Renin-Angiotensin Activation and Oxidative Stress in Early Heart Failure with Preserved Ejection Fraction.

Animal models have suggested a role of renin-angiotensin system (RAS) activation and subsequent cardiac oxidation in heart failure with preserved ejection fraction (HFpEF). Nevertheless, RAS blockade has failed to show efficacy in treatment of HFpEF. We evaluated the role of RAS activation and subsequent systemic oxidation in HFpEF. Oxidative stress markers were compared in 50 subjects with and without early HFpEF. Derivatives of reactive oxidative metabolites (DROMs), F2-isoprostanes (IsoPs), and ratios of oxidized to reduced glutathione (E h GSH) and cysteine (E h CyS) were measured. Angiotensin converting enzyme (ACE) levels and activity were measured. On univariate analysis, HFpEF was associated with male sex (p = 0.04), higher body mass index (BMI) (p = 0.003), less oxidized E h CyS (p = 0.001), lower DROMs (p = 0.02), and lower IsoP (p = 0.03). Higher BMI (OR: 1.3; 95% CI: 1.1-1.6) and less oxidized E h CyS (OR: 1.2; 95% CI: 1.1-1.4) maintained associations with HFpEF on multivariate analysis. Though ACE levels were higher in early HFpEF (OR: 1.09; 95% CI: 1.01-1.05), ACE activity was similar to that in controls. HFpEF is not associated with significant systemic RAS activation or oxidative stress. This may explain the failure of RAS inhibitors to alter outcomes in HFpEF.

Association of low plasma adiponectin with early diastolic dysfunction.

Diastolic dysfunction (DD) with preserved left ventricular (LV) ejection fraction (EF) has been linked to obesity. Adiponectin is a cytokine related to obesity and obesity-linked cardiovascular complications. The authors aimed to determine the independent association of DD with adiponectin. Fifty patients with impaired relaxation DD and a normal EF and age-matched normal controls were recruited. Plasma levels of total and high molecular weight (HMW) adiponectin were measured. Mid and low molecular weight (MMW+LMW) fractions of adiponectin were calculated by subtracting HMW fraction from total adiponectin. The DD group had significantly lower total (median, 4.4 vs 12.7 µg/mL; P=.001), HMW fraction (median, 1.3 vs 3.4 µg/mL; P=.02), and MMW+LMW fraction of adiponectin (median, 3.8 vs 7.2 µg/mL; P=.01). Body mass index (BMI) negatively correlated with total (r:-0.46, P=.003), HMW (r:-0.32, P=.038), and MMW+LMW (r:-0.40, P=.006) fractions of adiponectin. DD had an independent association with both BMI (P<.05) and total adiponectin (P<.001) in linear regression model using sex, BMI, blood pressure, and total adiponectin as covariates. DD was associated with BMI (P=.02), HMW fraction (P=.03), and MMW+LMW fraction (P=.004) in similar linear regression analyses. Adiponectin deficiency may be one explanation for the adiposity-related cardiac oxidation known to be involved in the pathogenesis of DD.

Statin therapy for the prevention of atrial fibrillation trial (SToP AF trial).

BACKGROUND: Inflammation and oxidative stress are associated with atrial fibrillation (AF). Statins have antioxidant and anti-inflammatory properties. We tested if atorvastatin reduced AF recurrence after DC cardioversion (CV) by modifying systemic oxidative stress and inflammation (NCT00252967). METHODS AND RESULTS: In a randomized, double-blinded, placebo-controlled trial, patients with atrial fibrillation/flutter (AF) were randomized to receive either atorvastatin 80 mg (n = 33) or placebo (n = 31) before CV. Treatment was continued for 12 months or until AF recurred. Serum oxidative stress markers (ratios of oxidized to reduced glutathione and cysteine, derivatives of reactive oxygen species, isoprostanes) and inflammatory markers (high-sensitivity C- reactive protein [hs-CRP], interleukin-6 [IL-6], interleukin-1ß[IL-1ß], tumor necrosis factor alpha [TNFα]) were measured at baseline and on follow-up. AF recurred in 22 (66.7%) of atorvastatin and 26 (83.9%) of placebo group (P = 0.2). The adjusted hazard ratio of having recurrence on atorvastatin versus on placebo was 0.99 (95% CI: 0.98-1.01, P = 0.3). There was no significant difference in the time to recurrence using Kaplan-Meier survival estimates (median [IR]: 29 [2-145] days versus 22 [7-70] days, P = 0.9). Although no significant effect was seen on oxidative stress, 2 of 4 inflammatory markers, IL-6 (adjusted OR: 0.59, 95% CI: 0.35-0.97, P = 0.04) and hs-CRP (adjusted OR: 0.59, 95% CI: 0.37-0.95, P = 0.03) were significantly lowered with atorvastatin. Cholesterol levels significantly decreased with atorvastatin (P = 0.03). CONCLUSIONS: High-dose atorvastatin did not reduce the recurrence of AF after CV. It reduced selective markers of inflammation without affecting systemic oxidative stress. Failure of atorvastatin to prevent AF recurrence may be due to its failure to affect oxidative stress.

Statins Decrease Oxidative Stress and ICD Therapies.

Recent studies demonstrate that statins decrease ventricular arrhythmias in internal cardioverter defibrillator (ICD) patients. The mechanism is unknown, but evidence links increased inflammatory and oxidative states with increased arrhythmias. We hypothesized that statin use decreases oxidation. Methods. 304 subjects with ICDs were surveyed for ventricular arrhythmia. Blood was analyzed for derivatives of reactive oxygen species (DROMs) and interleukin-6 (IL-6). Results. Subjects included 252 (83%) men, 58% on statins, 20% had ventricular arrhythmias. Average age was 63 years and ejection fraction (EF) 20%. ICD implant duration was 29 +/- 27 months. Use of statins correlated with lower ICD events (r = 0.12, P = .02). Subjects on statins had lower hsCRP (5.2 versus 6.3; P = .05) and DROM levels (373 versus 397; P = .03). Other factors, including IL-6 and EF did not differ between statin and nonstatin use, nor did beta-blocker or antiarrhythmic use. Multivariate cross-correlation analysis demonstrated that DROMs, statins, IL-6 and EF were strongly associated with ICD events. Multivariate regression shows DROMs to be the dominant predictor. Conclusion. ICD event rate correlates with DROMs, a measure of lipid peroxides. Use of statins is associated with reduced DROMs and fewer ICD events, suggesting that statins exert their effect through reducing oxidation.

Predictive value of normal dobutamine stress echocardiogram in patients with low-risk acute chest pain.

Dobutamine stress echocardiography (DSE) has been proposed as a tool for risk stratification of patients with acute chest pain (ACP). In this single-center study, we evaluated the negative predictive value of DSE in 178 patients who presented with low-risk ACP (normal or inconclusive electrocardiogram and negative markers of myocardial damage) and were discharged following a maximal DSE that did not reveal ischemia. During the follow-up (median 321 days), 2 of the 178 patients were admitted with an acute coronary syndrome and were diagnosed with obstructive coronary artery disease at angiography. In the time frame of the study, the negative predictive value of a normal and maximal DSE for an adverse cardiac event was 98.9% (95% CI: 96.0-99.8%). Thus, a normal DSE has a high negative predictive value and comprises a safe and effective tool for early risk stratification of patients who present with acute chest pain of low risk.

Oxidative stress markers are associated with persistent atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) has been associated with myocardial oxidative stress, and antioxidant agents have demonstrated antiarrhythmic benefit in humans. We compared serum markers of oxidation and associated inflammation in individuals with or without AF. METHODS: Serum markers of oxidative stress and inflammation were compared in a cross-sectional, case-control design study of 40 male individuals, with or without persistent or permanent AF, who were matched for age, sex, diabetes, and smoking status, known confounding variables for the measurement of oxidative stress. We used derivatives of reactive oxidative metabolites (DROMs) and ratios of oxidized to reduced glutathione (E(h) GSH) and cysteine (E(h) CySH) to quantify oxidative stress. We also measured inflammatory markers, including high-sensitivity C-reactive protein, interleukins 1beta and 6, and tumor necrosis factor alpha. RESULTS: Univariate, conditional logistical regression analysis showed that oxidative stress but not inflammatory markers were statistically associated with AF (P <0.05). The increase in the odds ratios for AF for E(h) GSH, E(h) CySH, and DROMs were 6.1 (95% CI, 1.3-28.3; P = 0.02), 13.6 (95% CI, 2.5-74.1; P = 0.01), and 15.9 (95% CI, 1.7-153.9; P = 0.02), respectively. There was a stronger correlation between E(h) GSH and E(h) CySH (r = 0.66) than between E(h) GSH and DROMs (r = 0.41). In multivariate analysis corrected for statins and other AF risk factors differing between the groups, the association of AF and oxidative stress remained significant. CONCLUSIONS: These data suggest that oxidative stress markers may have predictive value in AF management.

Long-term survival after successful inhospital cardiac arrest resuscitation.

BACKGROUND: Little is known about long-term outcomes of patients who survive inhospital cardiac arrest. METHODS: We examined long-term survival after inhospital cardiac arrest and whether procedural changes that improved survival to discharge impacted long-term survival. Consecutive inhospital arrests in the Atlanta Veterans Affairs Medical Center (Atlanta, GA) from 1995 to 2004 (n = 732) were retrospectively analyzed. Data regarding the arrest was obtained, including age, left ventricular ejection fraction, medications, and comorbidities, presenting rhythm, location of arrest, code duration, and outcomes. Long-term mortality data was obtained based on chart and Social Security Death Index reviews. Further data was gathered on internal cardioverter-defibrillator presence and use in survivors. RESULTS: Overall, 49 subjects (6.6%) survived to discharge. Univariate analysis found that ventricular tachycardia/ventricular fibrillation and the use of beta-blockers, angiotensin-converting enzyme inhibitors, and antiarrhythmics at the time of arrest were associated with increased survival, whereas advancing age and comorbidities were associated with a higher risk of mortality. Multivariate analysis determined that age, rhythm, and comorbidities independently affected survival. Implementation of a resuscitation program previously documented to improve survival to discharge did not translate to durable long-term survival. Three-year survival rate after discharge was only 41%. Alternatively, subjects with internal cardioverter-defibrillator showed a 36% improvement in 3-year survival rate to 77% (P = .001). CONCLUSIONS: Subjects with inhospital cardiac arrest have poor long-term prognoses. A strategy that improved inhospital survival did not alter long-term mortality rate. Thus, survival to discharge may not be a sufficient end point for future resuscitation trials.