Bruno K. Podesser

Apoptosis in heart failure and the senescent heart

The progressive loss of cardiac myocytes by apoptotic cell death has been discussed as an important pathogenic component in the failing myocardium as well in the aging heart. The degree to which apoptosis contributes to myocyte loss in these conditions, however, is a controversial issue. This review focuses on the regulation of apoptosis, evidence implicating apoptosis as a mechanism for the progression and development of heart failure, the role of apoptotic death in senescent cardiac dysfunction, as well as on the problems of detection of apoptosis.

Epicardial branches of the coronary arteries and their distribution in the rabbit heart: The rabbit heart as a model of regional ischemia

The rabbit heart has been frequently used to study regional ischemia, but there is hardly any detailed information on the epicardial branching of the coronary arteries. Therefore, we wanted to determine whether there is a constant branching pattern and how comparable this pattern is with the human heart.

Nifedipine reduces the incidence of myocardial infarction and transient ischemia in patients undergoing coronary bypass grafting.

A randomized study was performed on 104 patients undergoing elective coronary artery bypass grafting to examine whether the infusion of nifedipine (n = 53) reduces the incidence of perioperative myocardial ischemia and necrosis in the early postoperative period. Continuous hemodynamic and three-channel Holter monitoring was performed for 24 hours and serial assessment of serum enzymes and 12-lead electrocardiography were performed for 36 hours postoperatively. Nifedipine (minimum dose, 10 micrograms/kg/hr for 24 hours) was applied from the onset of extracorporal circulation. The control group (n = 51) received nitroglycerin (minimum dose, 1 micrograms/kg/min for 24 hours). Using the combined analyses of electrocardiography and Holter recordings, myocardial ischemia was defined as being either a transient ischemic event (TIE), transient coronary spasm (TCS), or myocardial infarction (MI). The two groups did not differ with respect to preoperative New York Heart Association classification, age, history of myocardial infarction, extracorporal circulation and aortic cross-clamp time, number of distal anastomoses, or systemic and pulmonary hemodynamics. The incidence of perioperative myocardial ischemia was substantially lower in the nifedipine than in the nitroglycerin group [TIE: three of 53 patients (6%) versus nine of 50 patients (18%), p less than 0.001; MI: two of 53 patients (4%) versus six of 50 patients (12%), p less than 0.001; and TCS: none of 53 patients (0%) versus two of 50 patients (4%), p = NS].(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous and intramyocardial injection of apoptotic white blood cell suspensions prevents ventricular remodelling by increasing elastin expression in cardiac scar tissue after myocardial infarction

Congestive heart failure developing after acute myocardial infarction (AMI) is a major cause of morbidity and mortality. Clinical trials of cell-based therapy after AMI evidenced only a moderate benefit. We could show previously that suspensions of apoptotic peripheral blood mononuclear cells (PBMC) are able to reduce myocardial damage in a rat model of AMI. Here we experimentally examined the biochemical mechanisms involved in preventing ventricular remodelling and preserving cardiac function after AMI. Cell suspensions of apoptotic cells were injected intravenously or intramyocardially after experimental AMI induced by coronary artery ligation in rats. Administration of cell culture medium or viable PBMC served as controls. Immunohistological analysis was performed to analyse the cellular infiltrate in the ischaemic myocardium. Cardiac function was quantified by echocardiography. Planimetry of the infarcted hearts showed a significant reduction of infarction size and an improvement of post AMI remodelling in rats treated with suspensions of apoptotic PBMC (injected either intravenously or intramoycardially). Moreover, these hearts evidenced enhanced homing of macrophages and cells staining positive for c-kit, FLK-1, IGF-I and FGF-2 as compared to controls. A major finding in this study further was that the ratio of elastic and collagenous fibres within the scar tissue was altered in a favourable fashion in rats injected with apoptotic cells. Intravenous or intramyocardial injection of apoptotic cell suspensions results in attenuation of myocardial remodelling after experimental AMI, preserves left ventricular function, increases homing of regenerative cells and alters the composition of cardiac scar tissue. The higher expression of elastic fibres provides passive energy to the cardiac scar tissue and results in prevention of ventricular remodelling.

The continuing evolution of the Langendorff and ejecting murine heart: new advances in cardiac phenotyping

The isolated retrograde-perfused Langendorff heart and the isolated ejecting heart have, over many decades, resulted in fundamental discoveries that form the underpinnings of our current understanding of the biology and physiology of the heart. These two experimental methodologies have proven invaluable in studying pharmacological effects on myocardial function, metabolism, and vascular reactivity and in the investigation of clinically relevant disease states such as ischemia-reperfusion injury, diabetes, obesity, and heart failure. With the advent of the genomics era, the isolated mouse heart preparation has gained prominence as an ex vivo research tool for investigators studying the impact of gene modification in the intact heart. This review summarizes the historical development of the isolated heart and provides a practical guide for the establishment of the Langendorff and ejecting heart preparations with a particular emphasis on the murine heart. In addition, current applications and novel methods of recording cardiovascular parameters in the isolated heart preparation will be discussed. With continued advances in methodological recordings, the isolated mouse heart preparation will remain physiologically relevant for the foreseeable future, serving as an integral bridge between in vitro assays and in vivo approaches.

Comparison of perioperative myocardial protection with nifedipine versus nifedipine and metoprolol in patients undergoing elective coronary artery bypass grafting

A randomized study was performed on 70 patients undergoing elective coronary bypass grafting to examine whether the combined infusion of the calcium channel blocker nifedipine (10 micrograms/kg per hour) and the beta 1-blocker metopropol (12 micrograms/kg per hour, n = 34) reduces the prevalence of perioperative myocardial ischemia and arrhythmias. The control group received nifedipine alone (n = 36). In both groups the infusion was started from the onset of extracorporal circulation and maintained over a period of 24 hours. Repeated 12-lead electrocardiographic and 3-channel Holter monitor recordings for 48 hours were used to define perioperative myocardial ischemia (transient ischemic event, myocardial infarction) and arrhythmias (sinus tachycardia, supraventricular tachycardia, atrial flutter/fibrillation, ventricular tachycardia). Hemodynamic parameters were repeatedly assessed for 24 hours and serum enzyme levels (creatine kinase, MB isoenzyme of creatine kinase) for up to 36 hours after the operation. The two groups did not differ significantly with respect to preoperative anamnestic and surgical data. No signs of perioperative myocardial infarction were detected in either group. However, a significantly lower incidence of transient ischemic episodes was observed in the nifedipine-metoprolol group than in the nifedipine group (3% vs 11%; p < 0.05). In addition, there was a tendency toward lower creatine kinase MB levels and peak values of creatine kinase and creatine kinase MB in the nifedipine-metoprolol group. With regard to perioperative arrhythmias, there was a significantly lower incidence of sinus tachycardia and atrial flutter/fibrillation in the nifedipine-metoprolol group (9% and 6%) than in the nifedipine group (33% and 27%, p < 0.05). In addition, postoperative heart rate was lower in the nifedipine-metoprolol group starting from the sixth hour after release of the aortic crossclamp (p < 0.05 and p < 0.01, respectively). No other hemodynamic parameters showed significant differences between the two groups and all returned to preoperative levels within 24 hours. In conclusion, perioperative application of nifedipine and metoprolol in patients undergoing elective coronary bypass grafting reduces the prevalence of perioperative myocardial ischemia and arrhythmias without significant negative inotropic effects. The combined infusion of the two drugs appears superior to nifedipine alone in preventing perioperative myocardial ischemia and reducing reperfusion-induced arrhythmias.

Irradiated cultured apoptotic peripheral blood mononuclear cells regenerate infarcted myocardium

Background  Acute myocardial infarction (AMI) is followed by post AMI cardiac remodelling, often leading to congestive heart failure. Homing of c‐kit+ endothelial progenitor cells (EPC) has been thought to be the optimal source for regenerating infarcted myocardium.

The erythrocyte-perfused “working heart” model: Hemodynamic and metabolic performance in comparison to crystalloid perfused hearts

A brief period of ischemia was used to evaluate an erythrocyte-enriched Krebs-Henseleit (KH) buffer (n=8) compared to KH only (n=8) in an isolated working rabbit heart. Experimental protocol was as follows: preischemic baseline, 5 min of global ischemia followed by 45 min of reperfusion. Preischemic heart rate was identical, coronary flow was significantly lower (2.7 versus 5.6 mL/min/g wet wt, p<0.01), the other hemodynamic and biochemical values were significantly higher in erythrocyte-perfused hearts: aortic flow 23.5 versus 12.0, p<0.01; cardiac output 26.2 versus 17.6, p<0.01; all in mL/min/g wet wt; dp/dt max 1286 versus 997 mmHg/s, p<0.01; myocardial oxygen consumption 3.5 versus 2.3 micromol/min/g wet wt, p<0.05. During early reperfusion, in the erythrocyte-perfused hearts, coronary flow further increased (p<0.003), the other hemodynamic parameters returned to baseline values in both groups. High-energy phosphates showed significantly higher values (ATP 2.0+/-0.1 versus 1.3+/-0.1, p<0.05; CrP 2.0+/-0.2 versus 1.6+/-0.1, p<0.05 all in micromol/g wct wt), water content was significantly lower (81% versus 74%, p<0.05) in erythrocyte-perfused hearts. It can be concluded that the erythrocyte-perfused working heart model provides excellent oxygenation, leading to superior hemodynamic and metabolic performance. Additionally, in the erythrocyte-perfused hearts preservation of coronary flow reserve underlines the physiological competency of this preparation.

Hemodynamic Changes during Prolonged Laparoscopic Surgery

7 healthy pigs, anesthetized with ketamine/azaperon/thiopentone and ventilated with O2/N2O by volume control, underwent anterior resection of the descending colon by laparoscopic view. During operation of pneumoperitoneum by inflating CO2 to an abdominal pressure of 14 mm Hg was installed. Immediately (+2 min) after the onset of insufflation, both systemic and pulmonary arterial pressure increased. However, pulmonary artery pressure started to decrease after 10 min, whereas systemic arterial pressure remained elevated until the end of the experimental protocol. Left ventricular (LV) pressure and LV dp/dt increased in parallel with the systemic arterial pressure. Peak inspiratory pressure and central venous pressure increased in parallel with the abdominal pressure. Blood gas analysis of arterial and pulmonary blood demonstrated increased pCO2 associated with mild acidosis. Arterial pO2 did not change significantly indicating that the decreased pulmonary distensibility did not endanger the oxygenation. Pulmonary pO2 and pulmonary O2 saturation increased early (+10 min) after start of insufflation and were stable during the 2 h of observation indicating either increased cardiac output or decreased O2 extraction. We conclude that the sharp initial rise of both arterial pressures could be the effect of a mechanical action, whereas sustained hemodynamic alterations would involve complex regulatory mechanisms like an increase of sympathetic activity, baroreceptor control, or a response to acidosis. The acute and, in the systemic circulation, stable increase of ventricular afterload should be considered in patients with underlying cardiac diseases such as ischemic heart disease or valvular dysfunction or in patients taking drugs which interfere with normal compensatory processes.

The anti-angiogenic factor PEDF is present in the human heart and is regulated by anoxia in cardiac myocytes and fibroblasts

Cardiac diseases such as myocardial infarction and heart failure are among the leading causes of death in western societies. Therapeutic angiogenesis has been suggested as a concept to combat these diseases. The biology of angiogenic factors expressed in the heart such as vascular endothelial growth factor (VEGF) is well studied, whereas data on anti‐angiogenic mediators in the heart are scarce. Here we study the expression of the anti‐angiogenic factor pigment epithelium‐derived factor (PEDF) in the human heart and in human cardiac cells. PEDF expression could be detected in human cardiac tissue on the protein and mRNA levels. PEDF mRNA levels were significantly lower in explanted human ischemic hearts as compared to healthy hearts. Our in vitro experiments showed that human adult cardiac myocytes and fibroblasts constitutively secrete PEDF. In addition to anoxic conditions, cobalt chloride, 2,2′dipyridyl and dimethoxally glycine, which stabilize hypoxia inducible factor‐α decreased PEDF expression. Furthermore we show that PEDF inhibits VEGF‐induced sprouting. We have identified PEDF in healthy and ischemic human hearts and we show that PEDF expression is down‐regulated by low oxygen levels. Therefore, we suggest a role for PEDF in the regulation of angiogenesis in the heart and propose PEDF as a possible therapeutic target in heart disease.