Aslan T. Turer

Pathogenesis of Myocardial Ischemia-Reperfusion Injury and Rationale for Therapy

Since the initial description of the phenomenon by Jennings et al 50 years ago, our understanding of the underlying mechanisms of reperfusion injury has grown significantly. Its pathogenesis reflects the confluence of multiple pathways, including ion channels, reactive oxygen species, inflammation, and endothelial dysfunction. The purposes of this review are to examine the current state of understanding of ischemia-reperfusion injury, as well as to highlight recent interventions aimed at this heretofore elusive target. In conclusion, despite its complexity our ongoing efforts to mitigate this form of injury should not be deterred, because nearly 2 million patients annually undergo either spontaneous (in the form of acute myocardial infarction) or iatrogenic (in the context of cardioplegic arrest) ischemia-reperfusion.

Histone Deacetylase Inhibition Blunts Ischemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy

Background— Reperfusion accounts for a substantial fraction of the myocardial injury occurring with ischemic heart disease. Yet, no standard therapies are available targeting reperfusion injury. Here, we tested the hypothesis that suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor approved for cancer treatment by the US Food and Drug Administration, will blunt reperfusion injury. Methods and Results— Twenty-one rabbits were randomly assigned to 3 groups: (1) vehicle control, (2) SAHA pretreatment (1 day before and at surgery), and (3) SAHA treatment at the time of reperfusion only. Each arm was subjected to ischemia/reperfusion surgery (30 minutes coronary ligation, 24 hours reperfusion). In addition, cultured neonatal and adult rat ventricular cardiomyocytes were subjected to simulated ischemia/reperfusion to probe mechanism. SAHA reduced infarct size and partially rescued systolic function when administered either before surgery (pretreatment) or solely at the time of reperfusion. SAHA plasma concentrations were similar to those achieved in patients with cancer. In the infarct border zone, SAHA increased autophagic flux, assayed in both rabbit myocardium and in mice harboring an RFP-GFP-LC3 transgene. In cultured myocytes subjected to simulated ischemia/reperfusion, SAHA pretreatment reduced cell death by 40%. This reduction in cell death correlated with increased autophagic activity in SAHA-treated cells. RNAi-mediated knockdown of ATG7 and ATG5, essential autophagy proteins, abolished SAHA’s cardioprotective effects. Conclusions— The US Food and Drug Administration–approved anticancer histone deacetylase inhibitor, SAHA, reduces myocardial infarct size in a large animal model, even when delivered in the clinically relevant context of reperfusion. The cardioprotective effects of SAHA during ischemia/reperfusion occur, at least in part, through the induction of autophagic flux.

Associations of visceral and abdominal subcutaneous adipose tissue with markers of cardiac and metabolic risk in obese adults.

Objective: Visceral (VAT) and abdominal subcutaneous (SAT) adipose tissues contribute to obesity but may have different metabolic and atherosclerosis risk profiles. We sought to determine the associations of abdominal VAT and SAT mass with markers of cardiac and metabolic risk in a large, multiethnic, population‐based cohort of obese adults.

Metabolomic Profiling Reveals Distinct Patterns of Myocardial Substrate Use in Humans With Coronary Artery Disease or Left Ventricular Dysfunction During Surgical Ischemia/Reperfusion

Background— Human myocardial metabolism has been incompletely characterized in the setting of surgical cardioplegic arrest and ischemia/reperfusion. Furthermore, the effect of preexisting ventricular state on ischemia-induced metabolic derangements has not been established. Methods and Results— We applied a mass spectrometry–based platform to profile 63 intermediary metabolites in serial paired peripheral arterial and coronary sinus blood effluents obtained from 37 patients undergoing cardiac surgery, stratified by presence of coronary artery disease and left ventricular dysfunction. The myocardium was a net user of a number of fuel substrates before ischemia, with significant differences between patients with and without coronary artery disease. After reperfusion, significantly lower extraction ratios of most substrates were found, as well as significant release of 2 specific acylcarnitine species, acetylcarnitine and 3-hydroxybutyryl-carnitine. These changes were especially evident in patients with impaired ventricular function, who exhibited profound limitations in extraction of all forms of metabolic fuels. Principal component analysis highlighted several metabolic groupings as potentially important in the postoperative clinical course. Conclusions— The preexisting ventricular state is associated with significant differences in myocardial fuel uptake at baseline and after ischemia/reperfusion. The dysfunctional ventricle is characterized by global suppression of metabolic fuel uptake and limited myocardial metabolic reserve and flexibility after global ischemia/reperfusion stress in the setting of cardiac surgery. Altered metabolic profiles after ischemia/reperfusion are associated with postoperative hemodynamic course and suggest a role for perioperative metabolic monitoring and targeted optimization in cardiac surgical patients.

Myocardial Ischemia Induced by Rapid Atrial Pacing Causes Troponin T Release Detectable by a Highly Sensitive Assay : Insights From a Coronary Sinus Sampling Study

OBJECTIVES The purpose of this study was to assess whether: 1) very small increases in troponin T, measured by a new highly sensitive cardiac troponin T (hs-cTnT), may reflect ischemia without necrosis; and 2) serial changes can discriminate ischemia from other causes of cardiac troponin T (cTnT) release. BACKGROUND A new hs-cTnT assay offers greater sensitivity than current assays. METHODS Nineteen patients referred for diagnostic catheterization underwent cannulation of the coronary sinus (CS). Serial CS and peripheral plasma samples were obtained at multiple time points during and after incremental rapid atrial pacing. cTnT was quantified using both a standard and a pre-commercial highly sensitive assay. Ischemia was determined by the presence of significant coronary artery disease (CAD) and myocardial lactate release with pacing. RESULTS cTnT concentrations in CS blood increased from a median of 6.8 pg/ml prior to pacing to 15.6 pg/ml 60 min after termination of rapid atrial pacing (p < 0.0001), changes that were mirrored at 180 min in peripheral blood (5.1 to 11.8 pg/ml, p < 0.0001). Although peripheral cTnT concentrations tended to be higher at 180 min following pacing for patients with CAD and lactate elution (n = 7) when compared with those without either marker (n = 5) (25.0 pg/ml vs. 10.2 pg/ml, p = 0.10), relative (1.7-fold vs. 5.2-fold) and absolute (6.8 pg/ml vs. 8.8 pg/ml, p = 0.50) changes were not different between groups. CONCLUSIONS Brief periods of ischemia, without frank infarction, cause low-level cTnT release, and small increases are common after periods of increased myocardial work, even among patients without objective evidence of myocardial ischemia or obstructive CAD. Additional research is needed before hs-cTnT assays are widely adopted in the management of subjects with chest pain syndromes.

The Relationship of Body Mass and Fat Distribution With Incident Hypertension: Observations From the Dallas Heart Study

BACKGROUND Obesity has been linked to the development of hypertension, but whether total adiposity or site-specific fat accumulation underpins this relationship is unclear. OBJECTIVES This study sought to determine the relationship between adipose tissue distribution and incident hypertension. METHODS Normotensive participants enrolled in the Dallas Heart Study were followed for a median of 7 years for the development of hypertension (systolic blood pressure [SBP] ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of blood pressure medications). Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) was quantified by magnetic resonance imaging and proton-spectroscopic imaging, and lower body fat (LBF) was imaged by dual-energy x-ray absorptiometry. Multivariable relative risk regression was performed to test the association between individual fat depots and incident hypertension, adjusting for age, sex, race/ethnicity, diabetes, smoking, SBP, and body mass index (BMI). RESULTS Among 903 participants (median age, 40 years; 57% women; 60% nonwhite; median BMI 27.5 kg/m(2)), 230 (25%) developed incident hypertension. In multivariable analyses, higher BMI was significantly associated with incident hypertension (relative risk: 1.24; 95% confidence interval: 1.12 to 1.36, per 1-SD increase). However, when VAT, SAT, and LBF were added to the model, only VAT remained independently associated with incident hypertension (relative risk: 1.22; 95% confidence interval: 1.06 to 1.39, per 1-SD increase). CONCLUSIONS Increased visceral adiposity, but not total or subcutaneous adiposity, was robustly associated with incident hypertension. Additional studies will be needed to elucidate the mechanisms behind this association.

Higher Natriuretic Peptide Levels Associate With a Favorable Adipose Tissue Distribution Profile

OBJECTIVES The goal of this study was to investigate the association between natriuretic peptides and body fat distribution in a multiethnic cohort. BACKGROUND Natriuretic peptides stimulate lipolysis, reduce weight gain, and promote adipocyte browning in animal models, but data are lacking in humans. METHODS A total of 2,619 participants without heart failure in the Dallas Heart Study underwent measurements of 1) B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP); and 2) body fat distribution by dual energy x-ray absorptiometry and magnetic resonance imaging. Cross-sectional associations of natriuretic peptides with adiposity phenotypes were examined after adjustment for age, sex, race, comorbidities, and body mass index. RESULTS Median BNP and NT-proBNP levels in the study cohort (mean age 44 years; 56% women, 48% African Americans, 32% obese) were 3.0 and 28.1 pg/ml, respectively. Natriuretic peptide levels above the median were associated with a more favorable body fat profile and less insulin resistance, including lower visceral fat, liver fat, and homeostasis model assessment of insulin resistance index, and increased lower body fat and higher adiponectin (p < 0.05 for each). In multivariable analyses, NT-proBNP remained inversely associated with visceral fat (beta coefficient = -0.08; p < 0.0001) and liver fat (beta coefficient = -0.14; p < 0.0001) and positively associated with lower body fat (beta coefficient = 0.07; p < 0.0001) independent of age, sex, race, and obesity status; findings were similar with BNP. Adjustment for body composition, homeostasis model assessment of insulin resistance index, circulating androgens, and adipocytokines did not attenuate the associations. CONCLUSIONS Higher natriuretic peptide levels were independently associated with a favorable adiposity profile, characterized by decreased visceral and liver fat and increased lower body fat, suggesting a link between the heart and adipose tissue distribution mediated through natriuretic peptides.

Relation of regional fat distribution to left ventricular structure and function.

Background— The relation of body fat distribution to left ventricular (LV) structure and function is poorly defined. Methods and Results— A total of 2710 participants without heart failure or LV dysfunction in the Dallas Heart Study underwent dual energy x-ray absorptiometry and MRI assessment of fat distribution, LV morphology, and hemodynamics. Cross-sectional associations of fat distribution with LV structure and function were examined after adjustment for age, sex, race, comorbidities, and lean mass. Mean age was 44 years with 55% women; 48% blacks; and 44% obese. After multivariable adjustment, visceral adipose tissue was associated with concentric remodeling characterized by lower LV end-diastolic volume (&bgr;=−0.21), higher concentricity (&bgr;=0.20), and wall thickness (&bgr;=0.09; P<0.0001 for all). In contrast, lower body subcutaneous fat was associated with higher LV end-diastolic volume (&bgr;=0.48), reduced concentricity (&bgr;=−0.50), and wall thickness (&bgr;=−0.28, P<0.0001 for all). Visceral adipose tissue was also associated with lower cardiac output (&bgr;=−0.10, P<0.05) and higher systemic vascular resistance (&bgr;=0.08, P<0.05), whereas lower body subcutaneous fat associated with higher cardiac output (&bgr;=0.20, P<0.0001) and lower systemic vascular resistance (&bgr;=−0.18, P<0.0001). Abdominal subcutaneous fat showed weaker associations with concentric remodeling and was not associated with hemodynamics. Among the subset of obese participants, visceral adipose tissue, but not abdominal subcutaneous fat, was significantly associated with concentric remodeling. Conclusions— Visceral adipose tissue, a marker of central adiposity, was independently associated with concentric LV remodeling and adverse hemodynamics. In contrast, lower body subcutaneous fat was associated with eccentric remodeling. The impact of body fat distribution on heart failure risk requires prospective study.

Continuous Versus Bolus Dosing of Furosemide for Patients Hospitalized for Heart Failure

Intravenous diuretics are the cornerstone of management for patients hospitalized for heart failure. Physiologic data suggest that intermittent high-dose furosemide promotes neurohormonal activation, which a slow continuous infusion might remediate. However, the limited clinical data comparing dosing schemes are confounded. This study was a randomized, open-label, single-center trial of twice-daily bolus injection versus continuous infusion furosemide in patients hospitalized with heart failure and volume overload. The primary outcome was change in creatinine from admission to hospital day 3 or discharge. Twenty-one patients were randomized to bolus injection and 20 patients to continuous infusion. Baseline characteristics were balanced between study arms except for gender, with a mean age of 60 +/- 15 years, a mean ejection fraction of 35 +/- 19%, and a mean creatinine level of 1.9 +/- 1.2 mg/dl. The mean doses of furosemide were similar between arms over the first 48 hours (162 +/- 48 and 162 +/- 52 mg/24 hours). None of the outcomes differed significantly between bolus and continuous dosing from admission to hospital day 3 or discharge (mean change in creatinine -0.02 vs 0.13 mg/dl, p = 0.18; urine output 5,113 vs 4,894 ml, p = 0.78; length of stay 8.8 vs 9.9 days, p = 0.69). All patients survived to discharge. In conclusion, there were no substantial differences between bolus injection and continuous infusion of equal doses of furosemide for the treatment of patients hospitalized with heart failure. Given the high prevalence of heart failure hospitalization and the disparate results of small studies regarding optimal dosing of loop diuretics to treat these patients, larger multicenter blinded studies are needed.

Adipose Tissue Biology and Cardiomyopathy: Translational Implications

It is epidemiologically established that obesity is frequently associated with the metabolic syndrome and poses an increased risk for the development of type 2 diabetes mellitus and cardiovascular disease. The molecular links that connect the phenomenon of obesity, per se, with insulin resistance and cardiovascular disease are still not fully elucidated. It is increasingly apparent that fully functional adipose tissue can be cardioprotective by reducing lipotoxic effects in other peripheral tissues and by maintaining a healthy balance of critical adipokines, thereby allowing the heart to maintain its full metabolic flexibility. The present review highlights both basic and clinical findings that emphasize the complex interplay of adipose tissue physiology and adipokine-mediated effects on the heart exerted by either direct effects on cardiac myocytes or indirect actions via central mechanisms through sympathetic outflow to the heart.