Metformin prevents ischaemic ventricular fibrillation in metabolically normal pigs.

AIMS/HYPOTHESIS: Metformin is the drug most often used to treat type 2 diabetes. Evidence suggests that metformin may reduce mortality of individuals with type 2 diabetes, but the mechanism of such an effect is unknown and outcomes of metformin treatment in people without diabetes have not been determined. If metformin favourably affected mortality of non-diabetic individuals, it might have even broader therapeutic utility. We evaluated the effect of metformin on myocardial energetics and ischaemic ventricular fibrillation (VF) in metabolically normal pigs. METHODS: Domestic farm pigs were treated with metformin (30 mg kg-1 day-1 orally for 2-3 weeks; n = 36) or received no treatment (n = 37). Under anaesthesia, pigs underwent up to 90 min low-flow regional myocardial ischaemia followed by 45 min of reperfusion. Pigs were monitored for arrhythmia, monophasic action potential morphology, haemodynamics and myocardial substrate utilisation, AMP-activated protein kinase (AMPK) phosphorylation activity and ATP concentration. RESULTS: Death due to VF occurred in 12% of pigs treated with metformin compared with 50% of untreated controls (p = 0.03). The anti-fibrillatory effect of metformin was associated with attenuation of action potential shortening in ischaemic myocardium (p = 0.02) and attenuation of the difference in action potential duration between ischaemic and non-ischaemic regions (p < 0.001) compared with untreated controls. Metformin had no effect on myocardial contractile function, oxygen consumption, or glucose or lactate utilisation. During ischaemia, however, metformin treatment amplified the activation of AMPK and preserved ATP concentration in myocardium compared with untreated controls (each p < 0.05). CONCLUSIONS/INTERPRETATION: Chronic treatment of metabolically normal pigs with metformin at a clinically relevant dose reduces mortality from ischaemic VF. This protection is associated with preservation of myocardial energetics during ischaemia. Maintenance of myocardial ATP concentration during ischaemia is likely to prevent action potential shortening, heterogeneity of repolarisation, and propensity for lethal arrhythmia. The findings suggest that metformin might be protective in non-diabetic individuals with coronary heart disease.

Arterial insulin resistance in Yucatan micropigs with diet-induced obesity and metabolic syndrome.

AIM: Metabolic syndrome affects a large proportion of the population and increases cardiovascular disease risk. Because metabolic syndrome often co-exists clinically with atherosclerosis, it is difficult to distinguish the respective contributions of the components to vascular abnormalities. Accordingly, we utilized a porcine dietary model of metabolic syndrome without atherosclerosis to investigate early abnormalities of vascular function and signaling. METHODS: Thirty-two Yucatan micropigs were fed either a high-fat, high-simple-sugar, high-calorie (HFHS) or standard chow diet (STD) for 6 months. Neither diet contained added cholesterol. Blood pressure and flow-mediated vasodilatation were assessed at baseline and 6 months. Aortas were harvested at 6 months to assess histology, insulin signaling, and endothelial nitric oxide (eNOS) phosphorylation. RESULTS: HFHS pigs developed characteristics of metabolic syndrome including obesity, dyslipidemia, and insulin resistance, but without histologic evidence of atherosclerosis. Although arterial intima-media thickness did not differ between groups, vascular dysfunction in HFHS was manifest by increased blood pressure and impaired flow-mediated vasodilation of the femoral artery. Compared with STD, aortas from HFHS exhibited increased p85α expression and Ser307 IRS-1 phosphorylation, and blunted insulin-stimulated IRS-1-associated phosphatidylinositol (PI) 3-kinase activity. In the absence of insulin stimulation, aortic Akt Ser473-phosphorylation was greater in HFHS than in STD. With insulin stimulation, Akt phosphorylation increased in STD, but not HFHS. Insulin-induced Ser1177-phosphorylation of eNOS was decreased in HFHS, compared with STD. CONCLUSIONS: Pigs with metabolic syndrome develop early vascular dysfunction and aortic insulin signaling abnormalities, and could be a useful model for early human vascular abnormalities in this condition.

Impaired contractile recovery after low-flow myocardial ischemia in a porcine model of metabolic syndrome.

Clinical metabolic syndrome conveys a poor prognosis in patients with acute coronary syndrome, not fully accounted for by the extent of coronary atherosclerosis. To explain this observation, we determined whether postischemic myocardial contractile and metabolic function are impaired in a porcine dietary model of metabolic syndrome without atherosclerosis. Micropigs (n = 28) were assigned to a control diet (low fat, no added sugars) or an intervention diet (high saturated fat and simple sugars, no added cholesterol) for 7 mo. The intervention diet produced obesity, hypertension, dyslipidemia, and impaired glucose tolerance, but not atherosclerosis. Under open-chest, anesthetized conditions, pigs underwent 45 min of low-flow myocardial ischemia and 120 min of reperfusion. In both diet groups, contractile function was similar at baseline and declined similarly during ischemia. However, after 120 min of reperfusion, regional work recovered to 21 ± 12% of baseline in metabolic syndrome pigs compared with 61 ± 13% in control pigs (P = 0.01). Ischemia-reperfusion caused a progressive decline in mechanical/metabolic efficiency (regional work/O2 consumption) in metabolic syndrome hearts, but not in control hearts. Metabolic syndrome hearts demonstrated altered fatty acyl composition of cardiolipin and increased Akt phosphorylation in both ischemic and nonischemic regions, suggesting tonic activation. Metabolic syndrome hearts used more fatty acid than control hearts (P = 0.03). When fatty acid availability was restricted by prior insulin exposure, differences between groups in postischemic contractile recovery and mechanical/metabolic efficiency were eliminated. In conclusion, pigs with characteristics of metabolic syndrome demonstrate impaired contractile and metabolic recovery after low-flow myocardial ischemia. Contributory mechanisms may include remodeling of cardiolipin, abnormal activation of Akt, and excessive utilization of fatty acid substrates.

Right heart failure in the intensive care unit.

PURPOSE OF REVIEW: This review summarizes the approach to and recent developments in the evaluation and treatment of acute right heart failure in the ICU. Right heart failure, defined as failure of the right ventricle to provide sufficient blood flow through the pulmonary circulation at normal central venous pressure, is a common problem caused by a combination of increased right-ventricular afterload and right-ventricular contractile dysfunction. RECENT FINDINGS: Management of acute right heart failure continues to be challenging because of insufficient understanding of its pathophysiology, a lack of guidelines, and few available tools. Recent research has contributed to an improved understanding of its mechanisms, helping to guide therapy and suggest future options. Right-ventricular assist devices are emerging as a promising approach to treatment when optimization of hemodynamics and conventional medical therapy fail. SUMMARY: Right heart failure causes venous congestion and systemic hypoperfusion. Once right heart failure is identified, the primary goal is to alleviate any reversible cause of excessive load or right-ventricular contractile failure. When the underlying abnormalities cannot be alleviated, trials of diuretic, vasodilator, or inotropic therapy may be required. Invasive monitoring helps guide therapy. Medically refractory right heart failure may potentially be treated with right-ventricular assist devices.

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 clinician's perspective and highlights several ongoing clinical trials that may help to clarify the therapeutic role of PPAR-γ activators in cardiovascular disease.

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.

Thiazolidinedione drugs promote onset, alter characteristics, and increase mortality of ischemic ventricular fibrillation in pigs.

PURPOSE: Despite favorable metabolic and vascular effects, thiazolidinedione (TZD) drugs have not convincingly reduced cardiovascular mortality in clinical trials, raising the possibility of countervailing, off-target effects. We previously showed that TZDs block cardiac ATP-sensitive potassium (K(ATP)) channels in pigs. In this study, we investigated whether TZDs affect onset, spectral characteristics, and mortality of ischemic ventricular fibrillation (VF) and whether such effects are recapitulated by a non-selective K(ATP) blocker (glyburide) or a mitochondrial K(ATP) blocker (5-hydroxydecanoate). METHODS: A total of 121 anesthetized pigs were pre-treated with TZD (pioglitazone or rosiglitazone, 1 mg/kg IV, resulting in clinically relevant plasma concentrations), glyburide (1 mg/kg IV), 5-hydroxydecanoate (5 mg/kg IV) or inert vehicle. Ischemia was produced by occlusion of the left anterior descending coronary artery. In a subset of pigs treated with rosiglitazone or vehicle, ischemic preconditioning was performed. RESULTS: VF developed in all but 6 pigs. In non-preconditioned pigs, onset of VF occurred sooner with pioglitazone (11±3 min, p<0.05) or rosiglitazone (14±3 min, p=0.06) than with vehicle (20±2 min). Defibrillation of VF was successful in 44% of pigs treated with vehicle, compared with 0% with pioglitazone (p=0.057) and 33% with rosiglitazone (NS). After ischemic preconditioning, defibrillation was successful in 62% of pigs treated with vehicle, compared with 26% treated with rosiglitazone (p=0.03). TZDs attenuated slowing of conduction due to ischemia and shifted ECG power spectra during VF toward higher frequencies. All effects of TZDs were recapitulated by glyburide, but not by 5-hydroxydecanoate, supporting an interaction of TZDs with the sarcolemmal K(ATP) channel. CONCLUSION: In a porcine model, TZDs promote onset and increase mortality of ischemic VF, associated with alterations of conduction and VF spectral characteristics. Similar effects in a clinical setting might adversely impact cardiovascular mortality.

Evaluation of right ventricular function.

Right ventricular (RV) function is a powerful prognostic factor in congestive heart failure and pulmonary hypertension, but assessing RV function is a challenge because of the right ventricle's complex geometry, its extreme sensitivity to loading conditions, and a limited understanding of underlying mechanisms of right heart failure. At present, a single widely accepted and generally applicable index of RV function is not available. Current approaches to assessment of RV function include physical examination, catheterization, conventional contrast and radionuclide angiography, nuclear perfusion scintigraphy, cardiac CT, MRI, echocardiography, and positron emission tomography. This review will discuss assessment of RV function in the context of RV physiology.

The right ventricle and pulmonary circulation: basic concepts.

The primary purpose of the right ventricle and pulmonary circulation is gas exchange. Because gas exchange occurs in thin, highly permeable alveolar membranes, pulmonary pressure must remain low to avoid pulmonary edema; because the right ventricle and the lungs are in series with the left ventricle and the systemic circulation, the entire cardiac output must pass through the lungs. This low pressure, high volume system, makes dramatically different demands on the right ventricle compared with the demands made on the left ventricle by the systemic circulation. Moreover, the right ventricle and pulmonary circulation must buffer dynamic changes in blood volume and flow resulting from respiration, positional changes, and changes in left ventricular cardiac output. The optimizations needed to meet these conflicting demands result in reduced capacity to compensate for increased afterload or pressure. Unfortunately, a large number of pathologic processes can result in acute and or chronic increases in afterload stress. As afterload stress rises, right heart failure may develop, and hemodynamic instability and death can occur abruptly. Several biochemical pathways have been identified that may participate in adaptation or maladaptation to excessive pressure loads.

Ventrículo derecho y circulación pulmonar: conceptos básicos / The right ventricle and pulmonary circulation: basic concepts

La función principal del ventrículo derecho y de la circulación pulmonar es el intercambio de gases. Dado que el intercambio de gases se produce en membranas alveolares finas y altamente permeables, la presión pulmonar debe mantenerse baja para evitar el edema pulmonar, debido a que el ventrículo derecho y los pulmones están en serie con el ventrículo izquierdo y la circulación sistémica, y todo el gasto cardiaco debe pasar a través de los pulmones. Este sistema de baja presión y volumen alto somete al ventrículo derecho a exigencias completamente distintas de las que la circulación sistémica implica para el ventrículo izquierdo. Además, el ventrículo derecho y la circulación pulmonar deben amortiguar los cambios dinámicos en el volumen y el flujo sanguíneo resultantes de la respiración, los cambios posicionales y los cambios en el gasto cardiaco del ventrículo izquierdo. Las adaptaciones necesarias para satisfacer estas exigencias contrapuestas tienen como consecuencia una capacidad de compensación reducida frente a un aumento de poscarga o presión. Desgraciadamente, un elevado número de procesos patológicos pueden tener como consecuencia aumentos agudos o crónicos en la poscarga. A medida que aumenta tal exceso de poscarga, puede aparecer insuficiencia cardiaca derecha y pueden sobrevenir repentinamente inestabilidad hemodinámica y muerte. Se han identificado varias vías bioquímicas que pueden participar en la adaptación apropiada o inadecuada a las sobrecargas de presión (AU)

The primary purpose of the right ventricle and pulmonary circulation is gas exchange. Because gas exchange occurs in thin, highly permeable alveolar membranes, pulmonary pressure must remain low to avoid pulmonary edema; because the right ventricle and the lungs are in series with the left ventricle and the systemic circulation, the entire cardiac output must pass through the lungs. This low pressure, high volume system, makes dramatically different demands on the right ventricle compared with the demands made on the left ventricle by the systemic circulation. Moreover, the right ventricle and pulmonary circulation must buffer dynamic changes in blood volume and flow resulting from respiration, positional changes, and changes in left ventricular cardiac output. The optimizations needed to meet these conflicting demands result in reduced capacity to compensate for increased afterload or pressure. Unfortunately, a large number of pathologic processes can result in acute and or chronic increases in afterload stress. As afterload stress rises, right heart failure may develop, and hemodynamic instability and death can occur abruptly. Several biochemical pathways have been identified that may participate in adaptation or maladaptation to excessive pressure loads (AU)

Pathophysiology of right ventricular failure.

Right ventricular failure may be defined as the inability of the right ventricle of the heart to provide adequate blood flow through the pulmonary circulation at a normal central venous pressure. Critical care specialists encounter right ventricular failure routinely in their practice, but until recently right ventricular failure as a primary clinical entity received scant consideration. Indeed, there is still not a single published practice guideline focused on right ventricular failure. Right ventricular failure is usually due to a combination of right ventricular pressure overload and contractile abnormalities of the right ventricular free wall. Decompensation may occur abruptly and catastrophically because of unique aspects of right ventricular physiology. This review will focus on the pathophysiology of acute right ventricular failure in the critical care setting and summarize the limited management options available.

Calpain inhibition attenuates right ventricular contractile dysfunction after acute pressure overload.

Right ventricular contractile failure from acute RV pressure overload is an important cause of morbidity and mortality, but the mechanism of RV failure in this setting is incompletely defined. We hypothesized that RV dysfunction from acute RV pressure overload is, in part, due to activation of calpain, and that calpain inhibition would therefore attenuate RV dysfunction. Anesthetized, open chest pigs were treated with the calpain inhibitor MDL-28170 or with inactive vehicle, and then subjected to acute RV pressure overload for 90 min. RV contractile function was assessed by the regional Frank-Starling relation. RV myocardial tissue was analyzed for evidence of calpain activation and calpain-mediated proteolysis. RV pressure overload caused severe contractile dysfunction, along with significant alterations in the endogenous calpain inhibitor calpastatin typical of calpain activation. MDL-28170 attenuated RV free wall dysfunction by more than 50%. However, there were no differences in degradation of spectrin, desmin, troponin-I or SERCA2 between SHAM operated pigs and pigs subjected to acute RV pressure overload, or between vehicle and MDL-28170 treated pigs. Acute RV pressure overload causes calpain activation, and RV contractile dysfunction from acute RV pressure overload is attenuated by the calpain inhibitor MDL-28170; however, the effect is not explained by inhibition of calpain-mediated degradation of spectrin, desmin, troponin-I or SERCA2. Because this is the first report of any agent that can directly attenuate RV contractile dysfunction in acute RV pressure overload, further investigation of the mechanism of action of MDL-28170 in this setting is warranted.