Cardioprotection by aldosterone receptor antagonism in heart failure. Part I. The role of aldosterone in heart failure.

In recent years understanding of the role of aldosterone has expanded beyond the known classic effects of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine, and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Therefore, the renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension and heart failure and is therefore, a key target for therapeutic interventions. Commonly prescribed medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including angiotensin converting enzyme inhibitors (ACE-I) and Angiotensin II (A-II) receptor antagonists. There is a well-documented increase in aldosterone levels that occurs over several months during chronic treatment with an ACE-I or A-II receptor antagonist. Such suppression of circulating aldosterone however, is transient, as exemplified by the term "escape" used to describe the phenomenon. This rebound of aldosterone even occurs when patients receive both an ACE-I and A-II receptor antagonist. In addition, ACE-I and A-II receptor antagonists are less effective in controlling BP in the estimated 60% of hypertensive patients who are salt (volume) sensitive and more prone to hypertension-associated morbidity such as black patients and type 2 diabetics. Thus chronic and complete blockade of aldosterone action requires an aldosterone receptor antagonist. The "Randomized Aldactone Evaluation Study" (RALES) trial results in patients with severe heart failure NYHA class III or IV and a left ventricular ejection fraction of no more than 35 percent showed that administration of a sub-hemodynamic dose of spironolactone (25 mg a day) as an add on therapy to ACE-I plus standard treatment resulted in a significant mortality reduction due both to decreased death from progressive heart failure and sudden cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of progressive heart failure. Although it is an effective antialdosterone agent, widespread use of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At standard doses, impotence and gynaecomastia can be induced in men, whereas pre-menopausal women may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist, eplerenone, appear promising for the effective blockade of aldosterone and its harmful effects without the sexual disturbances of spironolactone. Recently Eplerenone was successfully introduced for the treatment of hypertension and heart failure. Growing number of experimental studies are finding a broader role for Aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to conventional therapy aldosterone receptor blockers show benefits which are in addition to those conferred by ACE-I and/or AII receptor blockers.

Severe Serratia liquefaciens sepsis following vitamin C infusion treatment by a naturopathic practitioner.

A 66-year-old female patient developed severe Serratia liquefaciens sepsis following vitamin C infusion treatment by a naturopathic practitioner. The clinical course of the infection was characterized by several complications, and the direct costs of the hospital stay amounted to about 40000 Euro. Genotypically identical S. liquefaciens was isolated from the residue of the infusate given to the patient, as well as from the washbasin overflow and from two other infusion bottles. A careful inspection of the dispensing facilities and review of procedures used to prepare the infusate revealed several indications of poor hygiene. However, the source of contamination could not be fully clarified. This case report raises questions about the local facilities and personal qualifications required for naturopathic practitioners to conduct invasive procedures and demonstrates that lapses in hygiene can lead to severe morbidity and high cost.

Fatal arrhythmia in a juvenile athlete due to myocardial hypertrophy and infarction.

This report is a case history of a 16-year-old highly trained athlete who suffered from ventricular fibrillation during exhaustive physical activity. After resuscitation and admission into hospital ECG revealed posterior wall infarction. Thrombolytic therapy was advised and ST-segment elevation reversed. Within 48 h cerebral edema evolved due to hypoxic brain damage and the subject deceased after 16 days despite prolonged maximum antiedematous therapy. Autopsy confirmed the diagnosis of concentric myocardial hypertrophy (total heart weight 568 g) without signs of coronary artery disease. Systemic inflammatory diseases and drug abuse were ruled out by lab studies, evidence for viral infection was not found. Thus, relative coronary insufficiency in regard to myocardial hypertrophy during excessive athletic activity must be viewed as cause for the fatal arrhythmia.

The effects of orthostasis on the ventricular-evoked response.

AIMS: The effects of orthostasis on the morphology of the ventricular-evoked response were investigated. METHODS AND RESULTS: Seven patients (five females; 74.9 +/- 4.6 years) with second- or third-degree atrioventricular block received DDD pacemakers Physios CTM 01 with fractal-coated ventricular leads (both Biotronik, Germany). At their 3-month follow-up sessions, these patients underwent tilt-table tests. Heart rate, mean arterial blood pressure and ventricular-evoked response were measured continuously. Signals were averaged over 15 consecutive beats. Coefficients of correlation between selected ventricular-evoked response parameters and heart rate or mean arterial blood pressure were calculated. Tilt upwards affected heart rate, mean arterial blood pressure and ventricular-evoked response extremes showed non-uniform, patient-specific changes that were not related directly to other parameters. Heart rates significantly increased in six patients following tilt upwards. For all patients, ventricular-evoked response plateau amplitudes immediately increased with tilt upwards. Furthermore, repolarization times correlated with changes in heart rates (r = -0.78). CONCLUSIONS: Monitoring of the ventricular-evoked response during tilt-table testing revealed that the plateau amplitude of the ventricular-evoked response depends on the patient's position; ventricular-evoked response increased in the upright position and decreased in the supine position. Furthermore, repolarization time and heart rate correlated inversely; higher heart rates resulted in a shortening of the ventricular-evoked response.

Surgery in patients with coronary artery disease--silent ischaemia during transurethral resection of tumors of prostate or bladder.

BACKGROUND: Asymptomatic episodes of myocardial ischemia in clinically stable patients seem to occur frequently and may hint at a worse prognosis. HYPOTHESIS: This study was undertaken to determine whether surgical patients with coronary artery disease (CAD) have a higher risk of cardiac ischemia during the perioperative period compared with the late postoperative period and compared with patients without CAD. METHODS: In all, 14 patients with and 14 patients without CAD were examined by Holter monitoring during the perioperative and three days later during the postoperative periods for the presence of ST-segment depression as a marker of silent myocardial ischemia. RESULTS: While patients without CAD did not show ST-segment depression, patients with CAD were found to have had 143 episodes of ST-segment depression, 49% in the perioperative and 51% in postoperative recordings. CONCLUSION: Though patients were asymptomatic with antianginal therapy, there were episodes of ST-segment depression indicating silent myocardial ischemia in patients with CAD. Surgical interventions such as transurethral resection of tumors of prostate or bladder did not produce an increase of ischemic burden registered by Holter monitoring.

[Hypercalcemia in florid pulmonary and cervical lymph node tuberculosis]. / Hypercalcämie bei florider Lungen- und Halslymphknotentuberkulose.

A 57-year-old man with a history of tuberculosis (TB of the knee-joint 44 years ago and open pulmonary TB six months ago with poor patient drug compliance) had lost 10 kg in weight during the preceding six months. In addition, firm lymph-node swellings with redness of the overlying skin and a skin fistula developed on the right side of the neck. There was mild hypercalcaemia (albumin-corrected serum calcium concentration 2.59 mmol/l) and hyperphosphataemia (2.0 mmol/l) with low-normal serum concentrations of parathormone and of 25-hydroxy-vitamin D3 (14 ng/ml). Serum 1,25-dihydroxy-vitamin D3 concentration was reduced (16 ng/l). The activity of osseous isoenzyme of alkaline phosphatase was normal (19 U/l) and skeletal scintigraphy revealed no abnormality. The cervical lymph-nodes were excised (histology: active caseous lymph-node TB). Tuberculostatic treatment was begun with daily doses of 0.3 g isoniazid, 0.45 g rifampicin, 1.2 g ethambutol and 1.5 g pyrazinamide. Serum calcium concentration rose to 3.22 mmol/l (albumin-corrected) in the first two weeks, even though the patient was on a low-calcium diet. The various concentrations subsequently decreased, but remained slightly elevated throughout the period of observation (11 weeks). This is thus a case of TB-associated hypercalcaemia which was not caused by 1,25-dihydroxy-vitamin D3 or bone destruction.

[Silent myocardial ischemia in long-term ECG with various mani festations of coronary heart disease]. / Stumme Myokardischämie im Langzeit-EKG bei verschiedenen Manifestationsformen der koronaren Herzkrankheit.

Silent myocardial ischaemia seems to be of prognostic value in coronary artery disease. We examined 47 patients with coronary artery disease: 1. 20 patients with a history of myocardial infarction (MI), 2. 15 patients with chronic stable angina pectoris without a history of myocardial infarction (sAP), and 3. twelve patients with unstable angina with or without a history of myocardial infarction (uAP). Horizontal and downsloping ST-segment-depressions greater than or equal to 1 min and greater than or equal to 0.1 mV were defined as significant. There were 132 ST-segment-depressions, the relation between symptomatic and asymptomatic being 1:7.3, in MI 1:6.2, in sAP 1:5.3, in uAP 1:14. Heart rate increased before beginning of ST-segment-depression in 74% in MI, in 86% in sAP, but only in 38% in uAP. In sAP ST-segment-depressions were smaller (14% greater than 0.2 mV, none greater than 0.3 mV) than in patients with MI (42% greater than 0.2 mV, 12% greater than 0.3 mV) and uAP (25% greater than 0.2 mV, 9% greater than 0.3 mV). Mean duration of ST-segment-depression was 15.3 +/- 11.7 min in sAP (2 to 49 min), 28.5 +/- 35.6 min in MI (2 to 168 min), and 41.2 +/- 40 min in iAP (2 to 140 min). ST-segment-depressions in MI and sAP showed a circadian rhythm with a peak at midday and in the early evening and a small amount of ST-segment-depressions at night. In uAP ST-segment-depressions did not show that circadian variation. The number of ST-segment-depressions was higher in uAP than in MI and sAP.(ABSTRACT TRUNCATED AT 250 WORDS)

[The hemodynamic profile of amrinone and enoximone in patients with severe heart failure]. / Hämodynamisches Profil von Amrinon und Enoximon bei Patienten mit schwerer Herzinsuffizienz.

Hemodynamic measurements were done in 42 patients with congestive heart failure of NYHA classes III and IV after administration of the phosphodiesterase inhibitors amrinone und enoximone. Amrinone decreases mean arterial pressure (-4%), right atrial pressure (-39%), and systemic vascular resistance (-23%), while cardiac index and stroke volume index increase to 27% and 26%, respectively; heart rate is nearly unchanged. Enoximone administration in a dose of 1 mg/kg bw produces an increase in cardiac index of 13%, an increase in heart rate of 12%, and a decrease of systemic vascular resistance of 13%, whereas stroke volume index is unchanged. Enoximone in a dose of 1.5 mg/kg bw increases heart rate (+ 9%), cardiac index (+ 33%), and stroke volume index (+ 21%), and decreases systemic vascular resistance (-26%). The hemodynamic profile of amrinone and enoximone in an equal dose shows only slight differences. Furthermore, phosphodiesterase inhibitors produce an increase of cardiac index (+ 19%) and stroke volume index (+ 17%) in patients with pump failure having already received dopamine and dobutamine.

[Central hemodynamics of a new positive inotropic substance, adibendan. Data from a dose-finding study]. / Zentrale Hämodynamik unter der neuen positiv inotropen Substanz Adibendan. Daten einer Dosisfindungsstudie.

Central Hemodynamics from the New Positive-inotrope Substance Adibendan/An open dose-finding study We investigated the influence of Adibendan which is a new phophodiesterase inhibitor on central hemodynamics in an open dose-finding study. 10 patients with chronic heart failure NYHA II-IV (mean age 67 +/- 5 years) got Adibendan i.v. A maximum increase in cardiac index from 2.3 +/- 0.5 to 3.2 +/- 0.5 l/min.m2 (p less than 0.001) was seen after a cumulative dosage of 0.916 +/- 0.571 mg at a time interval of 107 +/- 43 min after injection of the first dosage of 0.125 mg. There was a pronounced increase in stroke volume index from 30 +/- 6 to 40 +/- 8 ml/m2 (p less than 0.01). Heart rate raised by 5% which was not significant. Systemic vascular resistance dropped by 30% from 1693 +/- 720 to 1177 +/- 292 dyn.s.cm-5 (p less than 0.05), pulmonary vascular resistance by 39% from 755 +/- 273 to 463 +/- 199 dyn.s.cm-5 (p less than 0.001). Blood pressure and right atrial pressure did not alter. Mean pulmonary artery pressure dropped by 14% from 37 +/- 7 to 32 +/- 11 mmHg. We conclude that Adibendan improves cardiac index markedly and causes a modest decrease in mean pulmonary artery pressure.

Cardiac function in endocrine diseases: I. Acromegaly.

The aim of our echocardiographic study was to characterize cardiac function and anatomy of 14 acromegalics (A: 9 women, 5 men; mean age: 42.4 yrs) more closely. The duration of acromegaly in 4 of these patients was between 3 and 12 years; the disease was diagnosed for the first time in the other patients. Double M-mode echocardiography was performed in all patients and the results compared with data obtained from a control group of 24 healthy volunteers (N: 22 men, 2 women; mean age: 23 yrs). The mean left ventricular diameter at end-diastole was greater in the acromegalics than in the controls (A: 55 +/- 6 mm, N: 50 +/- 4 mm; p less than 0.005, means +/- SD). After correction for age and body surface area, it, however, was outside the 95% confidence interval in 5 patients. Left ventricular hypertrophy was present in 3 patients, one of whom had coexistent arterial hypertension. A total of 3 patients were hypertensive. Significantly higher values for the maximal velocity of systolic wall thickening (A: 6.1 +/- 0.6 cm/s, N: 4.2 +/- 0.6 cm/s, p less than 0.001) and diameter change (A: 12.4 +/- 2.0 cm/s, N: 10.6 +/- 1.0 cm/s, p less than 0.005) indicate increased contractility with concurrently increased relaxation; fractional shortening did not differ significantly (A: 38 +/- 5%, N: 37 +/- 5%, ns). The isovolumetric relaxation period at diastole was slightly longer in the acromegalics (A: 70 +/- 17 ms, N: 61 +/- 13 ms, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of pimobendan on peripheral hemodynamics]. / Einfluss von Pimobendan auf die periphere Hämodynamik.

Peripheral hemodynamics and some metabolic parameters were studied in 20 patients with coronary artery disease (x = 59 +/- 9 y) and in 20 healthy volunteers (x = 25 +/- 3 y) at rest and after isometric handgrip exercise both before and after administration of pimobendan or placebo using a randomized, double-blind study. Forearm blood flow was measured using venous occlusion plethysmography. In pimobendan treated patients and volunteers an increase in forearm blood flow between 9% and 38% could be noticed. The increase in forearm blood flow was significant in comparison to placebo only, in volunteers under resting conditions. Heart rate increased significantly by 14-19% in all groups after administration of pimobendan. There were no alterations in blood pressure. Local resistance in forearm fell by 13-22%. Pimobendan did not change metabolic parameters.

Acute effects of enoximone in chronic heart failure.

In 19 patients with chronic heart failure in NYHA stages III and IV, hemodynamic measurements were made using a Swan-Ganz catheter before and 15 and 30 min after intravenous administration of enoximone. Group A (n = 10) received 1.0 mg of enoximone/kg of body weight and group B (n = 9) received 1.5 mg of enoximone/kg of body weight. In group A, there was a rise in the pulse rate of 13% and in the cardiac index of 13% with unchanged stroke volume index. At constant mean arterial pressure, the mean right atrial pressure fell by 28%, the mean pulmonary arterial pressure by 11%, the total peripheral resistance by 13%, and the total pulmonary resistance by 21% after 30 min. In group B, the pulse rate rose by 9.8%, the mean blood pressure by 2.7%, the cardiac index by 31.4%, and the stroke volume index by 18.4% 30 min after administration of enoximone, whereas a fall in the mean right atrial pressure by 57.4%, the mean pulmonary arterial pressure by 28.6%, the total peripheral resistance by 26.0%, and the total pulmonary resistance by 45.3% could be shown. At a low dosage of enoximone, the vasodilatory effects of this substance are most prominent, whereas an increase in the pumping performance of the heart could be clearly demonstrated in higher dose ranges.

[Aggressive mediastinal fibrosis, a rare cause of superior vena cava obstruction--case report and review of the literature]. / Die aggressive Mediastinalfibrose, eine seltene Ursache der oberen Einflussstauung--Fallbeschreibung und Literaturübersicht.

An aggressive mediastinal fibrosis was found to be a cause of superior vena caval obstruction in 1 to 2% of patients. Symptoms can be discrete for a long time, but the progressing disease can cause many symptoms. A 56-year-old man who, for half a year, suffered from thoracic pain during deep inspiration, and then rapidly developed superior vena caval obstruction caused by aggressive mediastinal fibrosis is discussed. The operative treatment consisted in complete replacement of the superior vena cava.

[Peripheral hemodynamics and metabolic parameters influenced by amrinone at rest and following handgrip stress]. / Periphere Hämodynamik und metabolische Parameter unter dem Einfluss von Amrinon in Ruhe und nach Handgrip-Belastung.

Peripheral hemodynamics and metabolic parameters were studied in 12 healthy volunteers (mean = 24.6 years) and in 12 patients with coronary artery disease (mean = 51.1 years) at rest and after isometric handgrip exercise both before and after application of amrinone (1.5 mg/kg body weight i.v.). Amrinone produced a significant decrease in diastolic blood pressure during handgrip in patients and in volunteers by 10%. Heart rate increased by 4 to 8%. After application of amrinone there was a pronounced increase in forearm blood flow at rest by 50% and after handgrip by 30%. Amrinone is an effective vasodilator without altering systolic and mean arterial blood pressure or heart rate strongly. Amrinone did not influence metabolic parameters.