Herbert Nägele

Effects of antihypertensives on plasma lipids and lipoprotein metabolism

There is good epidemiologic evidence that hypertension is associated with a high risk of cardiovascular disease. However, primary intervention trials have failed to demonstrate that a reduction in blood pressure in hypertensive patients reduces morbidity and mortality from cardiac events. Since various antihypertensive drugs adversely affect lipoprotein metabolism, these drugs may increase associated coronary risk and offset the beneficial effects of lowering blood pressure. This article reviews the effects of various antihypertensive drugs on plasma lipids, lipoproteins, and apolipoproteins. They can be summarized as follows: thiazide-type diuretics cause a marked elevation of plasma triglycerides and very low-density lipoprotein (VLDL) and minor increases in total cholesterol and low-density lipoprotein (LDL), but have little effects on high-density lipoprotein (HDL). The nonselective beta-blockers do not significantly affect total cholesterol and LDL, but increase total triglycerides and VLDL and decrease HDL. The changes in plasma lipids and lipoproteins caused by cardioselective beta-blockers and beta-blockers with intrinsic sympathomimetic activity are qualitatively similar but less pronounced. Calcium antagonists and angiotensin-converting enzyme inhibitors appear to have no significant effects on plasma lipids. alpha 1-Inhibitors reduce total triglycerides, total cholesterol, VLDL, and LDL and increase HDL. The possible mechanisms by which antihypertensive drugs affect cellular lipid metabolism (e.g., LDL receptor, lipid synthesis, lipoprotein lipase, lecithin cholesteryl acyltransferase, acylcholesteryl acyltransferase, and cholesteryl ester hydrolase) are described. The clinical significance of changes in blood lipids and cellular lipid metabolism caused by antihypertensive drugs is not yet totally clear. Nevertheless, before antihypertensive drug treatment is initiated, blood lipid levels should be measured to identify preexisting hyperlipidemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination therapy with carvedilol and amiodarone in patients with severe heart failure

Carvedilol and at least in some studies, amiodarone have been shown to improve symptoms and prognosis of patients with heart failure. There are no reports on the outcome of combined treatment with both drugs on top of angiotensin‐converting enzyme inhibitors (ACEI), diuretics and digitalis.

Experience with coronary sinus lead implantations for cardiac resynchronization therapy in 244 patients

ZusammenfassungEinleitungDie kardiale Resynchronisationstherapie (CRT) stellt ein neues Verfahren zur Behandlung der Herzinsuffizienz dar. Da die Implantation eines CRT-Systems komplexer als eine normale Schrittmacherimplantation ist, sind Daten zu perioperativer Sicherheit und Komplikationen von besonderer Bedeutung.MethodikVon Januar 1999 bis Juni 2005 wurde in unserem Zentrum bei 244 Patienten (Pat.; mittleres Alter 64±12 Jahre, 82% männlich) die Implantation eines CRT-Systems versucht. Bei 44% lag eine koronare Herzkrankheit und bei 29% Vorhofflimmern vor. Bei 71 Pat. wurde ein vorbestehender Schrittmacher aufgerüstet.ErgebnisseBei 239 Pat. (97%) gelang eine CRT-Implantation (285 Interventionen). 27% der Systeme verfügten über eine Defibrillationsmöglichkeit. 2 Patienten benötigten epikardiale Elektroden. Insgesamt 130 CS-Elektroden wurden posterolateral implantiert, 97 anterolateral und 28 anterior. 88% der Eingriffe erfolgten mit der „over-the-wire“-Technik. Es kam zu keinen perioperativen Todesfällen, jedoch zu 37 Komplikationen (12,5%): CS-Dissektion (n=9), CS-Perforation (n=1), Kammerflimmern (n=4), Asystolie (n=5), Lungenödem (n=1), Pneumothorax (n=2), CS-Elektrodenrevision wegen Dislokation (n=7) oder Zwerchfellzucken (n=12) und Explantation wegen Infektion (n=2). Bei 88% der Patienten besserte sich die NYHA-Klasse, jedoch nur bei 55% mit anteriorer Elektrodenlage.ZusammenfassungPerioperative Komplikationen traten bei ca. 10–15% aller CRT-Implantationen auf, jedoch ohne Todesfall oder bleibende Morbidität. Die meisten Patienten profitierten von dem Eingriff. Während der Implantation müssen externe Defibrillation und Stimulation verfügbar sein. Eine anteriore CS-Elektrodenposition sollte vermieden werden.SummaryIntroductionCardiac resynchronization therapy (CRT) using coronary sinus (CS) leads is a new method for the therapy of congestive heart failure (CHF). Because the intervention is more complex than regular pacemaker implantations, information on the feasibility and side effects of this method are of interest.MethodsFrom 1999 to June 2005, CRT implantations were attempted in 244 patients (pts; mean age 64±12 years, range 14–90 years), 82% were male, 44% had coronary artery disease, 29% were in atrial fibrillation, 71 had preexisting pacemakers.ResultsIn 97% of the pts the intervention was successful (27% of the systems with defibrillation capabilities). In 285 interventions, 255 CS leads were positioned according to CS vein anatomy in 130 posterolateral, 97 anterolateral and 28 anterior side branches (16 patients received 2 CS leads). Over-the-wire leads were used in 88%, 71% were additionally preshaped. We observed no mortality but 37 complications (12.5%): CS dissection in 9, CS perforation in 1, ventricular fibrillation in 4, asystole in 5, pulmonary edema in 1, pneumothorax in 2, need for early CS lead revision in 19 (dislodgement n=7, phrenic nerve stimulation n=12) and infection with explantation in 2 cases. An improvement in NYHA functional class was found in 88% of pts (only 55% if anterior lead position).ConclusionPerioperative complications during CS lead implantation occur in 10–15% of cases. Most patients responded well to CRT. Patients should be informed about the possible need for a reoperation. During implantation, immediate defibrillation and stimulation capabilities must be available. Anterior lead positions should be avoided.

Sudden death and tailored medical therapy in elective candidates for heart transplantation

BACKGROUND Due to the shortage of donor organs there is a long waiting time for heart transplantation. As a consequence, a high mortality rate on the waiting list diminishes the potential benefit of the procedure. Tailored medical therapy optimized according to the individual patients demands was introduced to select responding HTx candidates for continued management without transplantation. The development of modes of death over time (heart failure, sudden arrhythmic) in this population is unknown. METHODS In 434 elective candidates for heart transplantation, submitted to our institution in the years 1984-1997 (50% coronary artery disease, mean age 51.6 +/- 12 years, 86% males) medical therapy was adjusted according to the results of repeated right heart catherizations. Adjuncts to conventional therapy with ACE inhibitors, digitalis and diuretics were amiodarone, beta-blockers, spironolactone, oral anticogulants, molsidomine or nitrates. Only patients not responding to these measures were processed to HTx. Clinical events (death, mode of death, HTx, resuscitation) were noted and analyzed by the Kaplan-Meier method and related to patients characteristics by multivariance analysis. RESULTS During the mean follow-up of 2.36 +/- 2.4 years only 113 patients (25%) received a donor heart. One hundred-sixteen patients (26%) died without transplantation. Eighty-three (72%) of the deaths were sudden, 24 (20%) due to progression of heart failure and 9 (8%) due to other reasons. A shift from heart failure to sudden death was observed. Including 8 successful resuscitations due to documented VT/VF, there is a 20% risk of having a major arrhythmic event during the first two years of observation. Long-term (>1 year) medical responders had better hemodynamics at entry. Patients who died suddenly had similar clinical and hemodynamic data at entry than patients who needed an early transplant, but were in a comparable NYHA stage before death than long-term medical responders (2.15 +/- 0.8 vs 1.82 +/- 0.6, NS). Patients dying suddenly had significant more ventricular premature beats (1.6 +/- 2.9%/24 hours vs 1.06 +/- 2.8%/24 hours, p < .01) and complex ventricular arrhythmias (7.3 +/- 2.7/24 hours vs 1.98 +/- 5.6/24 hours, p < .01) than long-term responders. Seventy-five percent of all sudden death occurred during the first 2 observation years. CONCLUSIONS The rate of heart failure death in elective candidates for heart transplantation under optimized medical therapy is low when patients are followed closely and transplant can be done rapidly after deterioration is recognized. Sudden death represents the highest risk for most patients. This event occurred predominantly in stable patients under tailored medical therapy without indication for HTx at that time. Our results strongly demand strategies for risk stratification and the investigation of prophylactic measures in this population.

Rate-responsive pacing in patients with heart failure: long-term results of a randomized study

AIMS Chronotropic incompetence (CI) in patients with congestive heart failure (CHF) develops frequently under beta-blocker and amiodarone therapy. It can be corrected by pacing. We performed a randomized study to test whether pacing is beneficial in CHF patients with CI. METHODS AND RESULTS Congestive heart failure patients under combined beta-blocker and amiodarone therapy (n = 77) were randomly assigned to inhibited pacing (INH; basal rate 40 bpm/hysteresis 30 bpm; n = 38) or to DDDR pacing with optimized atrioventricular delay (OPT; stimulation rate 65-120 bpm, n = 39). Groups showed similar baseline values in NYHA class, heart rate, and ejection fraction (EF) and were followed up to 10 years. The resting and mean 24 h heart rate after 1 year decreased by -2.6/-5 bpm in INH, but increased by +3.6/+6.0 bpm in the OPT group (P < 0.001). The QRS interval after 1 year increased by 12 +/- 23 ms in the INH group, but +32 +/- 36 ms in the OPT group (P < 0.01). Patients with INH developed a greater left ventricular EF (LVEF) when compared with OPT patients (+10.6 +/- 8 vs. +2 +/- 10%, respectively; P = 0.04). Changes in LVEF were negatively correlated with heart rate, but not with QRS width changes. Prognosis and the event rate were better in the INH group. CONCLUSION In the long-term follow-up, single-site ventricular pacing in patients with CHF and low LVEF is associated with significant clinical events and a poor prognosis.

Effects of Calcium Antagonists and Adrenergic Antihypertensive Drugs on Plasma Lipids and Cellular Cholesterol Metabolism

Calcium antagonists and antihypertensive alpha-adrenergic and beta-adrenergic drugs may cause changes in plasma lipoprotein levels. Different mechanisms by which these antihypertensive agents effect cellular lipid metabolism have been proposed. The activity of lipoprotein lipase that determines the catabolism of very low density lipoproteins (VLDL) is decreased by the beta-blocker propranolol and increased by alpha 1-antagonists. The plasma cholesterol or low density lipoprotein (LDL) level is inversely associated with the number of LDL receptors. Catecholamines suppress the LDL receptor activity, thus leading to an increase in plasma cholesterol concentration. The calcium antagonist verapamil and the beta-blocker propranolol may increase LDL receptor activity either per se or by its antagonizing effect on the catecholamine action. The metabolism of high density lipoproteins (HDL) may be affected directly by catecholamines, which might increase HDL binding activity, thereby enhancing efflux of cholesterol from cells. Catecholamines inhibit cholesterol biosynthesis in extrahepatic cells. The effects are mediated by alpha 2- and beta 2-adrenergic receptors. Accordingly, the alpha 2-agonists clonidine and alpha-methyldopa mimicked and propranolol opposed the catecholamine action. In contrast, the alpha 1 antagonists indoramin, prazosin, and urapidil had no effect on cholesterol synthesis. The results provide evidence that calcium antagonists and various antihypertensive drugs, depending upon their action on beta- or alpha-adrenergic receptors, affect lipid metabolism differently. The metabolic effect may play a role in atherogenesis and may be of clinical importance when antihypertensive treatment is considered.

Long-term hemodynamic benefit of biventricular pacing depending on coronary sinus lead position

ZusammenfassungEinführungAkute Testungen unter biventrikulärer Stimulation zeigten, dass der hämodynamische Effek von der Position der Koronarsinus-(CS)-Elektrode abhängt. Langzeituntersuchungen hierzu liegen jedoch bislang nicht vor.MethodenBei 45 Patienten (Alter 59±10 Jahre) mit Herzinsuffizienz (17 dilatative Kardiomyopathie, 23 ischämische, 5 valvuläre) und Linksschenkelbock (QRS-Breite >150 ms) wurden biventrikuläre Schrittmachersysteme implantiert. Die CS-Elektroden wurden posterior (P, n=15), lateral (L, n=19) oder bei fehlenden anderen Optionen anterior (A, n=11) implantiert. Präoperativ und nach 6 Monaten wurden Klinik, BNP, Echokardiographie und Rechtsherzkatheter beurteilt.ErgebnisseEingangsparameter waren in den 3 Gruppen ähnlich. Nach 6 Monaten fanden sich 32/34 Responder in den Gruppen P und L verglichen mit 7/11 in Gruppe A (94 vs. 64%, p=0,025). Die Ejektionsfraktion steigerte sich in den Gruppen P und L um 40 und 41% vs. nur 19% in A (p<0,03 für A vs. P+L). BNP-Spiegel sanken deutlicher in den Gruppen P und L (–55 und –35% vs. –27%, p=0,05 für Avs. P). Die Hämodynamik verbesserte sich nur in den Gruppen P und L: Arterieller Druck +8 und 9% vs. +2%, PCWP –23 und –15% vs. –4%, Pulmonalisdruck –18 und –12% vs. –3% (p<0,01 für A vs. P+L), Herzindex +21 und +12% vs. +11% (p=0,03 für A vs. P).SchlussfolgerungChronische biventrikuläre Stimulation verbessert Klinik, Auswurffraktion, BNP und Hämodynamik bei Patienten mit posteriorer und lateraler CS-Elektrodenposition. Anteriore CS-Elektrodenpositionen sollten vermieden werden.SummaryBackgroundAcute studies in cardiac resynchronization therapy (CRT) showed that hemodynamic effects may depend on the coronary sinus (CS) lead position. However, there are no data on the longterm effect of CS lead position.MethodsIn 45 heart failure patients with left bundle branch block and QRS >150 ms (age 59±10 years, 17 dilative cardiomyopathy, 23 ischemic, 5 valvular), biventricular pacemakers were implanted. CS leads were positioned in posterior (P, n=15), lateral (L, n=19) or, if no other option available, anterior (A, n=11) side branches. Before and 6 months after implantation, clinical state, echocardiography, brain natriuretic peptide (BNP) and right heart catheterization were evaluated.ResultsBaseline parameters were similar between groups. After 6 months, there were 32/34 responders in groups P and L compared to 7/11 responders in group A (94 vs roups P and L: Arterial pressure +8 and +9% vs +2%; PCWP –23 and –15% vs –4%, pulmonary pressure –18 and –12% vs –3% (p<0.01 for A vs P+L); cardiac index +21 and +12% vs +11% (p=0.03 for A vs P). BNP was reduced by 55, 35, and 27% (p=0.05 for A vs P). Ejection fraction increased in P and L by 40 and 41%, respectively, but only by +19% in A (p<0.03 for A vs P+L).ConclusionChronic CRT improves ejection fraction, BNP and hemodynamic measurements predominantely in patients with lateral and posterior CS lead positions. Anterior lead positions should be avoided.

Tumor marker determination after orthotopic heart transplantation

BACKGROUND Because the risk of developing malignant tumors after heart transplantation is approximately 100-fold higher, methods for rapid diagnosis must be developed to allow early and aggressive treatment in these patients. Although tumor markers have been used frequently for surveying already detected cancer, we studied their value in screening for tumors in heart transplant patients. METHODS The levels of the tumor markers CEA, CA19-9, CA125, CA72-4, TPA, TPS, and CYFRA 21-1 were determined prospectively in 3-month intervals in 91 heart transplant patients between 1993 and 1998. RESULTS In eight patients a definite diagnosis of cancer was made during the marker survey (mean observation time 2.85 +/- 1.3 years), including bronchogenic carcinoma in six, renal carcinoma in one, and colon cancer in one. All patients with bronchogenic carcinoma were smokers. The markers had a sensitivity below 60% to detect cancer. Given a 2-fold cutoff level (10 ng/mL), the CEA was the only marker with sufficient specificity (93.8%, only one false-positive result). Two patients were symptom-free even though they had elevated CEA levels. In one of those patients, disseminated intractable cancer was diagnosed at first evaluation, whereas no tumor was found in the other case at first evaluation. Subsequently, by means of fluorodeoxyglucose positron emission tomography, a hypermetabolic region was found in the right upper mediastinum. Control computed tomographic scan 4 weeks after the first investigation showed disseminated intractable disease also in this patient. Another heart transplant patient with colon cancer showed a normalization of the CEA after hemicolectomy and an increase in the CEA when liver dissemination developed. There was a relationship between cardiac death and CA125 and TPS in some heart transplant patients. CONCLUSIONS We conclude that the CEA is the only tumor marker with adequate sensitivity and specificity to detect subclinical malignancies in the follow-up of heart transplant patients. However, because of several limitations (limited diagnostic and therapeutic possibilities and enormous costs), we cannot recommend screening by tumor markers on a regular basis. Because of the elevated risk of cancer in patients who had organ transplantation, further prophylactic measures, especially smoking cessation programs, must be developed. Once a malignancy is diagnosed, tumor markers can help target clinical decisions. Additionally, nonspecific increases in CA125 and TPS levels might be related to nonmalignant circulatory disturbances and cardiac death.

What can happen during coronary sinus lead implantation: dislocation, perforation and other catastrophes

ZusammenfassungDie kardiale Resynchronisationstherapie mittels Koronarsinus-Elektroden ist inzwischen eine etablierte Methode zur Behandlung der Herzinsuffizienz, wenn gleichzeitig eine kardiale Asynchronie vorliegt. Eine erfolgreiche Behandlung ist von der Platzierung linksventrikulärer Elektroden in der Regel via CS abhängig. Dieser Eingriff ist schwieriger als die Implantation konventioneller Schrittmachersysteme und bedarf sorgfältiger Vorüberlegungen. Ohne entsprechende Vorbereitung und Übung kann sich ein solcher Eingriff leicht zu einer zeitraubenden Katastrophe auswachsen. Es wird deshalb die CS-Implantationstechnik mit dem Fokus auf mögliche Komplikationen ausführlich beschrieben, basierend auf eigenen Erfahrungen von 500 Implantationen der Jahre 1999–2007 und einer Literaturrecherche.AbstractCardiac resynchronization therapy (CRT) using coronary sinus (CS) leads is an established method for the therapy of congestive heart failure (CHF) in the case of asynchronous ventricular contractions. Successful therapy depends on the placement of left ventricular leads usually via the coronary sinus (CS), a technically more challenging procedure than regular pacemaker implantations. Without specific precautions CRT implantation can be the gateway to a time consuming nightmare. Therefore CS lead implantation methods, with a focus on complications, were reviewed according to the literature and own experience with approximately 500 procedures from 1999–2007.

Aortic valve replacement with homografts. An overview

ZusammenfassungDie Implantation (eigentlich Transplantation) frischer oder kryokonservierter menschlicher Herzklappen (Homografts) in Aortenposition gehört seit über 30 Jahren zum herzchirurgischen Repertoire. Homografts sind attraktive Alternativen zu mechanischen oder xenobiologischen Klappen, da eine Antikoagulation vermieden und eine nahezu normale Anatomie hergestellt werden kann. Behandelnde Ärzte sollten über die verfügbaren Implantate, die Operationsmethoden und die zu erwartenden Ergebnisse informiert sein, um Patienten mit Klappenvitien entsprechend beraten zu können und individuelle Komplikationsmöglichkeiten in der Nachsorge früh zu erfassen.Dargelegt wird eine Literaturübersicht zum Thema Homograftklappen. Es erfolgt eine Schilderung des Verfahrens der Graftgewinnung, der Herstellung und der Konservierung. Die Einsatzgebiete von Homografts werden erläutert und die Operationstechniken (subkoronar, Miniroot, Wurzelersatz) sowie die Ross-Operation diskutiert. Erwähnung findet auch der Einsatz von Homograftklappen bei frühkindlichen Herzfehlern. Komplikationen und wichtige Aspekte der Nachsorge werden kommentiert.Homografts eignen sich zum Aorten- und Pulmonalklappenersatz bei speziellen Indikationen (jugendlicher Patient, Kontraindikation zur Antikoagulation, Endokarditis). Angaben zu Langzeitergebnissen schwanken je nach Zentrum, eingesetzter Operationsmethode und Klappentyp. Pulmonale Homografts in Aortenposition sind im Gegensatz zu aortalen Homografts negativ zu beurteilen. Der Stellenwert von Homografts und der Ross-Operation im Vergleich zu ungestützten Xenografts sollte durch weitere möglichst multizentrische Langzeitstudien überprüft werden. Im Bereich der Kinderherzchirurgie haben sich Homografts bewährt, vor allem zur Rekonstruktion der rechtsventrikulären Ausflussbahn. Homograftimplantate in Mitralposition gehören noch nicht zur klinischen Routine und zeigen bislang enttäuschende Resultate. Die wesentliche Limitation im Einsatz von Homografts ist ihre geringe Verfügbarkeit; deshalb können Homografts nur begrenzt für die oben erwähnten speziellen Indikationen zur Verfügung gestellt werden.AbstractThe implantation of fresh or cryopreserved human heart valves (homografts) in aortic position is a tool in cardiac surgery since 30 years. Homografts are attractive alternatives to the implantation of mechanical or xenobiological prostheses, because anticoagulation can be avoided and a near normal anatomy can be restored. Physicians should know about the several kinds of grafts and operative techniques to adequately take care of the patients in follow-up.This overview on the literature covers methods of harvesting, preparation and conservation of homografts according to standard protocols of the European Homograft Bank in Brussels. Their use in the therapy of human valvular disease is discussed with special emphasis to operative techniques (subcoronary, root) and the Ross procedure and in pediatric surgery. Complications and aspects of postoperative care are discussed including immunologic phenomena.Homografts are useful tools for aortic valve replacement, especially in juveniles, in the presence of contraindications for anticoagulation and in endocarditis. Whereas aortic homografts have excellent long-term results, pulmonic homografts show a significant rate of malformation. Further studies should be performed to clarify the role of the Ross operation or stentless xenografts compared to homografts in aortic position. In pediatric cardiac surgery homografts are of value especially for the reconstruction of the right ventricular outflow tract. Homografts in mitral position show dissapointing results up to now. The major limitation in the use of homografts is the mismatch of availability and request, therefore homografts can only be used for the above mentioned special indications.The implantation of fresh or cryopreserved human heart valves (homografts) in aortic position is a tool in cardiac surgery since 30 years. Homografts are attractive alternatives to the implantation of mechanical or xenobiological prostheses, because anticoagulation can be avoided and a near normal anatomy can be restored. Physicians should know about the several kinds of grafts and operative techniques to adequately take care of the patients in follow-up. This overview on the literature covers methods of harvesting, preparation and conservation of homografts according to standard protocols of the European Homograft Bank in Brussels. Their use in the therapy of human valvular disease is discussed with special emphasis to operative techniques (subcoronary, root) and the Ross procedure and in pediatric surgery. Complications and aspects of postoperative care are discussed including immunologic phenomena. Homografts are useful tools for aortic valve replacement, especially in juveniles, in the presence of contraindications for anticoagulation and in endocarditis. Whereas aortic homografts have excellent long-term results, pulmonic homografts show a significant rate of malfunction. Further studies should be performed to clarify the role of the Ross operation or stentless xenografts compared to homografts in aortic position. In pediatric cardiac surgery homografts are of value especially for the reconstruction of the right ventricular outflow tract. Homografts in mitral position show disappointing results up to now. The major limitation in the use of homografts is the mismatch of availability and request, therefore homografts can only be used for the above mentioned special indications.