Do gender differences exist in pacemaker implantation?--results of an obligatory external quality control program.

AIMS: The aim of the study was to evaluate the effects of patient gender onto primary pacemaker implantation, evaluating the database of the Institute of Quality Assurance Hessen in the federal state of Hessen, Germany. METHODS AND RESULTS: The database of the obligatory external quality control program for the years 2003-2006 was evaluated retrospectively. In 72 centres, 17 826 patients undergoing stationary primary pacemaker implantation have been registered. Male patients had more AV blocks when compared with women and less sick sinus syndrome and atrial fibrillation with bradycardia. In patients being 80 years and older, men received significantly more dual-chamber devices than women for the indications: AV block and sick sinus syndrome. In women, atrial pacing thresholds were significantly higher and P-wave amplitudes were significantly lower. Women had, independent from age or pacing system implanted, significantly more acute complications than men, with significant differences for pneumothorax and pocket haematoma. CONCLUSION: This large-scale real-life patient cohort of primary stationary pacemaker implantation showed that gender has an impact onto pacemaker implantation, with less favourable outcomes for women.

Do vascular compartments differ in the development of chronic rejection? AT(1) blocker candesartan versus Ace blocker enalapril in an experimental heart transplant model.

BACKGROUND: Accelerated coronary artery disease (ACAD), a serious consequence after heart transplantation, is characterized by diffuse, concentric myointimal proliferation in the arteries. Increasing evidence supports the existence of a local renin-angiotensin system and the role of angiotensin-II in smooth muscle cell proliferation. We investigated the effect of angiotensin-II blocker candesartan and angiotensin-converting enzyme (ACE) inhibitor enalapril on experimental ACAD in a rat model. METHODS: After heterotopic cardiac transplantation (Fisher to Lewis), recipients received 20 mg/kg/day candesartan or 40 mg/kg/day enalapril per os. Two groups of animals received additional pre-treatment with candesartan or enalapril 7 days before transplantation, and treatment was continued after grafting. All study groups including the controls received 3 mg/kg/day of sub-cutaneous cyclosporine for immunosuppression. A syngeneic group (Lewis to Lewis), serving as extra control, did not receive any treatment. Eighty days after grafting, we assessed the extent of ACAD in large and small arteries, using digitizing morphometry and expressed as mean vascular occlusion (MVO). RESULTS: In enalapril and candesartan pre- and post-treated animals, we observed significant reduction of MVO of intramyocardial arteries compared with the cyclosporine group (p < 0.005), to levels similar to the syngeneic transplants. MVO of epicardial arteries in enalapril and candesartan pre- or posttreated animals did not significantly differ from cyclosporine controls (p > 0.05). CONCLUSION: Our results support the hypothesis of 2 proliferative compartments in the development of ACAD, with differing receptor or enzyme distribution: the compartment of small, intramyocardial arteries in which ACAD can be reduced by ACE or AT(1) blockade, and that of large, epicardial arteries in which inhibition fails.

[Epidemiology-etiology of dilated cardiomyopathy]. / Epidemiologie--Atiologie der dilatativen Kardiomyopathie.

Among the cardiomyopathies,--dilated cardiomyopathy (dcm), hypertrophic cardiomyopathy, restrictive cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy--, dcm is the most frequent entity. Its prevalence in the United States amounts to 36 cases per 100,000 inhabitants, men being almost 3-fold more involved than women. The etiology of dcm is very heterogenous; 50% of the cases are due to idiopathic dcm whereas the other half comprises a broad spectrum of various etiologies such as myocarditis, ischemic heart disease, peripartal cardiomyopathy, hypertension, HIV infection, toxic cardiomyopathy and others. In 20 to 30% of the cases of idiopathic dcm a genetic transmission of the disease has been found. Another 20 to 30% of idiopathic dcm are associated with inflammatory and immunological phenomena. Infectious myocarditis with enteroviruses, especially with coxsackie-virus type B has been suggested to be an important trigger for an immune-mediated dcm. In both, familiar dcm and infection with coxsackie-virus B, an impairment of constituents of the myocardial cytoskeleton has been shown. This is regarded as a possible pathogenetic mechanism in the development of dcm.

Extension of generator longevity by use of high impedance ventricular leads.

The resistance of a pacing lead negatively correlates to current consumption. A prospective, randomized trial was conducted to evaluate the effect of a high impedance ventricular lead (CapSure Z) on generator longevity compared to a conventional lead (CapSure SP) eighty-nine patients were included in the study (51 male, 37 female, age 70.0+/-10.3 years). Forty-six patients received a CapSure SP lead (5024 bipolar), and 43 patients received a CapSure Z lead (5034 bipolar) in a randomized fashion. Follow-up data collected at 5 days, 3, 6, and 12 months postimplant included: lead impedance, pacing and sensing thresholds, impulse energy, and estimated time to replacement. All parameters were collected via pacemaker telemetry; the time to replacement was calculated automatically by a programmed algorithm of the pacemaker. There was no difference in the performance of the atrial lead when a dual chamber device was indicated. The CapSure Z leads displayed statistically significant higher impedance values than the CapSure SP lead in all follow-up periods. There was no significant difference in lead related complications. No significant differences were observed between pacing and sensing thresholds in both groups. The CapSure Z leads provided a significant reduction in current drain, resulting in a reduction of mean energy consumption at the 12-month follow-up from 10.4+/-5.0 microJ in the CapSure SP group to 6.6+/-1.4 microJ in the CapSure Z group (median from 9.9 microJ to 6.9 microJ, respectively), providing an estimated increase in mean longevity of more than 1 year from 81.1+/-23.5 months in the CapSure SP group to 94.5+/-13.4 months in the CapSure Z group (median: 76.5 months to 95.0 months, respectively). The use of a high resistance lead for ventricular pacing appears to result in a clinically relevant extension of generator longevity.

Vitamins C and E protect isolated cardiomyocytes against oxidative damage.

There is considerable evidence that oxygen free radicals are involved in reperfusion injury of ischemic myocardium. Epidemiologic studies showed an inverse correlation between plasma levels of alpha-tocopherol (vitamin E) and ascorbic acid (vitamin C) and mortality from ischemic heart disease. The present study examines the influence of both vitamins on the toxic effects of singlet oxygen on isolated rat cardiomyocytes. Freshly isolated cardiomyocytes from adult rats were exposed to singlet oxygen which was generated by photoactivation of the photosensitive dye rose bengal (10(-7) M). This procedure induced irreversible hypercontracture in about 95% of rod-shaped cardiomyocytes within 15 min after onset of photoactivation of rose bengal. Pretreatment with vitamin C (10(-5) to 10(-2) M) or E (10(-6) to 10(-3) M) reduced the number of hypercontracted cells after exposure to singlet oxygen in a concentration-dependent manner. Simultaneous application of both vitamins (vitamin E 10(-6) M plus vitamin C 10(-5) M or vitamin E 10(-5) M plus vitamin C 10(-4) M) revealed a marked overadditive protective effect against oxidative damage as compared with the single application of each vitamin. Our data show that alpha-tocopherol and ascorbic acid exert direct protective actions on isolated cardiomyocytes against oxidative damage and provide an overadditive effect if administered simultaneously.

New approach in the therapy of chronic rejection? ACE- and AT1-blocker reduce the development of chronic rejection after cardiac transplantation in a rat model.

BACKGROUND: Angiotensin II is one of the most potent mitogens of smooth muscle cell proliferation and plays a central role in the development of accelerated coronary artery disease (ACAD), which remains a serious consequence after heart transplantation and limits long-term survival. We investigated the effect of an angiotensin-II blocker, Losartan (angiotensin II Type 1 [AT(1)]-blocker), and an angiotensin-converting enzyme (ACE) inhibitor, Enalapril, on experimental ACAD in a rat cardiac transplant model (Fisher to Lewis). METHODS: After grafting, recipients were treated with 10 mg/kg/day per os Losartan or 40 mg/kg/day per os Enalapril. Two groups of animals received additional pre-treatment with Losartan or Enalapril 7 days before transplantation. All study groups, including the control group, received immunosuppression with cyclosporine (3 mg/kg/day sub-cutaneously). We assessed the extent of ACAD of large and small arteries 80 days after grafting using digitizing morphometry. RESULTS: We observed significant reduction of neointimal proliferation in small arteries in Losartan pre- and post-treated and in Enalapril pre-treated recipients compared with the cyclosporine-treated group (p < 0.05). In epicardial arteries, Enalapril pre- and post-treatment as well as Losartan post-treatment significantly reduced neointimal formation compared with the control group. Reduction of neointima by Enalapril post-treatment in small arteries and Losartan pre-treatment in large arteries trended toward but failed statistical significance. CONCLUSIONS: Our results suggest the important role of the renin-angiotensin system in neointimal proliferation, which can be reduced equally with ACE inhibitors or the angiotensin-II blocker. Therefore AT(1) blockade with Losartan is a useful therapeutic strategy for inhibition of ACAD after cardiac transplantation.

Effects of lovastatin and pravastatin on the survival of hamsters with inherited cardiomyopathy.

Cardiomyopathic hamsters develop heart disease early in life, which leads to congestive heart failure and death as these hamsters age. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to reduce ubiquinone concentrations and to deteriorate myocardial function in humans and in experimental animals. HMG-CoA reductase inhibitors differ regarding their ability to penetrate extrahepatic tissues. As a consequence, lovastatin inhibits cholesterol biosynthesis at least 100-fold more effectively than pravastatin in extrahepatic cells. We examined the effect of lovastatin and pravastatin (approximately 10 mg per kilogram of body weight and per day mixed in the diet) compared with controls on the lifespan of cardiomyopathic hamsters (BIO 8262 strain) in the heart-failure period. In male hamsters, neither lovastatin nor pravastatin significantly affected survival. In female hamsters, lovastatin reduced median survival time from 89 days (control animals) to 30 days (P <.05); pravastatin (median survival, 115 days) had no statistically significant effect. We conclude that lovastatin, but not pravastatin, at a daily dose of 10 mg per kilogram of body weight significantly increases the mortality of cardiomyopathic hamsters. This effect may be the result of inhibition of myocardial ubiquinone supply.

Lipoprotein(a) stimulates growth of human mesangial cells and induces activation of phospholipase C via pertussis toxin-sensitive G proteins.

BACKGROUND: Renal disease is commonly associated with hyperlipidemia and correlates with glomerular accumulation of atherogenic lipoproteins, for example, lipoprotein(a) [Lp(a)], and mesangial hypercellularity. Specific binding of Lp(a) to mesangial cells and induction of c-myc and c-fos expression has been demonstrated. Therefore, in this study, we investigated a possible growth stimulatory effect and mode of action of Lp(a) in human mesangial cells. METHODS: Lp(a) was purified from the regenerate fluid of a dextran sulfate column-based low-density lipoprotein apheresis system. Human mesangial cells were isolated by a sequential sieving technique from patients undergoing tumor nephrectomy. DNA synthesis was measured by [3H]-thymidine incorporation. The intracellular calcium concentration ([Ca2+]i) was determined by Fura 2-fluorescence, and inositol 1,4,5-trisphosphate (1,4,5-IP3) concentration was measured by a radioreceptor assay. RESULTS: The data show that Lp(a) bound to the cells with a Kd of 17.0 micrograms/ml and increased DNA synthesis and cell proliferation. Lp(a) caused a rapid increase in 1,4,5-IP3 and [Ca2+]i via a pertussis toxin-sensitive mechanism. The phospholipase C (PLC) inhibitor U73122 abolished Lp(a)-induced cell proliferation. In contrast, vasopressin-induced increase in 1,4,5-IP3 and [Ca2+]i was pertussis toxin insensitive. CONCLUSION: This study revealed that Lp(a) stimulates growth of human mesangial cells. Lp(a)-induced signaling involves binding to a receptor and stimulation of PLC via Gi proteins. Stimulation of PLC appears to be essential for the growth stimulatory effect of Lp(a). Whether these effects of Lp(a) contribute to the pathophysiology of renal disease needs to be determined.

Extracellular matrix structure after heart transplantation.

Following heart transplantation remodeling of the donor heart causes changes in the extracellular myocardial matrix. We investigated 20 right ventricular endomyocardial biopsies taken 17+/-4 days (group I, n=9) and 63+/-13 days (group II, n=11) after heart transplantation from 16 patients transplanted for end-stage cardiomyopathy (15 dilated/1 ischemic). Immunohistochemical staining for collagen I, collagen III, collagen IV, and fibronectin was used. Evaluation was performed at a magnification of 400x using a computer-assisted image analyzing system measuring the relative area stained by the immunoperoxidase method, the number of cells in the given area, and the total area. Collagen I per cell was 13.9+/-5.9 microm2 in group I and increased significantly 66+/-13 days after heart transplantation in the perimysium around the myocardial cells as well as in the endocardium to 49.9+/-15.1 microm2 (P<0.05). No quantitative change in collagen III was noted (75.7+/-12.4 versus 75.5+/-16.0 microm2 n.s.). Collagen IV was found in the perimysial, in the capillary bed and in the vascular network. Significant quantitative change in the amount of collagen IV was not found (64.1+/-12.6 versus 61.0+/-8.9 microm2). Fibronectin was found in the entire perimysial extracellular matrix and in the endocardium in relationship with collagen I and III. An increased amount of fibronectin from 87.09+/-9.9 microm2 (group I) to 140.8+/-17.9 microm2 (group II, P<0.05) was found. The cell area and cell diameters were not significantly different (group I; cell area 772+/-227 microm2, diameter 31.3 microm; group II; cell area 776+/-224 microm2, diameter 31.4 microm). It is concluded that remodeling of the donor heart after transplantation is characterized by a specific increase in collagen I and fibronectin, whereas a change in other collagen subtypes was not observed.

Glimepiride (Hoe490) inhibits the rilmakalim induced decrease in intracellular free calcium and contraction of isolated heart muscle cells from guinea pigs to a lesser extent than glibenclamide.

Glibenclamide is a potent inhibitor of the ATP-dependent potassium channel. Opening of the ATP-dependent potassium channel is regarded as a mechanism of ischemic preconditioning. This in vitro study examines the influence of glibenclamide and glimepiride, a new sulfonylurea, on the negative inotropic action of the potassium channel opener rilmakalim in isolated ventricular myocytes. Cardiac myocytes were isolated from adult guinea pig hearts by collagenase perfusion and incubated with rilmakalim (concentration range 0.1-12.0 microM), glibenclamide (concentration range 0.03-3.0 microM) plus rilmakalim (3.0 or 7.5 microM), and glimepiride (0.03-9.0 microM) plus rilmakalim (3.0 or 7.5 microM) and paced by electrical field stimulation. Contractility of the myocytes was evaluated by digital image analysis, intracellular free calcium was determined by means of fura-2 fluorescence measurements, and cell viability was assessed morphologically as well as by measurement of lactate dehydrogenase activity. Rilmakalim reduced the systolic intracellular free calcium and contractility of ventricular myocytes in a concentration dependent manner. This effect was antagonized by glibenclamide at lower concentrations (0.3 microM) than glimepiride (3.0 microM). The smaller antagonistic action of glimepiride on the negative inotropic effect of rilmakalim as compared with glibenclamide most likely reflects a less potent inhibition of ATP-dependent potassium channels by glimepiride.

Soluble interleukin-2-receptor levels as a marker of coronary microvascular dysfunction after heart transplantation.

BACKGROUND: Immunologic mechanisms operating in a milieu of nonimmunologic risk factors constitute the principal stimuli that result in progressive cardiac allograft vasculopathy. Interleukin-2 has a central role in the development of cell-mediated immunity and is a key factor in the induction of a complex network of cytokines. On exposure to cytokines, endothelial cells can undergo profound alterations of vasomotor function. In this study we characterized the relationship between coronary microvascular function and soluble interleukin-2 receptor (sIL-2R) levels after human heart transplantation. METHODS: We studied 15 heart transplant recipients after an average follow-up time of 39+/-22 months. We measured coronary artery blood flow in an endothelium-dependent manner with acetylcholine (50 microg) and in an endothelium-independent manner with dipyridamole (0.56 mg/kg) by intracoronary Doppler catheter. Blood samples from the superior vena cava were drawn 3 to 12 months after transplantation (early value) and at time of the coronary artery flow measurement (present value). Coronary artery flow reserve was correlated to sIL-2R levels, which were determined by use of an enzyme-linked immunoabsorbent assay. RESULTS: We found a significant inverse correlation between impaired endothelium-mediated (p = 0.03) but not endothelium-independent relaxation of the coronary microvasculature and elevated sIL-2R levels. In heart transplant recipients without acute rejection or an infection episode, an sIL-2R-level of more than 800 U/ml was defined as a cutpoint, indicating disturbed endothelium-dependent microvascular function. Additionally, there was a conspicuous trend toward an inverse correlation between early elevated sIL-2R-levels and endothelium-dependent microvascular dysfunction (p = 0.06). CONCLUSIONS: The results of this study demonstrate the utility of sIL-2R, an index of immunologic activity, to be used as a marker and predictor of impaired endothelial microvascular function in heart transplant recipients. These observations support the hypothesis that after heart transplantation endothelial dysfunction in the microcirculation is an immunologic phenomenon.

Prognostic significance of coronary flow reserve on left ventricular ejection fraction in cardiac transplant recipients.

BACKGROUND: Cardiac allograft vasculopathy is a common phenomenon in epicardial and microvascular vessels. Intramyocardial vessel disease may lead to small, stellate infarcts. The present study tested the impact of microvascular vasomotor function on changes in left ventricular systolic function in the long-term follow-up after cardiac transplantation. METHODS: Seventeen consecutive cardiac transplant patients, 40+/-21 months after cardiac transplantation, without angiographically visible cardiac allograft vasculopathy and without episodes of acute rejection were included in the study. Coronary microvascular reactivity was assessed by the endothelium-dependent stimulus acetylcholine (50 microg i.c.) and by the endothelium-independent stimulus dipyridamole (0.56 mg/kg i.v.) utilizing an Doppler catheter. Radionuclide ventriculography was performed at the time of coronary flow measurement and repeated 2 years later to correlate changes in left ventricular ejection fraction with the coronary flow reserve measurement 2 years previously. RESULTS: There was a statistically significant correlation between endothelium- independent coronary flow reserve to dipyridamole and changes in ejection fraction at rest (r=0.59; P < 0.01) and during exercise (r=0.48; P < 0.05). Twenty-four months later, patients with a coronary flow reserve to dipyridamole < 2.5 showed a significant decline in ejection fraction during exercise (-7 +/- 5%) compared to patients with a coronary flow reserve > 2.5 (1.1+/-5%; P=0.003). Coronary flow reserve to acetylcholine was not correlated with a reduced ejection fraction during exercise. CONCLUSIONS: Endothelium-independent microvascular dysfunction has prognostic importance for deterioration of left ventricular function in cardiac transplant recipients without angiographically visible coronary artery stenoses. These results reinforce the concept that microvascular and epicardial vessel disease after transplantation are two distinct entities with different functional consequences.