Relationship of High-Density Lipoprotein-Associated Arylesterase Activity to Systolic Heart Failure in Patients with and without Type 2 Diabetes.

High-density lipoprotein (HDL) confers protection against cardiovascular disease partly attributable to its robust anti-oxidant activities, which is largely impaired in diabetic conditions. In this study, we analyzed the anti-oxidant activity of HDL, as represented by the arylesterase activity of paraoxonase 1 (PON1) in HDL particles, in 216 consecutive HF patients with (n = 79) or without (n = 137) type 2 diabetes, and age- and gender-matched 112 diabetic and 189 non-diabetic non-HF controls. We found arylesterase activity was significantly decreased in patients with than without HF, and was further decreased when comorbid with diabetes. After adjusting for conventional risk factors and apolipoprotein A-I levels, arylesterase activity remained correlated positively with left ventricular ejection fraction in diabetic (r = 0.325, P = 0.020) but not non-diabetic patients (r = 0.089, P = 0.415), and negatively with NT-proBNP and NYHA functional class in both subgroups. In regression analyses, a higher risk of HF was observed in diabetic than non-diabetic patients when having low arylesterase activities. In conclusion, our data demonstrate that impaired serum arylesterase activity in patients with HF is further reduced when comorbid with diabetes. The relationship of impaired arylesterase activity to HF is especially enhanced in diabetic patients.

Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications.

Systolic and diastolic myocardial dysfunction has been demonstrated to be associated with an activation of the circulating and local renin-angiotensin-aldosterone system (RAAS), and with a subsequent inappropriately increased production of reactive oxygen species (ROS). While, at low concentrations, ROS modulate important physiological functions through changes in cellular signalling and gene expression, overproduction of ROS may adversely alter cardiac mechanics, leading to further worsening of systolic and diastolic function. In addition, vascular endothelial dysfunction due to uncoupling of the nitric oxide synthase, activation of vascular and phagocytic membrane oxidases or mitochondrial oxidative stress may lead to increased vascular stiffness, further compromising cardiac performance in afterload-dependent hearts. In the present review, we address the potential role of ROS in the pathophysiology of myocardial and vascular dysfunction in heart failure (HF) and their therapeutic targeting. We discuss possible mechanisms underlying the failure of antioxidant vitamins in improving patients' prognosis, the impact of angiotensin-converting enzyme inhibitors or AT1 receptor blockers on oxidative stress, and the mechanism of the benefit of combination of hydralazine/isosorbide dinitrate. Further, we provide evidence supporting the existence of differences in the pathophysiology of HF with preserved vs. reduced ejection fraction and whether targeting mitochondrial ROS might be a particularly interesting therapeutic option for patients with preserved ejection fraction.

Endothelial nitric oxide synthase polymorphism and prognosis in systolic heart failure patients.

BACKGROUND: The endothelial nitric oxide synthase (eNOS) gene single nucleotide polymorphism G894T is associated with thrombotic vascular diseases. However, its functional significance is controversial and data are scarce concerning its influence in heart failure (HF). METHODS: We studied 215 patients with chronic systolic HF. DNA was analyzed for eNOS gene G894T polymorphism using PCR and DNA sequencing. Evaluation of clinical characteristics and analysis of factors associated with 2-year mortality were performed for the homozygous G-allele G894T variant (GG), relative to the TT and GT variants. RESULTS: The genotype distributions of eNOS G894T alleles were: GG 135 patients (63%) and TT/GT 80 (37%). Two-year mortality was significantly higher in the GG variant (48%) than the combined TT/GT group (32%). The usage of nitrates was associated with increased 2-year mortality (HR 2.0, 95% CI 1.28-3.17; p = 0.003), which was most significant in the GG group treated with nitrates (73.5%) in comparison to the TT/GT group not treated with nitrates (34%); HR 2.75, 95% CI 1.57-4.79, P < 0.001. CONCLUSIONS: Homozygosity for the G allele of the eNOS G894T polymorphism was associated with worse survival in systolic HF patients, especially in those treated with nitrates. ENOS polymorphism may result in different mechanistic interactions in HF than in thrombotic vascular diseases, suggesting that overexpression of NO may be associated with deleterious effects in systolic HF.

Matrix metalloproteinase 9/neutrophil gelatinase associated lipocalin/tissue inhibitor of metalloproteinasess type 1 complexes are localized within cardiomyocytes and serve as a reservoir of active metalloproteinase in porcine female myocardium.

Matrix metalloproteinase 9 (MMP-9) is crucial for physiological tissue repair and pathophysiological myocardial remodeling. The regulation of its functioning has been shown to be mediated by formation of complexes with tissue inhibitor of metalloproteinases 1 (TIMP-1) and neutrophil gelatinase associated lipocalin (NGAL). We investigated the mRNA and protein expression of MMP-9, TIMP-1 and NGAL, the formation of complexes, their gelatinolytic activity and cellular localization in left ventricle (LV) from 10 female pigs with induced systolic heart failure (HF), 5 control pigs, and a woman with severe HF. The MMP-9, TIMP-1 and NGAL mRNA in LV did not differ between diseased and healthy pigs. In all pigs MMP-9, TIMP-1 and NGAL proteins were present in LV as high molecular weight (HMW) complexes (115, 130, 170 and 220 kDa), and no monomers were found. A 80 and 115 kDa gelatinolytically active bands were present in all LV homogenates. A 130-kDa active band was seen only in LV from pigs with severe HF. Similar results were found in the explanted heart of a female patient with severe HF. The incubation of the homogenates of porcine LV at 37°C resulted in appearance of 88 kDa active band, which was accompanied by a decreased intensity of HMW bands. The incubation of the homogenates of porcine LV (depleted of active MMP-9) with trypsin generated 80 and 115 kDa active bands. Immunohistochemistry revealed the presence of MMP-9 in the cytoplasm of porcine cardiomyocytes, but not in cardiofibroblasts. Our data suggest that MMP-9 originates from cardiomyocytes, forms the gelatinolytically inactive complexes with TIMP-1 and NGAL, present in normal and failing myocardium, likely serving as a reservoir of active MMP-9. Further studies are needed to elucidate the role of these HMW complexes in the extracellular matrix remodeling during the progression of HF, which presence should be considered when developing efficient strategies inhibiting myocardial matrix metalloproteinases.

N-terminal truncated intracellular matrix metalloproteinase-2 induces cardiomyocyte hypertrophy, inflammation and systolic heart failure.

Matrix metalloproteinase-2 (MMP-2) is increasingly recognized as a major contributor to progressive cardiac injury within the setting of ischemia-reperfusion injury and ischemic ventricular remodeling. A common feature of these conditions is an increase in oxidative stress, a process that engages multiple pro-inflammatory and innate immunity cascades. We recently reported on the identification and characterization of an intracellular isoform of MMP-2 generated by oxidative stress-mediated activation of an alternative promoter located within the first intron of the MMP-2 gene. Transcription from this site generates an N-terminal truncated 65 kDa isoform of MMP-2 (NTT-MMP-2) that lacks the secretory sequence and the inhibitory prodomain region. The NTT-MMP-2 isoform is intracellular, enzymatically active and localizes in part to mitochondria. Expression of the NTT-MMP-2 isoform triggers Nuclear Factor of Activated T-cell (NFAT) and NF-κB signaling with the expression of a highly defined innate immunity transcriptome, including Interleukin-6, MCP-1, IRF-7 and pro-apoptotic transcripts. To determine the functional significance of the NTT-MMP-2 isoform in vivo we generated cardiac-specific NTT-MMP-2 transgenic mice. These mice developed progressive cardiomyocyte and ventricular hypertrophy associated with systolic heart failure. Further, there was evidence for cardiomyocyte apoptosis and myocardial infiltration with mononuclear cells. The NTT-MMP-2 transgenic hearts also demonstrated more severe injury following ex vivo ischemia-reperfusion injury. We conclude that a novel intracellular MMP-2 isoform induced by oxidant stress directly contributes, in the absence of superimposed injury, to cardiomyocyte hypertrophy. inflammation, systolic heart failure and enhanced susceptibility to ischemia-reperfusion injury.

Polymorphisms of matrix metalloproteinases in systolic heart failure: role on disease susceptibility, phenotypic characteristics, and prognosis.

BACKGROUND: The role of matrix metalloproteinases (MMPs) polymorphisms on heart failure (HF) susceptibility, phenotypic characteristics, and prognosis has been poorly explored. METHODS AND RESULTS: We studied 313 HF patients with left ventricular systolic dysfunction and 367 healthy control subjects. Genotyping of MMP-1 (-1607 1G/2G), MMP-3 (-1171 5A/6A), and MMP-9 (-1562 C/T) polymorphisms was performed by polymerase chain reaction. Allelic and genotypic frequencies of MMP-1, -3, and -9 were similar in HF patients and controls. MMP1 2G allele carriers were positively associated to ischemic etiology and history of myocardial infarction (all P values <.05). Patients were followed-up for a median of 40 months and 58 HF-related deaths occurred during this period. HF-related survival was significantly better in MMP1 2G allele carriers (71% versus 42% for 1G/1G patients, P = .002) and in MMP-3 6A allele carriers (70% versus 61% for 5A/5A patients, P = .064), particularly in non-ischemic patients (P = .039). MMP1 2G allele was independently associated to HF survival after adjustment for several other predictors of risk (hazard ratio 0.47, 95% confidence interval 0.27 to 0.82; P = .008). CONCLUSIONS: MMP-1, -3, and -9 polymorphisms were not associated to HF susceptibility. However, MMP1 2G allele carriers were related to a higher prevalence of ischemic etiology among patients with systolic HF and better HF-related prognosis.

Modulation of sarcoplasmic reticulum Ca(2+) cycling in systolic and diastolic heart failure associated with aging.

Hypertension, atherosclerosis, and resultant chronic heart failure (HF) reach epidemic proportions among older persons, and the clinical manifestations and the prognoses of these worsen with increasing age. Thus, age per se is the major risk factor for cardiovascular disease. Changes in cardiac cell phenotype that occur with normal aging, as well as in HF associated with aging, include deficits in ss-adrenergic receptor (ss-AR) signaling, increased generation of reactive oxygen species (ROS), and altered excitation-contraction (EC) coupling that involves prolongation of the action potential (AP), intracellular Ca(2+) (Ca(i)(2+)) transient and contraction, and blunted force- and relaxation-frequency responses. Evidence suggests that altered sarcoplasmic reticulum (SR) Ca(2+) uptake, storage, and release play central role in these changes, which also involve sarcolemmal L-type Ca(2+) channel (LCC), Na(+)-Ca(2+) exchanger (NCX), and K(+) channels. We review the age-associated changes in the expression and function of Ca(2+) transporting proteins, and functional consequences of these changes at the cardiac myocyte and organ levels. We also review sexual dimorphism and self-renewal of the heart in the context of cardiac aging and HF.

Dysfunctional corin i555(p568) allele is associated with impaired brain natriuretic peptide processing and adverse outcomes in blacks with systolic heart failure: results from the Genetic Risk Assessment in Heart Failure substudy.

BACKGROUND: Corin, a transmembrane serine protease expressed in cardiomyocytes, cleaves pro-atrial natriuretic peptide and pro-brain natriuretic peptide (BNP) into biologically active peptide hormones. The minor corin I555(P568) allele, defined by the T555I and Q568P mutations, is common in persons of African ancestry and associated with increased risk for hypertension and cardiac concentric hypertrophy. The corin gene product containing the T555I and Q568P mutations has significantly reduced natriuretic peptide processing capacity. We hypothesized that the corin I555(P568) allele would be associated with adverse outcomes and impaired BNP processing in blacks with systolic heart failure. METHODS AND RESULTS: This is a retrospective study of 354 subjects in the African American Heart Failure Trial Genetic Risk Assessment in Heart Failure substudy. In the corin variant group (n=50) compared with corin nonvariant group (n=300), BNP-32 (amino acids 77 to 108) was lower (190 pg/mL versus 340 pg/mL, P=0.007), but the ratio of unprocessed BNP(1 to 108)/processed BNP-32 was significantly higher (P=0.05). Stratified analyses were conducted because of evidence of significant interaction between the corin I555(P568) allele and treatment assignment. In the placebo arm, multivariable analysis demonstrated that the corin I555(P568) allele was associated with increased risk for death or heart failure hospitalization (relative risk 3.49; 95% CI, 1.45 to 8.39; P=0.005); however, in the treatment arm (fixed-dose combination isosorbide-dinitrate/hydralazine), the corin I555(P568) allele was not associated with adverse outcomes. CONCLUSIONS: We have identified a pharmacogenomic interaction in blacks with systolic heart failure. The corin I555(P568) allele is associated with an increased risk for death or heart failure hospitalization in patients receiving standard neurohormonal blockade, but the addition of fixed-dose combination isosorbide-dinitrate/hydralazine ameliorates this risk. A plausible mechanism for this pharmacogenomic interaction is the impaired processing of BNP in carriers of the corin I555(P568) allele as compared with noncarriers.

Soluble angiotensin-converting enzyme 2 in human heart failure: relation with myocardial function and clinical outcomes.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is an endogenous counterregulator of the renin-angiotensin system. The relationship between soluble ACE2 (sACE2), myocardial function, and clinical outcomes in patients with chronic systolic heart failure is not well established. METHODS AND RESULTS: We measured sACE2 activity in 113 patients with chronic systolic heart failure (left ventricular ejection fraction [LVEF]