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Contains fulltext : 249977.pdf (Publisher’s version ) (Closed access) BACKGROUND: It is important to evaluate whether a new treatment for heart failure with reduced ejection fraction (HFrEF) provides additive benefit to background foundational treatments. As such, we aimed to evaluate the efficacy and safety of empagliflozin in patients with HFrEF in addition to baseline treatment with specific doses and combinations of disease-modifying therapies. METHODS: We performed a post-hoc analysis of the EMPEROR-Reduced randomised, double-blind, parallel-group trial, which took place in 520 centres (hospitals and medical clinics) in 20 countries in Asia, Australia, Europe, North America, and South America. Patients with New York Heart Association (NYHA) classification II-IV with an ejection fraction of 40% or less were randomly assigned (1:1) to receive the addition of either oral empagliflozin 10 mg per day or placebo to background therapy. The primary composite outcome was cardiovascular death and heart failure hospitalisation; the secondary outcome was total heart failure hospital admissions. An extended composite outcome consisted of inpatient and outpatient HFrEF events was also evaluated. Outcomes were analysed according to background use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), as well as β blockers and mineralocorticoid receptor antagonists (MRAs) at less than 50% or 50% or more of target doses and in various combinations. This study is registered with ClinicalTrials.gov, NCT03057977. FINDINGS: In this post-hoc analysis of 3730 patients (mean age 66·8 years [SD 11·0], 893 [23·9%] women; 1863 [49·9%] in the empagliflozin group, 1867 [50·1%] in the placebo group) assessed between March 6, 2017, and May 28, 2020, empagliflozin reduced the risk of the primary outcome (361 in 1863 participants in the empagliflozin group and 462 of 1867 in the placebo group; HR 0·75 [95% CI 0·65-0·86]) regardless of background therapy or its target doses for ACE inhibitors or ARBs at doses of less than 50% of the target dose (HR 0·85 [0·69-1·06]) and for doses of 50% or more of the target dose (HR 0·67 [0·52-0·88]; p(interaction)=0·18). A similar result was seen for β blockers at doses of less than 50% of the target dose (HR 0·66 [0·54-0·80]) and for doses of 50% or more of the target dose (HR 0·81 [0·66-1·00]; p(interaction)=0·15). Empagliflozin also reduced the risk of the primary outcome irrespective of background use of triple therapy with an ACE inhibitor, ARB, or ARNI plus β blocker plus MRA (given combination HR 0·73 [0·61-0·88]; not given combination HR 0·76 [0·62-0·94]; p(interaction)=0·77). Similar patterns of benefit were observed for the secondary and extended composite outcomes. Empagliflozin was well tolerated and rates of hypotension, symptomatic hypotension, and hyperkalaemia were similar across all subgroups. INTERPRETATION: Empagliflozin reduced serious heart failure outcomes across doses and combinations of disease-modifying therapies for HFrEF. Clinically, these data suggest that empagliflozin might be considered as a foundational therapy in patients with HFrEF regardless of their existing background therapy. FUNDING: Boehringer Ingelheim and Eli Lilly and Company.

Objectives The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. Background Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. Methods In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction Results Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. Conclusions Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.

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.

Wir berichten in der vorliegenden Kasuistik uber einen 74-jahrigen Patienten, bei dem es nach Perforation eines Bauchaortenaneurysmas in die Vena cava inferior durch den konsekutiven Links-Rechts-Shunt zu einem akuten Lungenodem mit kardiogenem Schock gekommen war. Die Diagnostik wurde durch Kontrastmittel-unterstutzte Computertomographie sowie transabdominelle Duplex-Sonographie gestellt. Nach erfolgreicher Operation (Verschluss der Perforationsstelle an der Vena cava inferior sowie Interposition einer Bifurkationsprothese aortoiliacal) konnte der Patient nach insgesamt 30-tagiger intensivmedizinischer Behandlung (28 Tage Beatmung, 15 Tage Hamodiafiltration postoperativ) in die Anschlussheilbehandlung verlegt werden. Die Entlassung aus der Rehabilitationsbehandlung erfolgte nach weiteren 38 Tagen, der Patient erholte sich vollstandig.

Unter den Kardiomyopathien – dilatative Kardiomyopathie (DCM), hypertrophische Kardiomyopathie, restriktive Kardiomyopathie, arrhythmogene rechtsventrikulare Kardiomyopathie – stellt die DCM die haufigste Form dar. Ihre Pravalenz wird in den Vereinigten Staaten mit 36 Fallen auf 100.000 Einwohnern angegeben, Manner sind im Verhaltnis von fast 3:1 haufiger betroffen als Frauen. Die Atiologie der DCM ist sehr heterogen, 50% der Falle gehen auf eine idiopathische DCM zuruck, die anderen 50% verteilen sich auf ein breites Spektrum unterschiedlicher Atiologie wie Myokarditis, ischamische Kardiomyopathie, infiltrative Kardiomyopathie, peripartale Kardiomyopathie, hypertensive Herzerkrankung, HIV-Infektion, toxische Kardiomyopathie u. a. Bei 20–30% der an idiopathischer Kardiomyopathie Erkrankten kann eine familiare Genese nachgewiesen werden. Weitere 20–30% der idiopathischen DCM werden in Verbindung mit immunologischen Vorgagen gebracht, wobei in den industrialisierten Landern eine Virusmyokarditis, insbesondere mit Enteroviren der Coxsackie-Virus-B-Gruppe als wesentlicher Ausloser angesehen wird. Sowohl bei der familiaren DCM als auch bei einer Infektion mit Coxsackie-Virus B wurden Defekte in Proteinen des Zytoskeletts festgestellt, so dass moglicherweise die Schadigung von Bestandteilen des myokardialen Zytoskeletts ein pathogenetisches Prinzip in der Entstehung der DCM darstellt.

Myocardial calcium overload in chronic heart failure is still a debatable issue. The aim of this study was to investigate the myocardial calcium content and intracellular calcium distribution in end-stage dilated cardiomyopathy. The explanted hearts of 13 patients (9 male, 4 female, mean age 49 ± 12 years) undergoing heart transplantation because of end-stage dilated cardiomyopathy were examined. Samples were obtained from the right and left ventricular free wall and from the septum. Calcium and magnesium content were measured by atomic absorption spectrophotometry. Ultrastructural calcium distribution was examined in dilated cardiomyopathy using the phosphate-pyroantimonate method. Ultrastructural calcium distribution was also examined in left ventricular biopsies obtained from 3 patients (male, mean age 47 ± 3.6 years) with nonfailing hearts. The number of mitochondrial calcium precipitates was estimated morphometrically by a point counting method. Myocardial calcium and magnesium content in dilated cardiomyopathy did not differ significantly among the right and left ventricles and septum ranging from 8.5 to 10.8 mmol/kg dry weight. The phosphate-pyroantimonate method visualized calcium precipitates being confined to the sarcolemma, T-tubules, intercalated disks, and mitochondria in both nonfailing myocardium and dilated cardiomyopathy. Because mitochondria may act as buffers of cytoplasmic calcium, mitochondrial calcium precipitates served as a criterion for a possible cellular calcium overload. No differences in the amount of mitochondrial calcium deposits were observed between dilated cardiomyopathy and nonfailing hearts. The data suggest that there is no global myocardial calcium overload in human eng-stage dilated cardiomyopathy.

The acute cardiotoxicity of cyclosporine was investigated in isolated cardiomyocytes from adult rats. In a first study, myocytes were incubated with CsA ranging from 1 to 10 micrograms/ml and paced by electrical-field stimulation. After 30 min of stimulation the number of surviving rod-shaped myocytes was significantly reduced at 2.5 micrograms/ml (77.9%) and 5 micrograms/ml CsA (64.2%) as compared with the drug vehicle methanol (88.8%, P less than 0.05) with a further decrease at 10 micrograms/ml CsA (30.1% vs. 81.2%, P less than 0.005). In a second study, with the use of digital image processing of fura-2 fluorescence, the mean intracellular free calcium concentration, integrated over 1 sec, of single myocytes in the presence of 5 micrograms/ml CsA, the solvent methanol, or pure Krebs Ringer Hepes buffer was measured. Starting 2 Hz field stimulation increased the intracellular free calcium concentration from 100.1 to 177.9 nM in buffer and from 145.7 to 200.6 nM calcium with methanol. In contrast, there was a 3-fold increase of the intracellular free calcium concentration with 5 micrograms/ml CsA from 128.8 to 376.1 nM calcium. The intracellular free calcium during electrical stimulation was significantly higher with CsA than with the solvent (376.1 nM vs. 200.6 nM, P less than 0.001). In a further study, myocytes were incubated with calcium ranging from 0.5 to 8 mM calcium in the presence of 5 micrograms/ml CsA or the solvent methanol and electrically stimulated. Here, with increasing extracellular calcium the number of rod-shaped myocytes decreased significantly with CsA as compared with the solvent (P less than 0.02). The data suggest that CsA exerts a dose-dependent toxic effect on isolated rat cardiomyocytes that depends on the extracellular calcium concentration. There is direct evidence that CsA increases the intracellular free calcium concentration in rat cardiomyocytes.

The effect of nebivolol treatment on the survival of cardiomyopathic hamsters (BIO82.62) who had developed congestive heart failure was investigated. Five percent of the hamsters included in the study had died between 200 and 220 days of age, indicating development of congestive heart failure. At age 220 days, a treatment protocol was initiated and the remaining animals received either nonmedicated food (n = 34) or food supplemented with nebivolol (1 mg/kg/day, n = 33). The death rate was similar in both groups during the first 27 days of treatment, after which nebivolol significantly delayed mortality (p = 0.011). The median survival time was 293 days in controls vs 321 days in the nebivolol group. It is concluded that nebivolol prolongs survival in this animal model of congestive heart failure, although further investigation is needed to clarify the mechanism of action.

The acute cardiotoxicity of cyclosporin A was studied in isolated cardiac myocytes from adult rats. In an initial series of 7 animals, myocytes were incubated with concentrations of cyclosporin A ranging from 1 microgram/ml to 50 micrograms/ml. Shape changes of untreated cells, cells treated with cyclosporin A and cells treated with the solvent of cyclosporin A, Tween 80/ethanol, were evaluated. After 8 hours and 16 hours, respectively, of incubation 92 +/- 4.3% and 72 +/- 8.7% of the non-treated control cells were still rod-shaped. Cyclosporin A, however, in a concentration of 5 micrograms/ml decreased the number of rod-shaped cells (79 +/- 3.2% at 8 hours and 51 +/- 3.5% at 16 hours) in comparison to the solvent (94 +/- 3.5% at 8 hours and 76 +/- 5.8% at 16 hours, P less than 0.02). This effect became more pronounced with higher concentrations of cyclosporin A. On the other hand, Tween 80/ethanol alone in higher concentrations also led to a reduced number of rod-shaped cells. In a second series of 7 animals using Tween 80/ethanol and methanol as drug vehicles, myocytes were incubated for 16 hours with 15 micrograms/ml of cyclosporin A in a calcium containing medium (1 mM) or a calcium free medium (10(-4) M ethylene glycol-bis(beta-aminoethyl ether) N,N,N',N'-tetraacetic acid). The number of remaining rod-shaped cells was higher in the calcium free medium as opposed to the medium containing calcium when the cells were exposed to cyclosporin A. It is concluded that in the applied model cyclosporin A at high concentrations has an acute cardiotoxic effect which in part appears to be calcium related.

Cardiogenic shock (CS) complicating acute myocardial infarction is strongly associated with mortality. Even though there has been previous research regarding gender specific differences in these patients, the results so far are conflicting and, moreover, there is insufficient data for the

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.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).In enalapril and candesartan pre- and post-treated animals, we observed significant reduction of MVO of intramyocardial arteries compared with the cyclosporine group (p0.005), 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 (p0.05).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.

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.

Die meisten antibradykarden Systeme bieten erweiterte diagnostische Speicher zur Erfassung atrialer bzw. ventrikularer Rhythmusstorungen. Jedoch fehlte bisher zur Validierung dieser gespeicherten Ereignisse ein intrakardialer EKG-Speicher. Die DISCOVERY und PULSAR Schrittmachersysteme haben die Moglichkeit bis zu 20 intrakardiale Episoden mit einer Gesamtdauer von 80 Sekunden zu speichern. Die Aktivierung des Speichers erfolgt durch Vorhofarrhythmien, ventrikulare Tachykardien, oder kann durch den Patienten selbst ausgelost werden. Bei 87 Patienten wurde ein DISCOVERY oder ein PULSAR Schrittmacher implantiert. Die EKG-Speicher wurden bei allen Patienten kurz nach Implantation aktiviert und nach 1 Monat abgerufen. Einen Monat nach der Implantation zeigten 88% der Patienten in den abgespeicherten intrakardialen EKGs mehr als eine Arrhythmie-Episode. Insgesamt wurden 192 EKG’s gespeichert. In 12 Fallen erbrachten die intrakardialen EKGs zusatzliche klinisch relevante Informationen: undersensing (2), oversensing (8), multiple ventrikulare Extrasystolen (1), Kammerflimmern als Todesursache (1). Intrakardiale EKG-Speicher bieten eine neue wertvolle diagnostische Moglichkeit, um klinisch relevante Arrhythmien und Schrittmacherdysfunktionen zu erkennen.

In a double-blind study 8 healthy male subjects received 100 micrograms human atrial natriuretic facotr-(99-126) (hANF) and NaCl0.9% in random order on different days. Following hANF injection a significant increase in cardiac beat-to-beat variation was observed (4.65% vs 5.95%). This shows that in vivo human atrial natriuretic factor stimulates cardiac parasympathetic activity in man.

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.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.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).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.

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.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.There was a statistically significant correlation between endothelium- independent coronary flow reserve to dipyridamole and changes in ejection fraction at rest (r=0.59; P0.01) and during exercise (r=0.48; P0.05). Twenty-four months later, patients with a coronary flow reserve to dipyridamole2.5 showed a significant decline in ejection fraction during exercise (-7 +/- 5%) compared to patients with a coronary flow reserve2.5 (1.1+/-5%; P=0.003). Coronary flow reserve to acetylcholine was not correlated with a reduced ejection fraction during exercise.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.

Interactions of leukocytes with vascular endothelium are important components of inflammation tissue reactions and have been implicated in cardiac transplant rejection and demonstrated to be mediated by cell adhesion molecules (CAM's). The expression of ICAM-1, VCAM-1 and E-selectin in human myocardium is variable and little is known about the expression of LFA-1 and Mac-1 during allograft rejection. This study investigated these CAM's in myocardial biopsies of transplanted hearts (HTX) and of coronary artery disease eligible for coronary artery bypass grafting (CABG) as non-inflammatory controls and explicitly examines vascular endothelium, cardiomyocytes and infiltrating cells. Immunohistochemistry was performed using the APAAP-method and directing specific mouse anti-human monoclonal antibodies against ICAM-1 (CD54), VCAM-1 (CD106), E-selectin (CD62E), alpha-LFA-1 (CD11a), alpha-Mac-1 (CD11b), alpha-p150/95 (CD11c) and the beta2-integrin chain (CD18). CD18, LFA-1 (CD11a), Mac-1 (CD11b) and p150/95 (CD11c) were markedly expressed on infiltrating immunocytes in HTX compared to CABG where no expression of beta2-integrins was observed. Cardiac allografts demonstrated a strong expression of ICAM-1 on vascular endothelium and on infiltrating cells. ICAM-1 was not detected on cardiomyocytes. In CABG a weak expression of ICAM-1 was observed on endothelial cells but not on myocytes. VCAM-1 was expressed on vascular endothelium and perivascular infiltrating cells in HTX but not in CABG. VCAM-1 was not found to be expressed on myocytes. There was no evidence for the presence of E-selectin in any of our biopsy specimens. Our study shows that the study of cell adhesion molecules adds to the pathophysiological understanding of inflammation after transplantation in cardiac disease. This offers a potential for the development of diagnostic tools and new therapeutic strategies.

Central venous puncture is required for endomyocardial biopsy to identify rejection after cardiac transplantation. We evaluated our use of the Seldinger technique to determine the safety of this invasive method.In 42 immunosuppressed patients central venous puncture was performed after cardiac transplantation using the Seldinger technique for right heart biopsy. Together with physical examinations, chest X-ray and cardiac ultrasonography were performed during the inhospital follow-up. Outpatient follow-up continues and all reported adverse effects were evaluated by the attending cardiologist.There were a total of 620 central venous punctures, most via the right internal jugular vein (77.9%). The planned puncture could not be performed in 3.2% of the cases and an alternative site was used. The femoral approach was associated with the longest radiation time. No severe adverse effects were observed and no complications (infection, large haematoma, pneumothorax, severe rhythm disorders) were recorded.Even in immunosuppressed patients frequently requiring central venous puncture, right heart endomyocardial biopsy can be safely performed to evaluate rejection.

Endomyocardial biopsy in cardiac transplantation is still the most exact test (gold standard) to confirm or exclude a suspected rejection. Up to now, all available noninvasive tests suffer from a low sensitivity and specificity. For a further reduction of biopsies early available noninvasive methods are desirable. In the data presented a comparison between histological findings and heart volume measurements is shown in 40 patients (112 histological findings) after orthotopic cardiac transplantation. In 46 cases with no evidence of histological rejection the echocardiographically or radiologically determined heart volume was 869 +/- 142 ml/1.73 m2 body surface area, compared to 1026 +/- 178 ml/1.73 m2 in 29 cases with mild cardiac rejection. In 37 cases with a moderate or severe rejection heart volume as 1094 +/- 181 ml/1.73 m2. The diagnosis of a moderate or severe rejection by biopsy is combined with a heart volume above 950 ml/1.73 m2 with a sensitivity of 78% and a specificity of 73%. Intramyocardial edema as well as an increase in right and left ventricular volumes due to heart failure may be the causes for heart volume increase in rejection. Thus, heart volume measurement which can be performed easily during routine echocardiography gives additional information about whether a rejection has to be assumed or can be excluded. Today, sensitivity and specificity of the test does not allow a reduction of biopsy frequency. Further investigations are necessary to analyze the course of heart volume changes during an episode of rejection.

BASIC CONSIDERATION: Hypertrophic cardiomyopathy is defined as a primary myocardial disease associated with a hypertrophic non-dilated left ventricle with no other heart or systemic disease that might lead to hypertrophy of the left ventricle. The leading symptoms are effort-associated angina and dyspnea, rapid fatigue, dizziness and syncope.The hemodynamic situation is characterized by a hyperdynamic systole and impaired diastole and left-ventricular filling. In the obstructive form, hypertrophy of the basal septum and an anteriorly moving mitral valve during systole result in an end-systolic reduction in the cross-section of the outflow tract associated with considerable intraventricular pressure gradients. Disturbances in the myocardial calcium metabolism are presently suspected to be causally involved in the diastolic function impairment.

30-day-old polymyopathic hamsters (strain BIO 82.62) were orally treated with either magnesium pyridoxal 5-phosphate glutamate 100 mg/kg, equimolar amounts of magnesium alone (MgCl2 55 mg/kg), or water b.i.d. for 30 days, or sacrificed before treatment. 60-day-old healthy hamsters (strain CLAC) served as controls. Magnesium pyridoxal 5-phosphate glutamate lowered the myocardial calcium content (42.8 +/- 13.1 mmol/kg dry weight) as compared to MgCl2 (70.3 +/- 11.9 mmol/kg dry weight) and water (72.7 +/- 13.6 mmol/kg dry weight). The serum and tissue lipid pattern did not differ between BIO 82.62 and normal hamsters except high serum cholesterol and triglyceride levels in 30-day-old BIO 82.62 hamsters. Myocardial necroses were influenced by neither magnesium pyridoxal 5-phosphate glutamate nor MgCl2. Cytochemical investigation of the ultrastructural calcium localization in the aorta revealed less calcium precipitates with magenesium pyridoxal 5-phosphate glutamate in media myocytes. It is concluded that magnesium pyridoxal 5-phosphate glutamate exerts a calcium antagonistic effect in the cardiomyopathy of the Syrian hamster which is related neither to the magnesium content of magnesium pyridoxal 5-phosphate glutamate nor to its lipid lowering activity.

Die INSIDE-Studie vergleicht prospektiv randomisiert den Stellenwert der VDD-Stimulation im Vergleich zur DDD-Stimulation. VDD-Schrittmacher detektierten niedrigere P-Wellenamplituden als Zweikammerschrittmacher; die atriale Sensitivitat war dementsprechend auf empfindlichere Werte programmiert worden. Die Sinusknotenfrequenz stieg in der Fahrradergometrie in beiden Gruppen gleichermasen an. Atriales Undersensing war sowohl im Langzeit-EKG als auch wahrend der Belastungsuntersuchung selten in der DDD-Gruppe nachweisbar und in der VDD-Gruppe nicht signifikant erhoht. In beiden Behandlungsgruppen fanden sich keine Beschwerden infolge atrialen Undersensings.

Indium-111-labeled Fab fragment imaging using a murine antimyosin monoclonal antibody (Myoscint, Centocor, Leiden) was evaluated for efficacy in detecting cardiac allograft rejection. Diagnosis of rejection was made by endomyocardial biopsy with four to five samples taken for each procedure. Eighty-one studies were performed in 25 patients (21 men, four women, mean age 50 +/- 9 years) from 2 weeks to 45 months after cardiac transplantation. 0.5 mg of the monoclonal antibody labeled with 60 MBq Indium-111 (Antimyosin-Fab-DTPA) was administered i.v. Planar scintigraphic images were obtained in LAO 45 and anterior projections as well as "half-body-scintigrams" 48 h after injection. Using the regions-of-interest-(ROI)technique the relative uptake over the lung and the heart was determined and an index of In-111 uptake was calculated. A heart-to-lung ratio of 1.5 or higher was considered indicative for moderate to severe rejection. Specificity was 86% (nine false-positive In-111 studies in 68 negative biopsy studies), sensitivity was 85% (two false-negative In-111 studies in 13 pathological biopsy studies). It is concluded that the In-111 method has a high sensitivity and specificity in detecting heart transplant rejection and may be useful in the monitoring of patients in the chronic phase after heart transplantation. The 48-h delay in establishing the diagnosis limits the applicability in acute severe rejection.

Five patients with hypertrophic cardiomyopathy developed left-ventricular dilatation and congestive heart failure during an observation period of 16-29 years. In one patient cardiac transplantation had to be performed. The initial predominant symptoms of outflow-tract obstruction and diastolic dysfunction developed into progressive left-ventricular systolic failure. The question of whether this is a well-defined subgroup of patients with hypertrophic cardiomyopathy, or whether hypertrophic cardiomyopathy turns into a phase of left-ventricular dilatation and failure after some years remains to be elucidated by long-term studies.

Left ventricular systolic and diastolic performance was evaluated by radionuclide angiography in 17 patients following cardiac transplantation and compared with normal persons. Both groups performed supine bicycle exercise during the investigation, the control group at 102 +/- 73 W and the transplanted patients at 61.2 +/- 15 W. The ejection fraction increased in the normal persons from 61 +/- 8 to 69 +/- 10% whereas in the transplanted patients it did not increase significantly. There were no relevant changes in systolic parameters during exercise in the transplant recipients. The changes in diastolic parameters were significantly smaller in transplant patients than in normals. After correction for heart rate-induced changes a significantly different time course of the systolic-diastolic sequence during the cardiac cycle became evident in the transplanted group at rest. During exercise the systolic-diastolic sequence during the cardiac cycle became similar in both groups. It is concluded that the reduced exercise capacity of patients in the late phase after cardiac transplantation is partially due to the absence of an EF increase and a limitation of diastolic reserve during exercise.

From 1979 to 12/1990 795 organ transplants have been performed at our hospital (kidney n:737, liver n:23, heart n:35). Our data reveal vascular problems in 10 percent of the transplanted patients - not concerning the vascular anastomosis. The therapeutic approach should be determined interdisciplinary. Due to the low complication rate of operative or interventionel procedures in this patients, even relative indications--to improve "quality of live"--can be accepted.

Cardiomyopathy of the Syrian hamster is characterized by myocardial calcium overload and focal myocardial necrosis. The cause of the myocardial calcium overload is not yet fully understood. In this study, the ultrastructural localization of calcium was determined in normal hamster hearts and in non-necrotic and necrotic myocardium of cardiomyopathic hamsters (strain BIO 82.62). In many cells from the non-necrotic myocardium of the cardiomyopathic hamsters the calcium deposits, visible as 20 nm particles, were confined to the inner leaflet of the plasma membrane, the T-tubules and the intercalated disks. This corresponds to the calcium distribution found in normal hamsters and other mammalian species. A number of morphologically normal cells, however, displayed an increased amount of calcium precipitate in the mitochondria as well as at the sarcolemma indicating that, in the cardiomyopathic hamster, focal calcium overload is detectable cytochemically in cells which otherwise do not show gross abnormalities. In cells showing morphological signs of myolytic degeneration a marked redistribution of calcium precipitate took place. Sarcolemma became devoid of calcium deposits whereas an enormous amount of clustered precipitate occurred in largely swollen mitochondria. These data are in support of a relationship between impaired ion homeostasis and degeneration events in cardiomyopathy. Furthermore, there appears to be a clear parallelism in calcium redistribution between hypoxic and cardiomyopathic myocardium.

Procedures of nuclear cardiology are applied to the diagnosis and follow-up of hypertrophic cardiomyopathy in two aspects: (a) in the determination of myocardial thickening and (b) to document functional response to therapy. For morphological studies, T1-201 myocardial scintigraphy was introduced by Bulkeley in 1975 (7). Using a gated SPECT technique for myocardial scintigraphy, the wall thickening in different myocardial regions could be recorded (25). Soon after their introduction, gated blood pool studies were utilized to image regional dimension and motion of the myocardial wall (17). Later, instead of gated blood pool studies, one and two dimensional echocardiography were employed (8, 16). Besides morphological parameters, regional functional data at rest are available which enable one to quantify regional disorders and responses to drugs (6, 9, 21, 24). Nuclear cardiological measurements of global left ventricular functions, based on analysis of the left ventricular volume curve (time activity curve), were introduced by Bonow (3) in patients with hypertrophic cardiomyopathy before and during verapamil treatment.

A case is reported of right ventricular outflow obstruction caused by hypertrophic cardiomyopathy. The pressure gradient between the inflow tract and the outflow tract of the right ventricle was 84 mm Hg. Resection of the hypertrophic muscle bundles practically eliminated the obstruction leaving only an insignificant subvalvular gradient of 2 mm Hg. Histologic examination revealed cardiac muscle cell hypertrophy and disorganization.

Left ventricular function was investigated by radionuclide ventriculography in 13 patients (11 male, two female) with hypertrophic cardiomyopathy, aged from 22-57 years (mean 45.5 years) at rest and during exercise. Ten patients had hypertrophic obstructive cardiomyopathy with maximal left ventricular outflow tract gradients of 64-290 mmHg (mean 147 mmHg). Left ventricular enddiastolic pressure of all patients ranged from 8-35 mmHg (mean 21 mmHg). Radionuclide ventriculography was performed without therapy, after acute application of a single oral dose of gallopamil (50 mg), and after longterm treatment for 3 weeks (50 mg tid). Ejection fraction at rest after single dose increased from 69.2% to 72.9% (p less than 0.02), peak ejection rate (PER) increased from 333.5 to 362.0/s (p less than 0.01) and peak filling rate (PFR) from 284.5 to 316.5/s (p less than 0.02). Under exercise single dose as well as longterm treatment led to a slight but significant shift in the ratio of PFR/PER (from 1.02 to 1.12 after single dose [p less than 0.04], and to 1.18 with longterm treatment [p less than 0.03]). There was no correlation between the individual response to gallopamil treatment and histopathological parameters such as hypertrophy or fibrosis. These data demonstrate that gallopamil in patients with hypertrophic cardiomyopathy leads to an improvement mainly in left ventricular diastolic function which appears to be most effective under exercise.