Decline In Left Ventricular Function Research Articles

The α-MSH analogue AP214 attenuates rise in pulmonary pressure and fall in ejection fraction in lipopolysaccharide-induced systemic inflammatory response syndrome in pigs

The effect of an α-melanocyte stimulating hormone (α-MSH) analogue (AP214) on experimentally endotoxin-induced systemic inflammatory response syndrome (SIRS) was studied, because α-MSH in rodent models has shown promise in attenuating inflammatory response markers and associated organ damage in SIRS. SIRS is associated with considerable morbidity and mortality. Consequently, new treatment modalities are still warranted to address the different aspects of the pathophysiological process. SIRS was induced by lipopolysaccharide (LPS) (Escherichia coli endotoxin) infusion in anaesthetized Danish Landrace pigs (20-25 kg). The pigs received an α-MSH analogue (AP214) or saline as a bolus at the initiation of the LPS infusion. The hemodynamic response was registered as well as echocardiographic indices of left ventricular function. The cardiovascular response was recorded together with echocardiographic indices of left ventricular function in control and in intervention animals. AP214 reduced the early peak in pulmonary pressure and pulmonary vascular resistance by approximately 33%. Furthermore, AP214 prevented the decline in left ventricular fractional shortening as observed in the control group. Mean change and standard deviation in fractional shortening (ΔFS) in control group: - 7·3 (4·7), AP214 (low dose): 0·9 (8·2) and AP214 (high dose) 4·1 (6·0), P < 0·05 for both intervention groups versus control. In the porcine model, the peak increase in pulmonary pressure was attenuated, and the LPS-induced decline in left ventricular function was prevented.

Exercise & Sports Science Australia Position Statement on exercise training and chronic heart failure

Chronic heart failure (CHF) is a complex syndrome characterised by progressive decline in left ventricular function, low exercise tolerance and raised mortality and morbidity. Regular exercise participation has been shown to be a safe and effective treatment modality in the majority of CHF patients, partially reversing some of the maladaptations evident in myocardial and skeletal muscle function, and resulting in improvements in physical fitness and quality of life, and perhaps reduced mortality. The volume and intensity of exercise that is recommended depends on the syndrome severity, however in most patients it should consist of a combination of low-to-moderate intensity aerobic (endurance) exercise on most days of the week and individually prescribed low-to-moderate intensity resistance (strength) training at least twice per week. Additionally, all patients should be closely monitored prior to and during exercise for contraindications by an appropriately trained health professional. The purpose of this statement is to inform and guide exercise practitioners and health professionals in the safe and effective prescription and supervision of exercise for patients with CHF.

Attenuation of doxorubicin-induced cardiac injury by mitochondrial glutaredoxin 2

While the cardiotoxicity of doxorubicin (DOX) is known to be partly mediated through the generation of reactive oxygen species (ROS), the biochemical mechanisms by which ROS damage cardiomyocytes remain to be determined. This study investigates whether S-glutathionylation of mitochondrial proteins plays a role in DOX-induced myocardial injury using a line of transgenic mice expressing the human mitochondrial glutaredoxin 2 (Glrx2), a thiotransferase catalyzing the reduction as well as formation of protein–glutathione mixed disulfides, in cardiomyocytes. The total glutaredoxin (Glrx) activity was increased by 76% and 53 fold in homogenates of whole heart and isolated heart mitochondria of Glrx2 transgenic mice, respectively, compared to those of nontransgenic mice. The expression of other antioxidant enzymes, with the exception of glutaredoxin 1, was unaltered. Overexpression of Glrx2 completely prevents DOX-induced decreases in NAD- and FAD-linked state 3 respiration and respiratory control ratio (RCR) in heart mitochondria at days 1 and 5 of treatment. The extent of DOX-induced decline in left ventricular function and release of creatine kinase into circulation at day 5 of treatment was also greatly attenuated in Glrx2 transgenic mice. Further studies revealed that heart mitochondria overexpressing Glrx2 released less cytochrome c than did controls in response to treatment with tBid or a peptide encompassing the BH3 domain of Bid. Development of tolerance to DOX toxicity in transgenic mice is also associated with an increase in protein S-glutathionylation in heart mitochondria. Taken together, these results imply that S-glutathionylation of heart mitochondrial proteins plays a role in preventing DOX-induced cardiac injury.

Myocardial microcirculatory dysfunction after prolonged ventricular fibrillation and resuscitation

The etiology of postresuscitation myocardial stunning is unknown but is thought to be related to either ischemia occurring during cardiac arrest and resuscitation efforts and/or reperfusion injury after restoration of circulation. A potential common pathway for postischemia/reperfusion end-organ dysfunction is microvascular injury. We hypothesized that myocardial microcirculatory function is markedly abnormal in the postresuscitation period. In vivo study of myocardial microvascular function. University animal laboratory. Five swine (25 +/- 2 kg). Measurements before and after cardiac arrest and resuscitation. Baseline data were not different among the five subjects. Left ventricular ejection fraction was significantly lower at all postresuscitation time periods (p < .05), reaching a nadir of 19% at 1 hr postresuscitation. Cardiac output declined following fibrillation and resuscitation and was significantly lower than baseline at 1 and 4 hrs postresuscitation (p < .05). Prearrest coronary flow reserve, a ratio of normal to maximal intracoronary flow velocity, was 3.4 ("normal" ratio is 2:4), but was below normal (<2) throughout the 4-hr post resuscitation period (p < .05). This in vivo study showed that normal myocardial microcirculatory function is quickly lost after prolonged ventricular fibrillation and resuscitation. As early as 30 min postresuscitation the myocardial microcirculatory function is less than 50% of its prearrest baseline level. This dysfunction persists for at least 4 hrs. During the postresuscitation period, both left ventricular ejection fraction and cardiac output decline from their prearrest levels. No cause and effect relationship was proven, but a parallel decline in left ventricular function and coronary flow reserve is evident.

Cardiotoxic drugs: clinical monitoring and decision making

Through a variety of mechanisms, the heart is a target of injury for many drugs, both medically prescribed and not. Drugs with potential cardiac toxicity are particularly prominent in cancer...

Magnetic resonance imaging measurement of left ventricular blood flow and coronary flow reserve in patients with chronic heart failure due to coronary artery disease

Coronary sinus flow reflects global cardiac perfusion and has been used for the assessment of myocardial flow reserve, which is reduced in chronic heart failure(CHF). Coronary flow reserve (CFR) can be measured by using phase-contrast (PC)velocity-encoded cine (VEC) magnetic resonance imaging (MRI). To quantify and compare global left ventricular (LV) perfusion and CFR inpatients with CHF and in a healthy control group by measuring coronary sinus flow with PC VEC MRI, and to correlate this with global LV perfusion, segmental first-pass perfusion, and viability in the same patients. Cardiac MRI was performed in 20 patients with CHF of ischemic origin and in a control group of healthy subjects (n=11) at rest and after pharmacological stress induced by i.v. dipyridamole. The MRI protocol included cine MRI, VEC MRI, first-pass perfusion, and delayed contrast-enhanced MRI for viability.Global LV perfusion was quantified by measuring coronary sinus flow on VEC MRI at rest in all subjects. CFR was determined as the ratio of global LV perfusion before and after pharmacologic stress. At rest, global LV perfusion was not significantly different in patients with CHF and the control group. After administration of dipyridamole, global LV perfusion and CFR were significantly lower in patients with CHF compared to the control group(P<0.001). An inverse correlation was observed between CFR and the number of infarcted and/or ischemic segments (P=0.083, P=0.037). A combined cardiac MRI protocol including function and perfusion techniques together with VEC MRI can be used to evaluate global LV perfusion and CFR in patients with CHF. Global LV perfusion and CFR measurements may have potential in the monitoring of CHF. Impaired CFR may contribute to progressive decline in LV function in patients with CHF.

Mid-term echocardiographic follow up of left ventricular function with permanent right ventricular pacing in pediatric patients with and without structural heart disease

BackgroundChronic right ventricular apical pacing may have detrimental effect on left ventricular function and may promote to heart failure in adult patients with left ventricular dysfunction.MethodsA group of 99 pediatric patients with previously implanted pacemaker was studied retrospectively. Forty-three patients (21 males) had isolated congenital complete or advanced atrioventricular block. The remaining 56 patients (34 males) had pacing indication in the presence of structural heart disease. Thirty-two of them (21 males) had isolated structural heart disease and the remaining 24 (13 males) had complex congenital heart disease. Patients were followed up for an average of 53 ± 41.4 months with 12-lead electrocardiogram and transthoracic echocardiography. Left ventricular shortening fraction was used as a marker of ventricular function. QRS duration was assessed using leads V5 or II on standard 12-lead electrocardiogram.ResultsLeft ventricular shortening fraction did not change significantly after pacemaker implantation compared to preimplant values overall and in subgroups. In patients with complex congenital heart malformations shortening fraction decreased significantly during the follow up period. (0.45 ± 0.07 vs 0.35 ± 0.06, p = 0.015). The correlation between the change in left ventricular shortening fraction and the mean increase of paced QRS duration was not significant. Six patients developed dilated cardiomyopathy, which was diagnosed 2 months to 9 years after pacemaker implantation.ConclusionChronic right ventricular pacing in pediatric patients with or without structural heart disease does not necessarily result in decline of left ventricular function. In patients with complex congenital heart malformations left ventricular shortening fraction shows significant decrease.

Intramyocardial injection of skeletal myoblasts: long-term follow-up with pressure–volume loops

The human heart has a limited capacity for self-repair because, unlike most other cells, cardiomyocytes do not regenerate. Therefore, if a substantial number of myocytes is lost after a myocardial infarction, the performance of the heart may become severely limited, leading to a condition of heart failure. Recently, cell transplantation has emerged as a potential therapy for patients with end-stage heart failure. Of the various cell types being investigated for this purpose, skeletal myoblasts are an attractive option, because they are readily available from muscle biopsies and, if autologous cells are used, immunosuppression is not required and ethical issues are avoided. Several studies have shown that the cells can survive and differentiate after transplantation, and promising clinical results have been reported. However, effects of this therapy on left ventricular function remain largely unknown. In the present study, we investigated the long-term hemodynamic effects of intramyocardial injection of autologous skeletal myoblasts in patients with ischemic heart failure. Our findings indicate hemodynamic improvement after follow-up for up to 1 year, which is especially promising in view of the expected decline in left ventricular function in these patients.

Mitoxantrone and Melphalan Conditioning Regimen for Autologous Peripheral Blood Stem Cell Transplantation in Adults with Acute Myelogenous Leukemia.

High dose mitoxantrone and melphalan (Mito/Mel) has been reported as an effective and well tolerated conditioning regimen for autologous peripheral blood stem cell transplantation (APBSCT) in patients with lymphoma. We review our experience with Mito/Mel as a conditioning regimen in 18 adults with intermediate or high risk acute myelogenous leukemia (AML) who underwent APBSCT. Median age at time of APBSCT was 51 years (range 19–70). Sixteen patients were transplanted in first complete remission (CR); two in second CR. All patients received mitoxantrone 60mg/m2 IV on day −4 and melphalan 180mg/m2 IV on day −1 followed by infusion of autologous peripheral blood stem cells on day 0. The 100 day survival was 94%. One patient died in CR of suspected pulmonary embolism 3 months post transplant. With a median follow-up of 24 months, 10 patients are alive. The median disease free and overall survival is 40 months and 47 months, respectively. All 18 patients received anthracycline based induction therapy prior to APBSCT. Cardiac toxicity was monitored by echocardiogram. A significant decline in left ventricular function developed in only one patient who had underlying diabetes and hypertension. We conclude that high dose mitoxantrone and melphalan is an easily administered conditioning regimen with a low risk of significant cardiac toxicity despite prior treatment with anthracycline based chemotherapy. This regimen when used for APBSCT in adults with AML results in favorable disease free and overall survival.

Metabolic therapy for the diabetic patients with ischaemic heart disease

Diabetic patients with ischaemic heart disease have a greater amount of myocardial ischaemia, often silent, and an increased incidence of heart failure compared to nondiabetic patients. This is the result of altered myocardial metabolism and accelerated atherogenesis with involvement of peripheral coronary segments causing chronic hypoperfusion and diffuse hybernation. In patients with diabetes mellitus and myocardial ischaemia, the metabolic changes occurring as a consequence of the mismatch between blood supply and cardiac metabolic requirements are heightened by the diabetic metabolic changes. An important metabolic alteration of diabetes is the increase in free fatty acid concentrations and increased muscular and myocardial free fatty acid uptake and oxidation. This increased uptake and utilization of free fatty acid during stress and ischaemia is responsible for the increased susceptibility of the diabetic heart to myocardial ischaemia and to a greater decrease of myocardial performance for a given amount of ischaemia compared to nondiabetic hearts. Given the metabolic alterations of the diabetic heart at rest and during episodes of myocardial ischaemia, a therapeutic approach aimed at an improvement of cardiac metabolism through manipulations of the utilization of metabolic substrates should result in an improvement of myocardial ischaemia and of left ventricular function. Modulation of myocardial free fatty acid metabolism should be the key target for metabolic interventions in patients with coronary artery disease with and without diabetes. In diabetic patients, the effects of modulation of free fatty acid metabolism should be even greater than those observed in patients without diabetes. The inhibition of FFA oxidation with trimetazidine improves cardiac metabolism at rest, decreases cardiac ischaemia and therefore prevents the decline of left ventricular function due to chronic hypoperfusion and repetitive episodes of myocardial ischaemia. Because of its effect on cardiac metabolism at rest, its effects on myocardial ischaemia and left ventricular function trimetazidine should always be considered for the treatment of diabetic patients with ischaemic heart disease with or without left ventricular dysfunction.

Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy

Growing evidence suggests that thyroid dysfunction may contribute to progression of cardiac disease to heart failure. We investigated the effects of a therapeutic dose of thyroid hormones (TH) on cardiomyopathic (CM) hamsters from 4 to 6 mo of age. CM hamsters had subclinical hypothyroidism (normal thyroxine, elevated TSH). Left ventricular (LV) function was determined by echocardiography and hemodynamics. Whole tissue pathology and isolated myocyte size and number were assessed. TH treatment prevented the decline in heart rate and rate of LV pressure increase and improved LV ejection fraction. The percentage of fibrosis/necrosis in untreated 4-mo-old CM (4CM; 15.5 +/- 2.2%) and 6-mo-old CM (6CM; 21.5 +/- 2.4%) hamsters was pronounced and was reversed in treated CM (TCM; 11.9 +/- 0.9%) hamsters. Total ventricular myocyte number was the same between 4- and 6-mo-old controls but was reduced by 30% in 4CM and 43% in 6CM hamsters. TH treatment completely prevented further loss of myocytes in TCM hamsters. Compared with age-matched controls, resting and maximum coronary blood flow was impaired in 4CM and 6CM hamsters. Blood flow was completely normalized by TH treatment. We conclude that TH treatment of CM hamsters with subclinical hypothyroidism normalized impaired coronary blood flow, which prevented the decline in LV function and loss of myocytes.

Evolution of left ventricular function in pediatric patients with permanent right ventricular pacing with and without structural heart disease

Background Chronic right ventricular (RV) pacing may have detrimental effect on left ventricular (LV) function and may promote to heart failure in adults. The effect of chronic RV pacing on left ventricular performance is not well studied in a pediatric population. Aim The aim of this retrospective study was to assess the evolution of LV function in a pediatric pacemaker population with and without structural heart disease (HD). Methods and Results 98 pediatric patients (59 males) were studied retrospectively. 42 patients had pacemaker indication without structural heart disease. 25 out of the remaining 56 patients had isolated and the others complex congenital malformation. Patients were distributed in six age groups (group I: <1 yr, group II: 1-2 yrs, group III: 3-4 yrs, group IV: 5-7 yrs, group V: 8-11 yrs, group 6: 12-15 yrs) and were followed up for an average of 58.69±45.23 months (ranging: 3-188.5 months) with ECG and transthoracic echocardiography. LV fractional shortening (FS) was used as a marker of LV function. LV FS did not change statistically in the age groups (group I: 0.43± 0.09, group 6: 0.39±0.08 ;p=NS). When the progression of LV FS was assessed in the subgroups according to the presence or absence of structural HD, there could be only tendencies observed (isolated: group I: 0.51±0.06, group 6 0.31±0.09, p=NS; complex: group I: 0.42±0.06, group 5: 0.33±0.06, p=NS). Conclusion Chronic RV pacing in pediatric patients with and without structural HD does not necessarily results in decline of LV function.

Issue Highlights

HomeCirculationVol. 111, No. 2Issue Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIssue Highlights Originally published18 Jan 2005https://doi.org/10.1161/circ.111.2.119Circulation. 2005;111:119CLINICAL PROGRESSION OF INCIDENTAL, ASYMPTOMATIC LESIONS DISCOVERED DURING CULPRIT VESSEL CORONARY INTERVENTION, by Glaser et al.“To intervene or not to intervene” remains one of the outstanding questions for the interventional cardiologist when incidental nontarget lesions are identified during coronary angiography. Recent advances in vascular biology have contributed to our understanding of the vulnerable plaque and suggest that early intervention of these lesions may improve long-term outcomes. Furthermore, in the drug-eluting stent era, restenosis rates have declined to the single digits, and data now exist to demonstrate that these results remain durable over several years. In this issue of Circulation, Glaser et al provide the final piece of the puzzle: Data from the National Heart, Lung and Blood Institute Dynamic Registry are used to determine how many patients annually have progression of nontarget lesions resulting in clinical events. See p 143.MESENCHYMAL STEM CELLS DIFFERENTIATE INTO AN ENDOTHELIAL PHENOTYPE, ENHANCE VASCULAR DENSITY, AND IMPROVE HEART FUNCTION IN A CANINE CHRONIC ISCHEMIA MODEL, by Silva et al.Bone marrow–derived stem cells have been carefully studied for use as potential regenerative therapy for myocardial infarction. Cell populations generally have been heterogeneous, and most studies have been performed in the setting of acute myocardial infarction or in the early post–myocardial infarction phase. In this issue, Silva and colleagues advance the field by isolating mesenchymal stem cells for intramyocardial injection, and use a canine model of chronic ischemia, representing hibernation and chronic ischemic cardiomyopathy. They report that the cell therapy reversed the progressive decline in left ventricular function at rest and during stress, and that the cells differentiated into smooth muscle cells and endothelial cells rather than myocytes, resulting in increased vascularity. These data advance our understanding of the fate of injected stem cells and extend the potential therapeutic indications to the chronic ischemic state. See p 150.CARDIOVASCULAR MAGNETIC RESONANCE IN CARDIAC AMYLOIDOSIS, by Maceira et al.Detection of cardiac involvement in amyloidosis can be a vexing clinical challenge and often relies on combinations of signs from ECG and echocardiography or on invasive myocardial biopsy. In this issue, Maceira and colleagues report on the use of cardiovascular magnetic resonance to define patterns of gadolinium enhancement and gadolinum kinetics in patients with cardiac amyloidosis. They report that diffuse subendocardial enhancement is commonly seen. Moreover, relaxation times were distinct in amyloid patients compared with those with nonamyloid hypertrophy, and were correlated with markers of amyloid burden. These data set the stage for wider investigations of cardiovascular magnetic resonance in populations with suspected amyloid heart disease, as well as serial follow-up of disease burden and potential response to therapy. See p 186.Visit www.circ.ahajournals.org:Cardiology Patient PageRed Wine and Your Heart. See p e10.Images in Cardiovascular MedicineSingular Coronary Artery Aneurysm: Imaging With Coronary Angiography Versus 16-Slice Computed Tomography, Transesophageal Echocardiography, and Magnetic Resonance Tomography. See p e12.False Aneurysm of the Ascending Aorta Caused by a Sternal Wire. See p e14. Download figureDownload PowerPointCorrespondenceSee p e15. Previous Back to top Next FiguresReferencesRelatedDetails January 18, 2005Vol 111, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.111.2.119 Originally publishedJanuary 18, 2005 PDF download Advertisement

Heart failure and sudden death in patients with tachycardia-induced cardiomyopathy and recurrent tachycardia.

Tachycardia-induced cardiomyopathy is a reversible cause of heart failure. We hypothesized that although left ventricular ejection fraction measurements normalize after heart rate or rhythm control in patients with tachycardia-induced cardiomyopathy, recurrent tachycardia may have abrupt and deleterious consequences. Patients with tachycardia-induced cardiomyopathy that developed over years were evaluated and treated. Tachycardia episodes and outcomes were assessed. Twenty-four patients were identified. All had NYHA functional class III heart failure or greater on presentation. One third were heart transplant candidates. There were 17 men and 7 women with a mean age of 46+/-16 years and mean left ventricular ejection fraction of 0.26+/-0.09 at the index visit. The cause was atrial fibrillation (n=13), atrial flutter (n=4), atrial tachycardia (n=3), idiopathic ventricular tachycardia (n=1), permanent junctional reciprocating tachycardia (n=2), and bigeminal ventricular premature contractions (n=1). Within 6 months of rate control or correction of the rhythm, left ventricular ejection fraction improved or normalized and symptoms abated in all. Five patients had tachycardia recur. In these patients, left ventricular ejection fraction dropped precipitously and heart failure ensued within 6 months, even though the initial impairment took years. Rate control eliminated heart failure and improved or normalized ejection fraction in 6 months. Three of 24 patients died suddenly and unexpectedly. Tachycardia-induced cardiomyopathy develops slowly and appears reversible by left ventricular ejection fraction improvement, but recurrent tachycardia causes rapid decline in left ventricular function and development of heart failure. Sudden death is possible.

Erythropoietin reduces myocardial infarction and left ventricular functional decline after coronary artery ligation in rats

Erythropoietin (EPO), well known for its role in stimulation of erythropoiesis, has recently been shown to have a dramatic neuroprotective effect in animal models of cerebral ischemia, mechanical trauma of the nervous system, and excitotoxins, mainly by reducing apoptosis. We studied the effect of single systemic administration of recombinant human EPO (rhEPO) on left ventricular (LV) size and function in rats during 8 weeks after the induction of a myocardial infarction (MI) by permanent ligation of the left descending coronary artery. We found that an i.p. injection of 3,000 units/kg of rhEPO immediately after the coronary artery ligation resulted, 24 h later, in a 50% reduction of apoptosis in the myocardial area at risk. Eight weeks after the induction of MI, rats treated with rhEPO had an infarct size 15-25% of the size of that in untreated animals. The reduction in myocardial damage was accompanied by reductions in LV size and functional decline as measured by repeated echocardiography. Thus, a single dose of rhEPO administered around the time of acute, sustained coronary insufficiency merits consideration with respect to its therapeutic potential to limit the extent of resultant MI and contractile dysfunction.

Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy.

Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiomyopathy, progressive decline in left ventricular function, and congestive heart failure. Because the molecular mechanisms involved in apoptosis of cardiocytes are not completely understood, we studied the biochemical and ultrastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hearts from patients undergoing heart transplantation were studied by electron microscopy or immunoblotting to detect release of mitochondrial cytochrome c and activation of caspase-3. The hearts explanted from five victims of motor vehicle accidents or myocardial ventricular tissues from three donor hearts were used as controls. Evidence of apoptosis was observed only in endstage cardiomyopathy. There was significant accumulation of cytochrome c in the cytosol, over myofibrils, and near intercalated discs of cardiomyocytes in failing hearts. The release of mitochondrial cytochrome c was associated with activation of caspase-3 and cleavage of its substrate protein kinase C delta but not poly(ADP-ribose) polymerase. By contrast, there was no apparent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls. The present study provides in vivo evidence of cytochrome c-dependent activation of cysteine proteases in human cardiomyopathy. Activation of proteases supports the phenomenon of apoptosis in myopathic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive heart failure, the present demonstration of an activated apoptotic cascade in cardiomyopathy could provide the basis for novel interventional strategies.

Modulation of coronary perfusion pressure can reverse cardiac dysfunction after brain death

Background. Brain death results in a rapid decline in left ventricular function, which has clinical relevance for organ transplantation. The aim of the present study was to investigate coronary perfusion changes during brain death and their role in cardiac dysfunction. Methods. In an in situ isolated canine heart model, brain death was induced by inflation of a subdural balloon catheter. The heart was perfused separately with the animal’s own blood by a pressure-controlled roller pump that was coupled to the measured aortic pressure. Myocardial contractility was estimated by the slope of the end-systolic pressure–volume relation. Results. Induction of brain death resulted in a transient hyperdynamic response, followed by a significant decrease in systemic vascular resistance, coronary blood flow, and the end-systolic pressure–volume relation ( p < 0.05). However, if coronary perfusion pressure was decoupled from aortic pressure and elevated to pre–brain death levels, coronary blood flow and the end-systolic pressure–volume relation were also restored to baseline levels. Conclusion. Severe impairment of coronary blood flow may contribute to decreased contractility after brain death that can be reversed by modulation of coronary perfusion pressure.

Intracellular calcium dynamics in mouse model of myocardial stunning.

Intracellular calcium (Cai2+) and left ventricular (LV) function were determined in the coronary-perfused mouse heart to study Cai2+-related mechanisms of injury from myocardial ischemia and reperfusion. Specifics for loading of the photoprotein aequorin into isovolumically contracting mouse hearts under constant-flow conditions are provided. The method allows detection of changes in Cai2+ on a beat-to-beat basis in a model of myocardial stunning and permits correlation of interventions that regulate Ca2+ exchange with functional alterations. Twenty-three coronary-perfused mouse hearts were subjected to 15 min of ischemia followed by 20 min of reperfusion. In 13 hearts, the perfusate included the calmodulin antagonist W7 (10 microM) to inhibit Ca(2+)-calmodulin-regulated mechanisms. Peak Cai2+ was 0.77 +/- 0.03 microM in the control group and was unaffected by W7 at baseline. Ischemia was characterized by a rapid decline in LV function, followed by ischemic contracture, accompanied by a gradual rise in Cai2+. Reperfusion was characterized by an initial burst of Cai2+ and a gradual recovery to nearly normal systolic Cai2+ while LV pressure recovered to 55% after 20 min of reperfusion (stunned myocardium). These results in the mouse heart confirm that stunning does not result from deficiency of Cai2+ but rather from a decreased myofilament responsiveness to Cai2+ due to changes in the myofilaments themselves. In hearts perfused with W7, the rise in Cai2+ during ischemia was significantly attenuated, as was the magnitude of mean Cai2+ during early reflow. Ischemic contracture was abolished or delayed. Hearts perfused with W7 showed significantly improved recovery of LV pressure, rate of contraction, and rate of relaxation. Diastolic Cai2+ was increased in control hearts during stunning but returned to baseline in hearts perfused with W7. Simultaneous assessment of Cai2+ and LV function demonstrates that calmodulin-regulated mechanisms may contribute to the pathogenesis of myocardial stunning in the mouse heart.

Apoptosis in heart failure: a tale of heightened expectations, unfulfilled promises and broken hearts em leader.

Although apoptosis contributes significantly to remodeling of the fetal heart during evolution of cardiac chambers and correct routing of the great vessels, it has been believed that apoptosis does not occur in terminally differentiated adult cardiac muscle cells. However, apoptosis has recently been demonstrated in animal models of heart failure as well as in explanted hearts from patients with end-stage heart failure undergoing cardiac transplantation. Ventricular dilatation and neurohormonal activation, the hall-marks of heart failure, lead to upregulation of transcription factors, induce muscle cell hypertrophy and prepare cells for entry into the cell-division cycle. However, since terminally differentiated myocytes cannot divide, they die by apoptosis. It has been proposed that low-grade apoptosis in failing heart may be responsible for inexorable decline in left ventricular function. Better understanding of the molecular and cellular basis of apoptosis in the failing myocardium may lead to development of strategies aimed at preventing progressive myocyte loss and deterioration in left ventricular function.

LOW CHOLESTEROL AND IMPAIRED CARDIAC FUNCTION FOLLOWING HEART TRANSPLANTATION

1. During follow-up of 59 cardiac transplant recipients over 2 or more years, a small group of subjects was observed who displayed an unpredictable, relatively marked, reduction in plasma cholesterol. 2. A significant proportion of these subjects were subsequently observed as having experienced a marked decline in left ventricular function at the time of routine radionuclide ventriculography. 3. While the mechanism for this fall in cholesterol is unclear, the observation of such an unexpected reduction in total cholesterol, late after heart transplantation should be considered significant and prompt further investigation including an assessment of allograft function.