Michael F. Allard

Atrioventricular block after transcatheter balloon expandable aortic valve implantation.

OBJECTIVES Transcatheter aortic valve replacement (AVR) is a promising approach to aortic valve disease. The implications of this new therapy are not entirely known. We describe the potential for the development of new atrioventricular (AV) block. BACKGROUND Atrioventricular block is a known complication of conventional surgical AVR. Block is presumed to occur as a consequence of surgical trauma to the cardiac conduction tissue during excision of the diseased aortic valve and débridement of the calcified annulus. Whether AV block might occur as a consequence of nonsurgical implantation of an aortic stent valve is unknown. METHODS We reviewed our experience with patients undergoing transcatheter AVR using both the percutaneous transarterial and the open-chest direct left ventricular apical ventriculotomy approaches. Patients were considered at high risk for conventional surgery because of comorbidities. Continuous arrhythmia monitoring was performed for at least 48 h after the valve implantation procedure. Patients who developed apparently new, clinically significant AV block were identified. RESULTS Transcatheter AVR was successfully performed in 123 patients. Seventeen of these patients (13.8%) had pre-existing permanent pacemakers. Two patients (1.6%) required pacemaker implantation because of pre-existing intermittent bradycardia. Seven patients (5.7%) developed new and sustained complete AV block requiring pacemaker implantation. An additional 4 patients (3.3%) developed new and sustained left bundle branch block but did not require pacemaker implantation. CONCLUSIONS As with conventional AVR surgery, transcatheter AVR may result in impaired atrioventricular conduction. Physicians and patients should be aware of the potential for AV block and pacemaker dependence.

Energy Metabolism in the Hypertrophied Heart

In response to a prolonged pressure- or volume-overload, alterations occur in myocardial fatty acid, glucose, and glycogen metabolism. Oxidation of long chain fatty acids has been found to be reduced in hypertrophied hearts compared to non-hypertrophied hearts. However, this observation depends upon the degree of cardiac hypertrophy, the severity of carnitine deficiency, the concentration of fatty acid in blood or perfusate, and the myocardial workload. Glycolysis of exogenous glucose is accelerated in hypertrophied hearts. Despite the acceleration of glycolysis, glucose oxidation is not correspondingly increased leading to lower coupling between glycolysis and glucose oxidation and greater H+ production than in non-hypertrophied hearts. Although glycogen metabolism does not differ in the absence of ischemia, synthesis and degradation of glycogen are accelerated in severely ischemic hypertrophied hearts. These alterations in carbohydrate metabolism may contribute to the increased susceptibility of hypertrophied hearts to injury during ischemia and reperfusion by causing disturbances in ion homeostasis that reduce contractile function and efficiency to a greater extent than normal. As in non-hypertrophied hearts, pharmacologic enhancement of coupling between glycolysis and glucose oxidation (e.g., by directly stimulating glucose oxidation) improves recovery of function of hypertrophied hearts after ischemia. This observation provides strong support for the concept that modulation of energy metabolism in the hypertrophied heart is a useful approach to improve function of the hypertrophied heart during ischemia and reperfusion. Future investigations are necessary to determine if alternative approaches, such as glucose-insulin-potassium infusion and inhibitors of fatty acid oxidation (e.g., ranolazine, trimetazidine), also produce beneficial effects in ischemic and reperfused hypertrophied hearts.

Actions of insulin on the mammalian heart: metabolism, pathology and biochemical mechanisms

Time for primary review 23 days. Skeletal muscle, adipose tissue and liver are the quantitatively major targets for insulin action in vivo and regulation of critical steps in intermediary metabolism within these tissues account for many of the impacts of insulin on metabolic homeostasis. Many other tissues including the heart express insulin receptors and their functions may be importantly regulated by insulin. In this review we summarize the evidence that the heart is an important target of insulin action and that abrogation of these actions is important in disease states. Current understanding of the molecular basis of insulin actions on its target cells is drawn from a large literature emanating from studies of the major target tissues and also from a wide range of other cell types including studies of appropriately transfected and immortalized cell lines [1–4]. We introduce the basic concepts of the molecular basis of insulin actions, not to reiterate the extensive reviews recently published but rather to highlight aspects which are distinctive or which are poorly-defined in the heart. Our understanding of the biochemical mechanisms by which insulin exerts its effects in the heart are still substantially dependent upon extrapolation from studies of other cell types. It is important to recognize where such extrapolations may require qualification; we therefore focus particularly on the specific features of the myocardium which may lead to a distinct perspective of insulin action in this tissue. The actions of any individual external signal must be viewed in the context of a complex set of signals to which cells are exposed in vivo. Three issues are introduced (undoubtedly many more might deserve comment) to illustrate the importance of considering the basis against which we must attempt to judge the actions of insulin in the heart: (i) the constant pumping function of the … * Corresponding author. Tel.: +1 (604) 822-3810; Fax: +1 (604) 822-5227; e-mail: rogerb@unixg.ubc.ca

Metabolic actions of metformin in the heart can occur by AMPK-independent mechanisms

The metabolic actions of the antidiabetic agent metformin reportedly occur via the activation of the AMP-activated protein kinase (AMPK) in the heart and other tissues in the presence or absence of changes in cellular energy status. In this study, we tested the hypothesis that metformin has AMPK-independent effects on metabolism in heart muscle. Fatty acid oxidation and glucose utilization (glycolysis and glucose uptake) were measured in isolated working hearts from halothane-anesthetized male Sprague-Dawley rats and in cultured heart-derived H9c2 cells in the absence or in the presence of metformin (2 mM). Fatty acid oxidation and glucose utilization were significantly altered by metformin in hearts and H9c2 cells. AMPK activity was not measurably altered by metformin in either model system, and no impairment of energetic state was observed in the intact hearts. Furthermore, the inhibition of AMPK by 6-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-pyridin-4-yl-pyyrazolo[1,5-a] pyrimidine (Compound C), a well-recognized pharmacological inhibitor of AMPK, or the overexpression of a dominant-negative form of AMPK failed to prevent the metabolic actions of metformin in H9c2 cells. The exposure of H9c2 cells to inhibitors of p38 mitogen-activated protein kinase (p38 MAPK) or protein kinase C (PKC) partially or completely abrogated metformin-induced alterations in metabolism in these cells, respectively. Thus the metabolic actions of metformin in the heart muscle can occur independent of changes in AMPK activity and may be mediated by p38 MAPK- and PKC-dependent mechanisms.

Dichloroacetate improves postischemic function of hypertrophied rat hearts

OBJECTIVES We sought to determine whether improving coupling between glucose oxidation and glycolysis by stimulating glucose oxidation during reperfusion enhances postischemic recovery of hypertrophied hearts. BACKGROUND Low rates of glucose oxidation and high glycolytic rates are associated with greater postischemic dysfunction of hypertrophied as compared with nonhypertrophied hearts. METHODS Heart function, glycolysis and glucose oxidation were measured in isolated working control and hypertrophied rat hearts for 30 min before 20 min of global, no-flow ischemia and during 60 min of reperfusion. Selected control and hypertrophied hearts received 1.0 mmol/liter dichloroacetate (DCA), an activator of pyruvate dehydrogenase, at the time of reperfusion to stimulate glucose oxidation. RESULTS In the absence of DCA, glycolysis was higher and glucose oxidation and recovery of function were lower in hypertrophied hearts than in control hearts during reperfusion. Dichloroacetate stimulated glucose oxidation during reperfusion approximately twofold in both groups, while significantly reducing glycolysis in hypertrophied hearts. It also improved function of both hypertrophied and control hearts. In the presence of DCA, recovery of function of hypertrophied hearts was comparable to or better than that of untreated control hearts. CONCLUSIONS Dichloroacetate, given at the time of reperfusion, normalizes postischemic function of hypertrophied rat hearts and improves coupling between glucose oxidation and glycolysis by increasing glucose oxidation and decreasing glycolysis. These findings support the hypothesis that low glucose oxidation rates and high glycolytic rates contribute to the exaggerated postischemic dysfunction of hypertrophied hearts.

Eosinophilic myocarditis: case series and review of literature.

Although the etiology of eosinophilic myocarditis (EM) is not always apparent, several causes are identified, including hypersensitivity to a drug or substance, with the heart as the target organ. However, symptoms and signs of hypersensitivity are not found in all patients. EM can lead to progressive myocardial damage with destruction of the conduction system and refractory heart failure. The present report describes three cases of biopsy-proven EM with different presentations, including acute coronary syndrome, cardiogenic shock and newly diagnosed heart failure. In one patient, hypersensitivity to sumatriptan was suspected to be the underlying cause. All patients responded well to treatment with steroids, angiotensin-converting enzyme inhibitors and beta-blockers. There was a complete recovery of the ventricular function in all cases.

Glycogen Metabolism in the Aerobic Hypertrophied Rat Heart

BACKGROUND Rates of glycolysis from exogenous glucose are accelerated in hypertrophied hearts. In this study, we determined whether alterations in the metabolism of glycogen, an endogenous storage form of glucose, also occur in hypertrophied hearts. METHODS AND RESULTS Rates of glycolysis ([3H]H2O production) and oxidation ([14C]CO2 production) from exogenous glucose and glycogen were measured in isolated working hearts from control and aortic-banded rats. Hearts in which glycogen was prelabeled with [5-(3)H]- or [U-(14)C]glucose were perfused with buffer containing 11 mmol/L [5-(3)H]- or [U-(14)C]glucose (different from the isotope used to prelabel glycogen), 0.4 mmol/L palmitate, 0.5 mmol/L lactate, and 100 microU/mL insulin. Rates of glycolysis from exogenous glucose were greater (3471+/-114 versus 2665+/-194 nmol glucose x min(-1) x g dry wt(-1), P<.05, n=4 to 6, mean+/-SEM) and rates of exogenous glucose oxidation (445+/-36 versus 619+/-16 nmol glucose x min(-1) x g dry wt(-1), P<.05, n=4 to 6) were lower in hypertrophied hearts than in control hearts. Rates of glycolysis and oxidation from glycogen were not different between hypertrophied and control hearts. A greater proportion of glycogen was oxidized (80% to 100%) than the proportion of exogenous glucose oxidized (13% to 24%) in both groups. Additionally, 10.5+/-1.4 and 12.3+/-1.0 micromol/g dry wt of glycogen was synthesized in hypertrophied and control hearts, respectively, indicating that simultaneous synthesis and degradation (ie, glycogen turnover) occurred in both groups. CONCLUSIONS Thus, aerobic myocardial glycogen metabolism in the hypertrophied heart is similar to that observed in the normal heart even though exogenous glucose metabolism is altered in the hypertrophied heart.

Pyruvate dehydrogenase and the regulation of glucose oxidation in hypertrophied rat hearts.

OBJECTIVE Coupling of glucose oxidation to glycolysis is lower in hypertrophied than in non-hypertrophied hearts, contributing to the compromised mechanical performance of hypertrophied hearts. Here, we describe studies to test the hypothesis that low coupling of glucose oxidation to glycolysis in hypertrophied hearts is due to reduced activity and/or expression of the pyruvate dehydrogenase complex (PDC). METHODS We examined the effects of dichloroacetate (DCA), an inhibitor of PDC kinase, and of alterations in exogenous palmitate supply on coupling of glucose oxidation to glycolysis in isolated working hypertrophied and control hearts from aortic-constricted and sham-operated male Sprague-Dawley rats. It was anticipated that the addition of DCA or the absence of palmitate would promote PDC activation and consequently normalize coupling between glycolysis and glucose oxidation in hypertrophied hearts if our hypothesis was correct. RESULTS Addition of DCA or removal of palmitate improved coupling of glucose oxidation to glycolysis in control and hypertrophied hearts. However, coupling remained substantially lower in hypertrophied hearts. PDC activity in extracts of hypertrophied hearts was similar to or higher than in extracts of control hearts under all perfusion conditions. No differences were observed between hypertrophied and control hearts with respect to expression of PDC, PDC kinase, or PDC phosphatase. CONCLUSIONS Low coupling of glucose oxidation to glycolysis in hypertrophied hearts is not due to a reduction in PDC activity or subunit expression indicating that other mechanism(s) are responsible.

Mitral valve injury late after transcatheter aortic valve implantation

CLINICAL SUMMARY An 88-year-old man with symptomatic severe aortic stenosis underwent percutaneous TAVI with a 26-mm SAPIEN valve (Edwards Lifesciences LLC, Irvine, Calif). Comorbid conditions included coronary artery bypass with patent retrosternal grafts, transient ischemic attacks, bilateral carotid endarterectomies, atrial fibrillation, repaired abdominal aneurysm, prostate cancer, and renal failure. Estimated 30day mortality for AVR was 35% by means of logistic EuroSCORE and 11.1% by means of the Society of Thoracic Surgeons National Database Risk Calculator. The procedure was performed without difficulty, but the final valve position was suboptimal, being slightly low (ventricularly), with the ventricular aspect of the stent abutting the anterior leaflet of the mitral valve (MV). Moderate paravalvular aortic regurgitation (AR) was treated with repeated balloon redilation without altering the valve position. Six-month transthoracic echocardiographic analysis showed trivial AR and mitral regurgitation. The patient presented 11 months after implantation with fever and Streptococcus angiosus in blood cultures. Also noted were a dental visit 6 weeks before and lack of compliance with endocarditis prophylaxis. Transesophageal echocardiographic analysis demonstrated mild-to-moderate paravalvular AR, a 13 3 8–mm ruptured anterior mitral leaflet aneurysm contiguous with the aortic prosthesis, and severe mitral regurgitation (Figure 1). Redo sternotomy was performed during cardiopulmonary bypass after cannulating the right axillary artery and right internal jugular vein. The bioprosthesis was well-seated below the coronary arteries with incomplete endothelialization of the uppermost struts and covered with nodular excrescences (Figure 2). It withstood extraction while fully expanded but was removable when grasped with forceps, which were

Metoprolol improves cardiac function and modulates cardiac metabolism in the streptozotocin-diabetic rat

The effects of diabetes on heart function may be initiated or compounded by the exaggerated reliance of the diabetic heart on fatty acids and ketones as metabolic fuels. beta-Blocking agents such as metoprolol have been proposed to inhibit fatty acid oxidation. We hypothesized that metoprolol would improve cardiac function by inhibiting fatty acid oxidation and promoting a compensatory increase in glucose utilization. We measured ex vivo cardiac function and substrate utilization after chronic metoprolol treatment and acute metoprolol perfusion. Chronic metoprolol treatment attenuated the development of cardiac dysfunction in streptozotocin (STZ)-diabetic rats. After chronic treatment with metoprolol, palmitate oxidation was increased in control hearts but decreased in diabetic hearts without affecting myocardial energetics. Acute treatment with metoprolol during heart perfusions led to reduced rates of palmitate oxidation, stimulation of glucose oxidation, and increased tissue ATP levels. Metoprolol lowered malonyl-CoA levels in control hearts only, but no changes in acetyl-CoA carboxylase phosphorylation or AMP-activated protein kinase activity were observed. Both acute metoprolol perfusion and chronic in vivo metoprolol treatment led to decreased maximum activity and decreased sensitivity of carnitine palmitoyltransferase I to malonyl-CoA. Metoprolol also increased sarco(endo)plasmic reticulum Ca(2+)-ATPase expression and prevented the reexpression of atrial natriuretic peptide in diabetic hearts. These data demonstrate that metoprolol ameliorates diabetic cardiomyopathy and inhibits fatty acid oxidation in streptozotocin-induced diabetes. Since malonyl-CoA levels are not increased, the reduction in total carnitine palmitoyltransferase I activity is the most likely factor to explain the decrease in fatty acid oxidation. The metabolism changes occur in parallel with changes in gene expression.