Clifford Greyson

Multiple abnormalities of myocardial insulin signaling in a porcine model of diet-induced obesity.

Heightened cardiovascular risk among patients with systemic insulin resistance is not fully explained by the extent of atherosclerosis. It is unknown whether myocardial insulin resistance accompanies systemic insulin resistance and contributes to increased cardiovascular risk. This study utilized a porcine model of diet-induced obesity to determine if myocardial insulin resistance develops in parallel with systemic insulin resistance and investigated potential mechanisms for such changes. Micropigs (n = 16) were assigned to control (low fat, no added sugars) or intervention (25% wt/wt coconut oil and 20% high-fructose corn syrup) diet for 7 mo. Intervention diet resulted in obesity, hypertension, and dyslipidemia. Systemic insulin resistance was manifest by elevated fasting glucose and insulin, abnormal response to intravenous glucose tolerance testing, and blunted skeletal muscle phosphatidylinositol-3-kinase (PI 3-kinase) activation and protein kinase B (Akt) phosphorylation in response to insulin. In myocardium, insulin-stimulated glucose uptake, PI 3-kinase activation, and Akt phosphorylation were also blunted in the intervention diet group. These findings were explained by increased myocardial content of p85alpha (regulatory subunit of PI 3-kinase), diminished association of PI 3-kinase with insulin receptor substrate (IRS)-1 in response to insulin, and increased serine-307 phosphorylation of IRS-1. Thus, in a porcine model of diet-induced obesity that recapitulates many characteristics of insulin-resistant patients, myocardial insulin resistance develops along with systemic insulin resistance and is associated with multiple abnormalities of insulin signaling.

Right ventricular dysfunction persists following brief right ventricular pressure overload

OBJECTIVE Acute pulmonary hypertension may cause right ventricular (RV) contractile failure. While it has been assumed that restoration of normal loading conditions after acute pulmonary hypertension is sufficient for complete recovery of RV function, this has not been rigorously examined. The purpose of this study was to test the hypothesis that acute RV pressure overload produces RV contractile dysfunction that persists following restoration of control loading conditions. METHODS We subjected 18 autonomically-blocked, chloralose-anesthetized, open-chest pigs to 1 h of pulmonary artery constriction to increase RV systolic pressure from 35 +/- 1 to 55 +/- 1 mmHg, followed by 2 h of measurements after pulmonary artery constriction release. We determined regional RV free wall function from pressure-segment length loops and preload recruitable stroke work relations, and global RV function from stroke work vs. end-diastolic pressure relations. RESULTS As expected, RV free wall systolic shortening diminished during pulmonary artery constriction, but the endo/epi blood flow ratio, lactate uptake, and coronary venous pH were not significantly changed. Following release of pulmonary artery constriction, RV systolic and diastolic pressure returned to control values. Nonetheless, contractile dysfunction persisted, with depressed RV free wall systolic shortening (70 +/- 22% of control), RV regional external work (59 +/- 11% of control at control end-diastolic length), and global RV stroke work (56 +/- 14% of control at control end-diastolic pressure). Depressed regional work was due to a parallel, rightward shift of the preload recruitable stroke work relation. Five pigs identically instrumented but not subjected to pulmonary artery constriction showed no significant over 3 h. CONCLUSIONS Acute pulmonary hypertension causes RV contractile dysfunction that persists at least 2 h after restoration of control loading conditions. Contractile dysfunction is not attributable to RV ischemia during pressure overload.

PPAR-γ as a Therapeutic Target in Cardiovascular Disease: Evidence and Uncertainty

Peroxisome proliferator-activated receptor γ (PPAR-γ) is a key regulator of fatty acid metabolism, promoting its storage in adipose tissue and reducing circulating concentrations of free fatty acids. Activation of PPAR-γ has favorable effects on measures of adipocyte function, insulin sensitivity, lipoprotein metabolism, and vascular structure and function. Despite these effects, clinical trials of thiazolidinedione PPAR-γ activators have not provided conclusive evidence that they reduce cardiovascular morbidity and mortality. The apparent disparity between effects on laboratory measurements and clinical outcomes may be related to limitations of clinical trials, adverse effects of PPAR-γ activation, or off-target effects of thiazolidinedione agents. This review addresses these issues from a clinicians perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-γ activators in cardiovascular disease.

Low-dose inotropic stimulation during left ventricular ischaemia does not worsen post-ischaemic dysfunction

OBJECTIVE Inotropic agents are used clinically to improve ventricular function during ischaemia. The goal of this study was to determine whether inotropic stimulation during moderate left ventricular (LV) ischaemia exacerbated post-ischaemic LV dysfunction. METHODS In 18 open-chest, anesthetized pigs, LV pressure versus subendocardial segment length loops were used to generate regional preload-recruitable stroke work (PRSW) and LV end-diastolic pressure (EDP) versus end-diastolic segment length (EDL) relations. Ischaemia was produced by constant, partial constriction of the mid anterior descending coronary artery for 90 min. Nine pigs received dobutamine (4 micrograms.kg-1.min-1, i.v.) during the final 60 min of ischaemia (Group 2), while 9 other pigs did not (Group 1). RESULTS During unstimulated ischaemia, anterior subendocardial blood flow (Group 1, 0.27 +/- .05; Group 2, 0.30 +/- .07 ml.g-1.min.-1, mean +/- s.e.m.) and steady-state PRSW (Group 1, 30 +/- 4%; Group 2, 27 +/- 5% of baseline) were similar in both groups. Dobutamine stimulation during ischaemia increased heart rate, mean arterial pressure, subendocardial blood flow, oxygen consumption and steady-state PRSW of the ischaemia zone, but not lactate release. After 60 min reperfusion, steady-state ischaemic zone PRSW remained markedly and nearly equally reduced in both groups (Group 1, 28 +/- 4%; Group 2, 23 +/- 5% of baseline). Reduced PRSW after reperfusion was due primarily to persistent rightward shift of the PRSW intercept with only a modest contribution from reduced PRSW slope. CONCLUSIONS Low-dose inotropic stimulation during moderate regional LV ischaemia increases aerobic, but not anaerobic energy metabolism, and does not worsen post-ischaemic dysfunction.

Calpain Inhibition Preserves Talin and Attenuates Right Heart Failure in Acute Pulmonary Hypertension

Right heart failure from right ventricular (RV) pressure overload is a major cause of morbidity and mortality, but its mechanism is incompletely understood. We tested the hypothesis that right heart failure during 4 hours of RV pressure overload is associated with alterations of the focal adhesion protein talin, and that the inhibition of calpain attenuates RV dysfunction and preserves RV talin. Anesthetized open-chest pigs treated with the calpain inhibitor MDL-28170 (n = 20) or inactive vehicle (n = 23) underwent 4 hours of RV pressure overload by pulmonary artery constriction (initial RV systolic pressure, 64 ± 1 and 66 ± 1 mm Hg in MDL-28170 and vehicle-treated pigs, respectively). Progressive RV contractile dysfunction was attenuated by MDL-28170: after 4 hours of RV pressure overload, RV systolic pressure was 44 ± 4 mm Hg versus 49 ± 6 mm Hg (P = 0.011), and RV stroke work was 72 ± 5% of baseline versus 90 ± 5% of baseline, (P = 0.027), in vehicle-treated versus MDL-28170-treated pigs, respectively. MDL-28170 reduced the incidence of hemodynamic instability (death or systolic blood pressure of < 85 mm Hg) by 46% (P = 0.013). RV pressure overload disrupted talin organization. MDL-28170 preserved talin abundance in the RV free wall (P = 0.039), and talin abundance correlated with the maintenance of RV free wall stroke work (r = 0.58, P = 0.0039). α-actinin and vinculin showed similar changes according to immunohistology. Right heart failure from acute RV pressure overload is associated with reduced talin abundance and disrupted talin organization. Calpain inhibition preserves the abundance and organization of talin and RV function. Calpain inhibition may offer clinical utility in treating acute cor pulmonale.

ROSIGLITAZONE ALTERS CHARACTERISTICS OF ISCHEMIC VENTRICULAR FIBRILLATION IN PIGS

Background: Despite favorable metabolic effects of anti-diabetic thiazolidinedione drugs (TZDs), it is uncertain if TZDs reduce cardiovascular mortality. We previously showed that TZDs exert an off-target effect to block cardiac ATP-sensitive potassium (KATP) channels and may increase propensity for ischemic ventricular fibrillation (VF) in pigs. In this study, we tested the hypothesis that a TZD drug, rosiglitazone (ROSI), alters spectral characteristics of ischemic VF through effects on KATP channels.