Ravi Ramani

Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion

AIMS Nitrated fatty acids (NO(2)-FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions. Herein the in vivo generation of nitro-oleic acid (OA-NO(2)) and nitro-linoleic acid (LNO(2)) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO(2) on I/R injury was evaluated. METHODS AND RESULTS In C57/BL6 mice subjected to 30 min of coronary artery ligation, endogenous OA-NO(2) and LNO(2) formation was observed after 30 min of reperfusion, whereas no NO(2)-FA were detected in sham-operated mice and mice with myocardial infarction without reperfusion. Exogenous administration of 20 nmol/g body weight OA-NO(2) during the ischaemic episode induced profound protection against I/R injury with a 46% reduction in infarct size (normalized to area at risk) and a marked preservation of left ventricular function as assessed by transthoracic echocardiography, compared with vehicle-treated mice. Administration of OA-NO(2) inhibited activation of the p65 subunit of nuclear factor kappaB (NFkappaB) in I/R tissue. Experiments using the NFkappaB inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO(2) was in part mediated by inhibition of NFkappaB. OA-NO(2) inhibition of NFkappaB activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis. CONCLUSION This study reveals the de novo generation of fatty acid nitration products in vivo and reveals the anti-inflammatory and potential therapeutic actions of OA-NO(2) in myocardial I/R injury.

Effect of the Asp298 Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

Background—Significant variation exists within the endothelial nitric oxide synthase (NOS3) gene that may influence cardiovascular risk. The Asp298 variant of NOS3 has a shorter half-life in endothelial cells. Given the importance of nitric oxide in the heart failure syndrome, we evaluated the effect of this variant on event-free survival in a population with systolic dysfunction. Methods and Results—Four hundred sixty-nine patients (72% male, 49% ischemic; mean age, 56±12 years) with systolic dysfunction (left ventricular ejection fraction ≤0.45) were enrolled in a study of Genetic Risk Assessment of Cardiac Events (GRACE). The polymorphism in exon 7 of NOS3, a G-T transition at position 894 that results in a Glu to Asp amino acid substitution for codon 298, was genotyped and subjects were followed prospectively to the end point of death or heart transplantation. Event-free survival was compared on the basis of the presence (group 1, n=266) or absence (group 2, n=203) of the Asp298 variant. Event-free survival was significantly poorer in patients with the Asp298 variant (percent event-free survival group 1 at 1/2/3 years=78/65/54; group 2=82/72/64, P =0.03). In subset analysis, the adverse impact of the Asp298 variant was primarily in patients with nonischemic cardiomyopathy (group 1=82/73/63; group 2=87/79/71, P =0.03) and was not apparent among patients with ischemic heart disease (group 1=75/59/47; group 2=74/62/54, P =0.71). Conclusions—For patients with heart failure caused by systolic function, the Asp298 variant of NOS3 is associated with poorer event-free survival, particularly in patients with nonischemic cardiomyopathy.

Heart transplantation for adults with congenital heart disease: results in the modern era.

BACKGROUND Heart transplantation in adults with congenital heart disease (CHD) has historically been associated with sub-optimal survival compared with other indications for transplantation. The purpose of this study was to evaluate survival outcomes after heart transplantation in a contemporary cohort of adults with CHD and to identify risk factors for mortality that may help guide recipient and donor selection. METHODS We performed a retrospective analysis of our adult heart transplant database, from January 2001 to February 2011, identifying 19 patients who underwent transplantation for CHD. These patients were compared with a control group of 428 patients who underwent transplantation for indications other than CHD. Kaplan-Meier survival analysis and Cox regression modeling were performed. RESULTS The mean age for the CHD group was 39.4 ± 13 years vs 54.7 ± 12 years (p < 0.001). There was no significant difference in survival (CHD vs control) at 30 days (89% vs 92%, p = 0.5567), 1 year (84% vs 86%, p = 0.6976) or 5 years (70% vs 72%, p = 0.8478). The only significant predictor of death in the CHD group was donor organ ischemic time >4 hours (HR 13.26, 95% CI 1.3 to 132.2, p = 0.028). There was no significant correlation with recipient age, history of failed Fontan surgery, pre-operative ventilator use, donor:recipient weight ratio <0.8, donor:recipient CMV mismatch, model for end-stage liver disease (MELD) score or percent reactive antibody >10%. CONCLUSIONS In the modern era, with careful donor and recipient selection, adults with CHD have excellent early and mid-term survival after heart transplantation, rivaling that of recipients with other indications for transplantation.

A Micro-Ribonucleic Acid Signature Associated With Recovery From Assist Device Support in 2 Groups of Patients With Severe Heart Failure

OBJECTIVES This study was conducted to test the hypothesis that cardiac micro-ribonucleic acid (miR) profiling in severe heart failure patients at the time of ventricular assist device (VAD) placement would differentiate those who remained VAD-dependent from those with subsequent left ventricular (LV) recovery. BACKGROUND The relationship of myocardial miR expression to ventricular recovery is unknown. METHODS We studied 28 patients with nonischemic cardiomyopathy requiring VAD support consisting of test and validation cohorts from 2 institutions: 14 with subsequent LV recovery and VAD removal and 14 clinically matched VAD-dependent patients. Apical core myocardium was studied for expression of 376 miRs by polymerase chain reaction (PCR) array and real-time-PCR methods. Samples from 7 nonfailing hearts were used in confirmatory studies. RESULTS By PCR array, 10 miRs were differentially expressed between LV recovery and VAD-dependent patients in the test cohort. The real-time PCR confirmed lower expression in LV recovery patients for 4 miRs (15b, -1.5-fold; 23a, -2.2-fold; 26a, -1.4-fold; and 195, -1.8-fold; all p < 0.04 vs. VAD dependent). The validation cohort similarly showed lower miRs expression in LV recovery patients (23a, -1.8-fold; and 195, -1.5-fold; both p < 0.03). Furthermore, miR 23a and 195 expression in nonfailing hearts was similar to LV recovery patients (both p < 0.04 vs. VAD dependent). The LV recovery patients also had significantly smaller cardiomyocytes by quantitative histology in both cohorts. CONCLUSIONS Lower cardiac expression of miRs 23a and 195 and smaller cardiomyocyte size at the time of VAD placement were associated with subsequent LV functional recovery. Differential expression of miRs at VAD placement may provide markers to assess recovery potential.

Tissue Inhibitor of Metalloproteinase-2 Gene Delivery Ameliorates Postinfarction Cardiac Remodeling

Hypothesis: Adenoviral‐mediated (AdV‐T2) overexpression of TIMP‐2 would blunt ventricular remodeling and improve survival in a murine model of chronic ischemic injury. Methods: Male mice (n = 124) aged 10–14 weeks underwent either (1) left coronary artery ligation to induce myocardial infarction (MI group, n = 36), (2) myocardial injection of 6 × 1010 viral particles of AdV‐T2 immediately post‐MI (MI + T2 group, n = 30), (3) myocardial injection of 6 × 1010 viral particles of a control adenovirus (MI + Ct, n = 38), or 4) received no intervention (controls, n = 20). On post‐MI day 7, surviving mice (n = 79) underwent echocardiographic, immunohistochemical, and biochemical analysis. Results: In infarcted animals, the MI + T2 group demonstrated improved survival (p < 0.02), better preservation of developed pressure and ventricular diameter (p < 0.04), and the lowest expression and activity of MMP‐2 and MMP‐9 (p < 0.04) compared with MI and MI + Ct groups. All infarcted hearts displayed significantly increased inflammatory cell infiltration (p < 0.04 vs. control, MI, or MI + T2), with infiltration highest in the MI + Ct group and lowest in the MI + T2 group (p < 0.04). Conclusions: Adenoviral mediated myocardial delivery of the TIMP‐2 gene improves post‐MI survival and limits adverse remodeling in a murine model of MI. Clin Trans Sci 2011; Volume 4: 24–31

The role of anticytokine therapy in heart failure: recent lessons from preclinical and clinical trials?

In summary, over a decade of investigation has demonstrated the pathophysiologic importance of TNF in the development and progression of cardiac dilatation and heart failure. Although the signaling pathways that regulate the cardiac production of TNF have not yet been identified and the potential benefits of TNF expression to the heart are not understood, the benefits of anticytokine therapy in animal models is marked. Unfortunately, these salutary effects in the laboratory have not transitioned to the bedside. To accomplish the translational portion of the cytokine story, we must identify the point in time during the transition from compensated to decompensated heart failure in which TNF is expressed. In addition, we must better understand the role that other down-stream and non-TNF-dependent cytokines play in the development of heart failure. Not all patients are the same; therefore, we must pursue clinical trials that will allow us to elucidate the optimal degree of TNF inhibition, identify the patients who are most likely to respond to TNF inhibition, and determine what the true, long-term effects of TNF inhibition may be. Finally, we must recognize that inflammatory activities can exist in tissues and organs in the absence of TNF. Thus, anticytokine strategies alone might not be effective in ameliorating the signs and symptoms of heart failure. It is hoped that the failure of recent studies to demonstrate salutary benefits in patients with class II to IV heart failure will not diminish enthusiasm for the long-term potential of anticytokine therapy.

Noninvasive Assessment of Acute Dyspnea in the ED

Background: We compared the ability of noninvasive measurements of cardiac output (CO) and thoracic fluid content (TFC) and their change in response to orthostatic challenges to diagnose acute decompensate heart failure (ADHF) from non-ADHF causes of acute dyspnea in patients in the ED. Methods: Forty-five patients > 44 years old presenting in the ED with dyspnea were studied. CO and TFC were monitored with a NICOM bioreactance device. CO and TFC were measured continuously while each patient was sitting, supine, and during a passive leg-raising maneuver (3 min each); the maximal values during each maneuver were reported. Orthostatic challenges were repeated 2 h into treatment. One patient was excluded because of intolerance to the supine position. Diagnoses obtained with the hemodynamic measurements were compared with ED diagnoses and with two expert physicians by chart review (used as gold standard diagnosis); both groups were blinded to CO and TFC values. Patient’s treatment, ED disposition, hospital length of stay, and subjective dyspnea (Borg scale) were also recorded. Results: Sixteen of 44 patients received a diagnosis of ADHF and 28 received a diagnosis of non-ADHF by the experts. Baseline TFC was higher in patients with ADHF (P = .001). Fifteen patients were treated for ADHF, and their Borg scale values decreased at 2 h (P < .05). TFC threshold of 78.8 had a receiver operator characteristic area under the curve of 0.81 (76% sensitivity, 71% specificity) for ADHF. Both ADHF and non-ADHF groups were similar in their increased CO from baseline to PLR and supine. Pre- and posttreatment measurements were similar. Conclusions: Baseline TFC can discriminate patients with ADHF from non-ADHF dyspnea in the ED.

The methionine 196 arginine polymorphism of the TNF receptor 2 gene (TNFRSF1B) is not associated with worse outcomes in heart failure

Tumor necrosis factor α (TNFα) may contribute to the pathologic process of congestive heart failure (CHF). TNFα signaling occurs through two receptors; TNFR1 (TNFRSF1A) and TNFRII (TNFRSF1B). In humans a single nucleotide polymorphism (rs1061622 in TNFRSF1B exon 6; T587G) encodes two different amino acids (M196R) in the transmembrane region. The 587G allele is associated with greater severity and/or prevalence of some inflammatory diseases, but its role in CHF in unknown. This study sought to test the hypothesis that the 587G allele is associated with a worse outcome or more severe phenotype in CHF. Peripheral blood DNA was isolated and genotyped from 379 heart failure patients enrolled in a genetic outcome study (GRACE); (44.7% ischemic, 70.4% male, 8.5% black race, age 55.6 ± 11.7 yr (SD), LVEF 24.5 ± 8.3%, NYHA 2.53 ± 0.64). Genotyping was performed by PCR-RFLP. Cardiac function was assessed from medical records at study entry. The distribution of genotypes in this population was 54% T/T, 38.4% G/T and 7.7% G/G. Mean LV ejection fraction (T/T 24.4 ± 8.2, T/G 25.0 ± 8.4, G/G 23.3 ± 8.6, n=352, p=ns) and LV end-diastolic dimensions (T/T 6.57 ± 0.93, T/G 6.53 ± 1.0, G/G 6.57 ± 0.78, n=211, p=ns) were comparable in all groups. Transplant-free survival (median 23 months (range 1-62 months) did not vary by genotype (p=0.95). A lack of effect (p=0.74) on transplant-free survival was also observed in a subset of patients with ischemic heart failure (n=169). The TNFRSF1B 587G allele is not associated with the severity of heart failure phenotype or clinical outcomes in patients with chronic CHF.

DOES LVAD INFLOW CANNULA POSITION CONTRIBUTE TO THE DEVELOPMENT OF PUMP THROMBOSIS REQUIRING DEVICE EXCHANGE

Pump thrombosis requiring device exchange is a dreaded complication after implantation of a left ventricular assist device (LVAD). Sub-optimal inflow cannula (IC) positioning at the time of implant or changes in IC position due to weight gain or ventricular remodeling may lead to non-laminar flow.

Acute heart failure management in the USA and Japan: overview of practice patterns and review of evidence: Acute heart failure management in the USA and Japan

Globally, acute heart failure (AHF) remains an ongoing public health issue with its prevalence and mortality increasing in the east and the west. Effective treatment strategies to stabilize AHF are important to alleviate clinical symptoms and to improve clinical outcomes. However, despite the progress in the management of stable and chronic heart failure, no single agent has been proven to play a definitive role in the management of AHF. As a consequence, contemporary treatment strategies for patients with AHF vary greatly by region. This manuscript reviews the medical treatment options for AHF, with an emphasis on the differences between the treatment strategies in the USA and Japan. This information would provide a framework for clinicians to evaluate and manage patients with AHF and highlight the remaining questions to improve clinical outcomes.