic markers of fibrosis and congestion and is associated with higher all‐cause mortality in HFpEF patients. NFS can be calculated simply and may be a useful tool to assess liver stiffness and prognosis in HFpEF patients.

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β-stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance.cyclic nucleotide | phosphodiesterase | cardiac remodeling | heart failure

ObjectiveLiver dysfunction due to heart failure (HF) is known as congestive hepatopathy. It has recently been reported that liver stiffness assessed by transient elastography reflects increased central venous pressure. The Fibrosis-4 (FIB4) index (age (years) × aspartate aminotransferase (IU/L)/platelet count (109/L) × square root of alanine aminotransferase (IU/L)) is expected to be useful for evaluating liver stiffness in patients with non-alcoholic fatty liver disease. We aimed to investigate the impact of the FIB4 index on HF prognosis, with consideration for liver fibrosis markers and underlying cardiac function.MethodsConsecutive 1058 patients with HF who were admitted to our hospital were divided into three groups based on their FIB4 index: first (FIB4 index <1.72, n=353), second (1.72≤FIB4 index <3.01, n=353) and third tertiles (3.01≤FIB4 index, n=352). We prospectively followed for all-cause mortality.ResultsDuring the follow-up period (mean 1047 days), 246 deaths occurred. In the Kaplan-Meier analysis, all-cause mortality progressively increased from the first to third groups (12.2%, 21.0% and 36.6%, p<0.01). In the Cox proportional hazard analysis, FIB4 index was an independent predictor of all-cause mortality in patients with HF (p<0.05). In comparisons of laboratory and echocardiographic findings, the third tertile had higher levels of type IV collagen 7S, procollagen type III peptide, hyaluronic acid, left atrial volume, mitral valve E/e’, inferior vena cava diameter and right atrial end systolic area (p<0.01, respectively).ConclusionThe FIB4 index, a marker of liver stiffness, is associated with higher all-cause mortality in patients with HF.

These data suggest that a high endogenous EPO level can predict a smaller infarct size in patients with acute MI subjected to successful primary PCI. This might be attributed to the potentially protective effect of endogenous EPO against ischemia-reperfusion injury in humans.

BackgroundThe Get With the Guidelines–Heart Failure (GWTG‐HF) risk score was developed using American Heart Association GWTG‐HF program data and predicts in‐hospital mortality in patients with acute heart failure (HF). We aimed to clarify the prognostic impacts of the GWTG‐HF risk score in patients with HF after discharge.Methods and ResultsWe examined the GWTG‐HF score in 1452 patients with HF, who were admitted to our hospital and discharged after treatment, by calculating 7 predetermined variables. We divided all subjects into 3 groups according to the GWTG‐HF risk score (low, moderate, and high score groups). The plasma B‐type natriuretic peptide level significantly increased with increasing GWTG‐HF risk score severity (median values of B‐type natriuretic peptide: 167.0 in low, 260.7 in moderate, and 418.2 pg/mL in high score groups). We followed up all subjects after discharge, and there were 347 (23.9%) all‐cause deaths and 407 (28.0%) cardiac events in follow‐up periods. A Kaplan‐Meier survival curve demonstrated that event rates of all‐cause death and cardiovascular events, including worsening HF and cardiac death, significantly increased with increasing GWTG‐HF risk score severity in all subjects, and also in 749 patients with HF with preserved ejection fraction (ejection fraction ≥50%) and 703 patients with HF with reduced ejection fraction (ejection fraction <50%) patients. The multivariable Cox proportional hazard regression analysis demonstrated that the GWTG‐HF risk score was one of the significant predictors of all‐cause mortality and cardiac events (all‐cause mortality: hazard ratio, 1.537, 95% confidence interval, 1.172–2.023; cardiac events: hazard ratio, 1.584, 95% confidence interval, 1.344–1.860, per 10‐point increase of GWTG‐HF score).ConclusionsThe GWTG‐HF risk score is a useful multivariable score model for several years after hospitalization in patients with HF in a Japanese population.