Reinhard C. Funck

Lisinopril-Mediated Regression of Myocardial Fibrosis in Patients With Hypertensive Heart Disease

BackgroundIn arterial hypertension, left ventricular hypertrophy (LVH) includes myocyte hypertrophy and fibrosis, which leads to LV diastolic dysfunction and, finally, heart failure. In spontaneously hypertensive rats, myocardial fibrosis was regressed and LV diastolic function was improved by treatment with the angiotensin-converting enzyme inhibitor lisinopril. Whether this holds true for patients with hypertensive heart disease was addressed in this prospective, randomized, double-blind trial. Methods and ResultsA total of 35 patients with primary hypertension, LVH, and LV diastolic dysfunction were treated with either lisinopril (n=18) or hydrochlorothiazide (HCTZ; n=17). At baseline and after 6 months, LV catheterization with endomyocardial biopsy, Doppler echocardiography with measurements of LV peak flow velocities during early filling and atrial contraction and isovolumic relaxation time, and 24-hour blood pressure monitoring were performed. Myocardial fibrosis was measured by LV collagen volume fraction and myocardial hydroxyproline concentration. With lisinopril, collagen volume fraction decreased from 6.9±0.6% to 6.3±0.6% (P <0.05 versus HCTZ) and myocardial hydroxyproline concentration from 9.9±0.3 to 8.3±0.4 &mgr;g/mg of LV dry weight (P <0.00001 versus HCTZ); this was associated with an increase in the early filling and atrial contraction LV peak flow velocity ratio from 0.72±0.04 to 0.91±0.06 (P <0.05 versus HCTZ) and a decrease in isovolumic relaxation time from 123±9 to 81±5 ms (P <0.00002 versus HCTZ). Normalized blood pressure did not significantly change in either group. No LVH regression occurred in lisinopril-treated patients, whereas with HCTZ, myocyte diameter was reduced from 22.1±0.6 to 20.7±0.7 &mgr;m (P <0.01 versus lisinopril). ConclusionsIn patients with hypertensive heart disease, angiotensin-converting enzyme inhibition with lisinopril can regress myocardial fibrosis, irrespective of LVH regression, and it is accompanied by improved LV diastolic function.

Prehospital initiation of tirofiban in patients with ST-elevation myocardial infarction undergoing primary angioplasty (On-TIME 2): a multicentre, double-blind, randomised controlled trial.

BACKGROUND The most effective magnitude and timing of antiplatelet therapy is important in patients with acute ST-elevation myocardial infarction (STEMI). We investigated whether the results of primary coronary angioplasty (PCI) can be improved by the early administration of the glycoprotein IIb/IIIa blocker tirofiban at first medical contact in the ambulance or referral centre. METHODS We undertook a double-blind, randomised, placebo-controlled trial in 24 centres in the Netherlands, Germany, and Belgium. Between June 29, 2006, and Nov 13, 2007, 984 patients with STEMI who were candidates to undergo PCI were randomly assigned to either high-bolus dose tirofiban (n=491) or placebo (N=493) in addition to aspirin (500 mg), heparin (5000 IU), and clopidogrel (600 mg). Randomisation was by blinded sealed kits with study drug, in blocks of four. The primary endpoint was the extent of residual ST-segment deviation 1 h after PCI. Analysis was by intention to treat. The trial is registered, number ISRCTN06195297. FINDINGS 936 (95%) patients were randomly assigned to treatment after a prehospital diagnosis of myocardial infarction in the ambulance. Median time from onset of symptoms to diagnosis was 76 min (IQR 35-150). Mean residual ST deviation before PCI (10.9 mm [SD 9.2] vs 12.1 mm [9.4], p=0.028) and 1 h after PCI (3.6 mm [4.6] vs 4.8 mm [6.3], p=0.003) was significantly lower in patients pretreated with high-bolus dose tirofiban than in those assigned to placebo. The rate of major bleeding did not differ significantly between the two groups (19 [4%] vs 14 [3%]; p=0.36). INTERPRETATION Our finding that routine prehospital initiation of high-bolus dose tirofiban improved ST-segment resolution and clinical outcome after PCI, emphasises that further platelet aggregation inhibition besides high-dose clopidogrel is mandated in patients with STEMI undergoing PCI.

Outcome of patients with sleep apnea–associated severe bradyarrhythmias after continuous positive airway pressure therapy

Twenty-nine patients in whom severe bradyarrhythmias occurred exclusively during obstructive sleep apnea and in whom advanced sinus node disease or atrioventricular conduction system dysfunction had been excluded by invasive electrophysiologic evaluation were prospectively followed on nasal continuous positive airway pressure. During 54 +/- 10 months follow-up, no syncope and no sudden deaths were observed, suggesting that patients with sleep apnea-associated bradyarrhythmias and a normal electrophysiologic study appear to have a favorable prognosis with continuous positive airway pressure.

Regulation and role of myocardial collagen matrix remodeling in hypertensive heart disease.

In hypertensive heart disease, reactive myocardial fibrosis represents as an excessive accumulation of fibrillar collagen within the normal connective tissue structures of the myocardium. The fact, that the myocardium of both ventricles is involved, irrespective of ventricular loading conditions, suggests that circulating factors, and not the hemodynamic load are primary responsible for this adverse response of the myocardial fibrous tissue. In various experimental in vivo models, it has been shown that myocardial fibrosis is always associated with activation of circulating or local renin-angiotensin-aldosterone systems (RAAS). Cardiac collagen metabolism is regulated by cardiac fibroblasts which express mRNAs for types I and III collagens, the major fibrillar collagens in the heart, and for interstitial collagenase or matrix metalloproteinase (MMP) 1 which is the key enzyme for interstitial collagen degradation. In order to elucidate the role of the RAAS effector hormones, angiotensin II (AngII) and aldosterone (ALDO), in the regulation of collagen synthesis or inhibition of MMP 1 production, adult human cardiac fibroblasts were cultured. Collagen synthesis was determined by 3H-proline incorporation, and MMP 1 activity by degradation of 14C-collagen measured under serum-free conditions in confluent fibroblasts after 24 hour-incubation with either AngII or ALDO over a wide range of concentrations (10(-11)-10(-6)M). In addition, the effects of the mineralocorticoid, deoxycorticosterone (DOC), and prostaglandin E2 (PGE2) on cardiac fibroblast function were determined. Compared with untreated control fibroblasts, collagen synthesis, normalized per total protein synthesis, showed a significant and dose-dependent increase after incubation with either mineralocorticoid hormone, ALDO or DOC, or after incubation with AngII. In contrast, collagen synthesis of cardiac fibroblasts was significantly decreased by PGE2 treatment. AngII type 1 or mineralocorticoid receptor antagonists, respectively, were able to completely inhibit the AngII- or mineralocorticoid-mediated increase of collagen synthesis. Furthermore, AngII significantly decreased MMP 1 activity while ALDO or DOC had no effect on cardiac fibroblast-mediated collagen degradation. In contrast, PGE2 significantly increased MMP 1 activity. Thus cardiac fibroblast function is modulated by either effector hormone of the RAAS, AngII and ALDO, via specific receptors that lead to progressive myocardial fibrosis in disease states where circulating or local RAAS is activated, i.e., in hypertensive heart disease. In contrast, PGE2, which would be elevated in myocardial tissue after angiotensin-converting enzyme inhibition, counteracts the fibrotic effects of the RAAS on myocardial tissue.

Complications of Third-Generation Implantable Cardioverter Defibrillator Therapy

To determine the incidence of complications of third‐generation implantable cardioverter defibrillator (ICD) therapy, 144 patients were prospectively studied who underwent first implant of third‐generation devices (i.e., ICD systems with biphasic shocks, ECC storage capability, and nonthoracotomy lead systems). During 21 ± 15 months of follow‐up, 41 (28%) patients had one or more complications. No patient died perioperatively (30 days) and no ICD infection was observed during follow‐up. Complications included bleeding or pocket hematoma (hemoglobin drop > 2 g/dL) in 5 (3%) patients, prolonged reversible ischemic neurological deficit in 1 (1%) patient, postoperative deep venous thrombosis of leg in 1 (1%) patient, pneumothorax in 2 (1%) patients, difficulty to defibrillate ventricular fibrillation intraoperatively in 2 (1%) patients, generator malfunction in 1 (1%) patient, arthritis of the shoulder in 3 (2%) patients, and allergic reaction to prophylactic antibiotics in 2 (1%) patients. A total of seven lead related complications were observed in six (4%) patients including endocardial lead migration in four (3%) patients. Twenty‐three (16%) patients received inappropriate shocks for supraventricular tachyarrhythmias (n = 13), non‐sustained ventricular tachycardia (VT) (n = 7), or myopotential oversensing (n = 3). We conclude that serious complications such as perioperative death or ICD infection are rare in patients with third‐generation ICDs. Lead‐related problems and inappropriate shocks during follow‐up are the most frequent complications of third‐generation ICD therapy. Recognition of these complications should promote advances in ICD technology and management strategies to avoid their recurrence.

Effect of the renin-angiotensinaldosterone system on the cardiac interstium in heart failure

The interaction of the renin-angiotensin-aldosterone system (RAAS) and cardiac growth is of great interest in chronic heart failure. The pressure or volume overloaded heart shows a hypertrophic growth of the myocardium, i.e., an enlargement of cardiac myocytes. In addition, cardiac fibroblast activation is responsible for the accumulation of fibrillar type I and type III collagens within the interstitium and adventitia of intramyocardial coronary arteries. This remodeling of the cardiac interstitium represents a major determinant of pathological hypertrophy in that it accounts for abnormal myocardial stiffness, leading to ventricular diastolic and systolic dysfunction and ultimately the appearance of symptomatic heart failure.The growth of cardiac fibroblasts is not primarily regulated by the hemodynamic load.In vivo andin vitro studies suggest that the effector hormones, angiotensin II and aldosterone, of the RAAS are primarily involved in regulating the structural remodeling of the myocardial collagen matrix. In cultured adult cardiac fibroblasts, angiotensin II and aldosterone has been shown to stimulate collagen synthesis while angiotensin II additionally inhibits matrix metalloproteinase I activity, which is the key enzyme for interstitial collagen degradation in the myocardium.These findings may serve as rationale for a remedial therapy with angiotensin converting enzyme inhibition or blockage of the RAAS in congestive heart failure in patients with hypertensive heart disease, post myocardial infarction or with dilated cardiomyopathy.

Influence of D-Net (European GSM-Standard) Cellular Phones on Pacemaker Function in 50 Patients with Permanent Pacemakers

The widespread use of cellular phones in the last years has prompted some recant studies to suggest an interference of pacemaker function by cellular phone usage. To determine the risk of pacemaker patients using D‐net cellular phones, we tested 50 patients with permanent pacemakers after routine pacemaker check by short phone calls using a cellular phone (Ericsson, D‐net, frequency 890–915 MHz, digital information coding, equivalent to the European Croupe Systemes Mobiles standard). A six‐channel surface ECG was continuously recorded from each patient to detect any interactions between pacemakers and cellular phones. Phone calls were repeated during the following pacemaker settings: (1) preexisting setting; (2) minimum ventricular rate of 90 beats/min and preexisting sensitivity; and (3) minimum ventricular rate of 90 beats/min and maximum sensitivity without T wave oversensing. Only 2 (4%) of 50 patients repeatedly showed intermittent pacemaker inhibition during calls with the cellular phone. Both pacemakers had unipolar sensing. Therefore, although interactions between cellular phone use and pacemaker function appear to be rare in our study, pacemaker dependent patients in particular should avoid the use of cellular phones.

Management of patients with suspected (peri-)myocarditis and inflammatory dilated cardiomyopathy.

Inflammatory cardiomyopathy and myocarditis are considered acquired forms of dilated cardiomyopathy. Whereas consensus documents on the diagnosis of myocarditis and perimyocarditis do exist, guidelines on the specific treatment have been established only for the management of pericardial diseases, which at least partly can be applied in analogy to myocarditis. Presently, feasible clinical pathways are available, which can lead to a correct diagnosis and specific treatment. This is illustrated with two cases of fulminant myocarditis, in one with successful diagnosis and treatment of a cardiac sarcoid and another one in which diagnostic nihilism led to a lethal outcome in giant cell myocarditis at necropsy. A case of active parvo B19-positive myocarditis demonstrates the role of immunoglobulin treatment under these conditions.ZusammenfassungMyokarditis und inflammatorische Kardiomyopathie gehören zu den erworbenen Kardiomyopathieformen. Gegenwärtig gibt es zwar Konsensusdokumente zur adäquaten Diagnostik der Myokarditis sowie eine Leitlinie der European Society of Cardiology zur Perikarditis, aber keine Leitlinien zur Therapie der Myokarditis, so dass wir auf rationale Behandlungspfade in der Betreuung von Patienten mit entzündlichen Myokarderkrankungen angewiesen sind. Der Sinn der Behandlungspfade wird anhand deren erfolgreicher Anwendung bei fulminanter Myokarditis und Herzsarkoidose sowie einer mit i.v. Immunglobulinen behandelten Parvo-B19-assoziierten Myokarditis illustriert. Diagnostischer Nihilismus führte in einem weiteren Fall erst post mortem zur korrekten Diagnose.

Dilated Cardiomyopathies as a Cause of Congestive Heart Failure

Definition and Classification: Cardiomyopathies are disorders affecting the heart muscle that frequently result in congestive heart failure. Five major forms are recognized: dilated, hypertrophic, restrictive, right ventricular, and nonclassifiable cardiomyopathies with distinct hemodynamic properties. Furthermore, the new WHO/WHF definition also comprises inflammatory cardiomyopathy, defined as myocarditis in association with cardiac dysfunction. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized. Viral cardiomyopathy is defined as viral persistence in a dilated heart. It may be accompanied by myocardial inflammation and then termed inflammatory viral cardiomyopathy (or viral myocarditis with cardiomegaly). If no inflammation is observed in the biopsy of a dilated heart (< 14 lymphocytes and macrophages/mm2), the term viral cardiomyopathy or viral persistence in dilated cardiomyopathy should be applied. Diagnosis and Treatment: In recent years, there have been breakthroughs in understanding the molecular and genetic mechanisms involved in this group of conditions, enabling improvement of diagnostic strategies and introduction of new therapies. Ongoing evaluation of antiviral, immunoglobulin, and immunosuppressive therapies including the European Study of Epidemiology and Treatment of Cardiac Inflammatory Diseases (ESETCID), removal of antibodies by immunoadsorption, anticytokine and gene therapy, as well as the mechanical support devices may provide new treatment options.Definition und Klassifikation: Die gegenwärtig akzeptierte klinisch-pathophysiologische Einteilung der Kardiomyopathien als Herzmuskelerkrankungen (WHO/ISFC Task Force), die mit einer kardialen Funktionsstörung einhergehen unterscheidet Kardiomyopathien nach ihrem klinischem Phänotyp, d. h. nach ihrer Hämodynamik und ihrer makroskopischen Anatomie in folgende Formen: dilatative, hypertrophische, restriktive, arrhythmogene rechtsventrikuläre und nicht klassifizierbare Kardiomyopathien. Diese Übersicht befasst sich mit der häufigsten Form der Kardiomyopathien, der dilatativen (früher kongestiven) Form (DCM). Hierunter fallen u. a. familiäre, genetisch determinierte und sporadische Kardiomyopathien unterschiedlicher Ätiologie. Bemerkenswert ist, dass selbst bei familiären Formen der klinische Phänotyp außerordentlich variabel sein kann (Heterogenitätsprinzip). Diagnostik: Ein besonderer Schwerpunkt der Übersicht liegt in der ätiopathogenetisch häufigen und deshalb klinisch und differentialdiagnostisch bedeutenden Ursache: der Entzündung bei Myokarditis bzw. bei der inflammatorischen Kardiomyopathie. Hier gehören die Quantifizierung des Infiltrats und der Nachweis des Erregers in der Endomyokardbiopsie mittels Polymerasekettenreaktion oder In-situ-Hybridisierung zum erforderlichen Standard. Nur so lässt sich die hämodynamische Klassifikation der DCM durch eine ätiopathogenetische Einteilung ergänzen bzw. ersetzen, damit die idiopathischen Kardiomyopathien von den ätiopathogenetischen bekannten “sekundären Formen” differenziert werden können.Hämodynamisch handelt es sich bei der DCM um einen überwiegend systolischen Pumpfehler. Die DCM ist charakterisiert durch eine Vergrößerung des linken und/oder rechten Ventrikels und eine Reduktion der Ejektionsfraktion. Eine begleitende Störung der Relaxation (Lusitropie) kann hinzutreten. Therapie: Die Therapieprinzipien der Herzinsuffizienz gelten auch für die DCM. Sie stellen auch die Basistherapie der spezifischen, ätiologisch bekannten Kardiomyopathien dar. Da bei der idiopathischen DCM die auslösenden Faktoren nicht bekannt sind, stehen nur symptomatische Maßnahmen (4 Ds) zur Verfügung. Das Prinzip der körperlichen Schonung gilt unverändert für entzündliche Kardiomyopathien. Bei den nicht entzündlichen Formen erscheint eine dosierte Bewegungstherapie die Lebensqualität zu verbessern, ohne die Prognose zu belasten. Die klassischen 4 Ds der Therapie umfassen :diätetische Maßnahmen mit Kochsalz- und Flüssigkeitsrestriktion, Alkoholkarenz, Nikotinverzicht; Gabe von Diuretika, Vasodilatatoren (z.B. ACE-Hemmer und/oder AT1-Rezeptor-Antagonisten) und Digitalistherapie, insbesondere bei tachykardem Vorhofflimmern, sowie die Betablockertherapie (langsam und mit niedrigen Dosen einschleichen und vorsichtig steigern). Kleinere Studien belegen positive Effekte durch eine chirurgische Verkleinerung des linken Ventrikels (umstritten: Batista-Operation, Ventrikelreduktionsplastiken). In Erprobung sind die biventrikuläre Stimulation (Ventrikelresynchronisation) bei Linksschenkelblock zur Optimierung des Kontraktionsablaufs oder die allgemeine oder spezifische Immunadsorption zur Elimination möglicherweise kardiodepressiver Antikörper u.a. gegen den β-Rezeptor. Als Ultima Ratio bei konservativ nicht mehr behandelbarer Kardiomyopathie ist an eine Herztransplantation zu denken.

How many patients with dilated cardiomyopathy may potentially benefit from cardiac resynchronization therapy

GRIMM, W., et al.: How Many Patients with Dilated Cardiomyopathy May Potentially Benefit from Cardiac Resynchronization Therapy? The clinical and electrocardiographic Marburg Cardiomyopathy database was analyzed to identify potential candidates for cardiac resynchronization therapy (CRT) with biventricular or left ventricular pacing among 566 patients with dilated cardiomyopathy (DCM). All of the following restrictive selection criteria were fulfilled by 38 patients (7%): NYHA functional class ≥ 3 ( n = 193 , 34%), left ventricular ejection fraction (LVEF) <30% (n = 238, 42%), sinus rhythm ( n = 437 , 77%), left bundle branch block (LBBB, n = 142 , 25%), and QRS duration ≥ 150 ms ( n = 136 , 24%). In 78 of the 566 patients (14%) all of the following less restrictive selection criteria were fulfilled: NYHA functional class ≥3 ( n = 193 , 34%), LVEF < 35% in presence of any underlying rhythm (n = 326, 58%), QRS duration ≥ 120 ms with right or left bundle branch block ( n = 223 , 39%). Thus, between 7% and 14% of patients with DCM were candidates for CRT depending on the application of strict versus less restrictive selection criteria.(PACE 2003; 26[Pt. II]:155–157)