Salvatore Pepe

Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure.

The technique of representational difference analysis of cDNA has been applied to screen for differentially expressed genes in a canine model of pacing-induced heart failure. We identified the canine homolog of the cardiac ankyrin repeat protein (CARP) which has been shown to be involved in the regulation of the transcription of cardiac genes. To confirm the significance for human heart failure, cardiac tissue specimens obtained from non-failing donor hearts and from explanted hearts from patients with end-stage heart failure were investigated. CARP mRNA and protein levels were markedly increased in failing left ventricles. Interestingly, alterations in CARP expression were restricted to ventricular tissue and were not observed in atria. Fractionation experiments revealed that CARP was expressed predominantly in the nuclei consistent with the proposed function of CARP as a modulator of transcription. Together, these findings raise the possibility that augmented ventricular CARP expression may play a role in the pathogenesis of human heart failure.

Mitochondrial Function In Ischaemia And Reperfusion Of The Ageing Heart

1. In addition to Ca2+‐dependent mediation of excitation– contraction coupling during cardiac work and ATP hydrolysis, Ca2+ also stimulates the Krebs’ cycle and mitochondrial matrix dehydrogenases to maintain the nicotinamide adenine dinucleotide redox potential and ATP synthesis. Thus, the balance between energy demand and supply is maintained during increases in cardiac work by elevated cytosolic Ca2+ that is transmitted to the mitochondrial matrix via regulation of uniporter and antiporter pathways across the inner mitochondrial membrane.

The effects of ageing on the response to cardiac surgery: protective strategies for the ageing myocardium.

Abstractyounger muscle. 4)Oral CoQ10 therapy before cardiac surgery improves efficiency of mitochondrial energy production, improves post-operative heart function, reduces intra-operative myocardial damage and shortens hospital stay.

Uridine preserves ATP during hypoxic perfusion of the rat heart

Abstract Background: The pyrimidine precursor, orotic acid, by minimising ischaemia-induced ATP loss, improves the functional performance of recently infarcted hearts that have been subjected to global ischaemia. However, we have also previously shown that orotic acid is not directly active in the heart but is preferentially taken up by the liver where it is metabolised to uridine. Aim: To investigate whether uridine itself can minimise hypoxia-induced ATP loss. Methods: Isolated Langendorff-mode perfused rat hearts were subjected to 4 protocols after 20 min normoxic stabilisation: normoxia for 30 min (n=12); hypoxia for 30 min (n=12); hypoxia in the presence of 17μM uridine for 30 min (n=12); and [U- 14 C]-uridine added directly to the hypoxic perfusate reservoir just prior to 30 min hypoxia (n=4). [U- 14 C]-uridine was used to assess the contribution of radiolabel to adenosine formation from adenine nucleotide hydrolysis. Coronary effluent was collected and hearts were freeze-clamped for metabolite assay. Results: Hypoxia reduced ATP, from 21.1±1.1 to 4.1±0.6 μmol/g dry weight (p Conclusion: In the present experimental model, uridine protects the hypoxic heart by predominantly enhancing glycolytic energy production.

Protective role of Coenzyme Q10 in two models of rat lung injury

Background:u2002 Ischaemia‐reperfusion injury is a life‐threatening complication of lung transplantation. Attempts to ameliorate this injury have included optimization of donor management and improving techniques of lung preservation. However, few investigators have sought to pretreat potential recipients. Coenzyme Q10 (CoQ10) is a potent antioxidant and cellular energizer that has been shown to protect the heart against injury. However, its protective effect in the lung is unknown. We therefore set out to study the impact of Coenzyme Q10 pretreatment in a model of mild and severe lung injury.

The Principles of Metabolic Therapy for Heart Disease

Metabolic therapy involves the administration of a substance normally found in the body to enhance a metabolic reaction within the cell. This may be achieved in two ways. First, for some systems, a substance can be given to achieve greater than normal levels in the body so as to drive an enzymic reaction in a preferred direction. Second, metabolic therapy may be used to correct an absolute or relative deficiency of a cellular component. Thus, metabolic therapy differs greatly from most standard cardiovascular pharmacologic therapy such as the use of ACE Inhibitors b-blockers, statins and calcium channel antagonists that are given to block rather than enhance cellular processes. In this review we highlight some metabolic substances that have potential benefit in treating heart disease or improving outcomes after cardiovascular interventions. Glucose-insulin-potassium therapy is protective against myocardial ischaemia by elevating myocardial glycogen levels. Coenzyme Q(10) is a lipid-soluble antioxidant that plays a crucial role in cellular ATP production. Magnesium orotate, a key intermediate in the biosynthetic pathway of glycogen, has been shown to improve the energy status of the cell and improve recovery from cardioplegic arrest. The amino acid aspartate plays an important role in providing energy substrates for oxidative phosphorylation in the myocyte. By improving cellular energy production, metabolic therapy has the potential to benefit cardiac function during the stress of cardiac surgery, myocardial infarction and cardiac failure.

Myocardial calcium control using a Na+/H+ exchange inhibitor vs low calcium in cardioplegic solutions

Background: Ca++ overload plays an important role in the pathogenesis of ischaemia/reperfusion injury. The standard technique to control Ca++ overload has been to reduce ionised calcium in the cardioplegic solutions (CP). Recent reports suggest that Na+/H+ exchange inhibitors can also prevent Ca++ overload. We set out to compare 3 crystalloid cardioplegic solutions (CP) which might minimise Ca++ overload in comparison with standard cardioplegia: 1) low Ca++ CP; 2) citrate CP (to reduce ionised Ca++); 3) addition of the Na+/H+ exchange inhibitor HOE642 (HOE). Methods: Isolated working rat hearts perfused with oxygenated KrebsHenseleit buffer were subjected to 60 min of cardioplegic arrest and reperfusion. Aortic flow (AF) was measured before and after ischaemia. Myocardial high energy phosphates were measured after reperfusion. Results: Low Ca++ CP (0.25mM Ca++) significantly improved recovery of postischaemic function in comparison with standard CP (1 .OmM Ca++); (%AF: 47.6k1.7 vs 58.3*2.5%, ~~0.05). Citrate CP significantly impaired postischaemic function (%AF: without citrate vs citrate, 58.3k2.5 vs 22.4+6.2%, ~~0.05). Addition of HOE (1 PM) to CP significantly improved postischaemic function (without HOE vs with HOE, 47.6&l .7 vs 62.4+1.7%, ~~0.05). Cardiac high-energy phosphate levels after arrest and reperfusion were significantly reduced by citrate CP. Conclusions: Lowering Ca++ in CP is beneficial. The use of citrate to chelate Ca++ is detrimental in the crystalloid perfused rat heart. HOE in CP is just as efficacious in preserving the myocardium as is directly reducing Ca++.