[Chronic heart failure: structural and functional deficit of our health policy?]. / Chronisch hartfalen: structureel en functioneel deficit van ons gezondheidsbeleid?

UNLABELLED: The problems concerning chronic heart failure can be summarized in 4 paradoxes which concern epidemiology, diagnosis, therapy, and financing respectively. Paradox I: The mortality due to chronic heart failure continues to increase worldwide despite a slow but significant decrease in mortality due to acute coronary syndromes. Paradox II: The clinical manifestations of chronic heart failure correlate poorly with the underlying pathophysiological progression. Paradox III: There is a striking discordance between the perception of evidence-based guidelines by the primary care physician and the actual reality in his/her private medical practice. Paradox IV: The inevitable increase in financial cost contrasts sharply with the many desperate attempts for cost reduction by the government. SOLUTION: Heart Failure Clinic. Since the introduction of the first heart failure clinics in Sweden in 1990, numerous studies in various countries have emphasized the medical-cardiological and economical benefit of such organizations, mainly as a result of a substantial reduction of more than 40% in hospitalization. Moreover, a more central role is attributed to the primary care general practicioner.

Combined endurance/resistance training reduces plasma TNF-alpha receptor levels in patients with chronic heart failure and coronary artery disease.

AIMS: Physical reconditioning of patients with chronic heart failure (CHF) improves exercise capacity and restores endothelial function and skeletal muscle changes. The effects of 4 months combined endurance/resistance exercise training on cytokines and cytokine receptors in patients with CHF were studied. In addition, changes in submaximal and maximal exercise performance were addressed. METHODS AND RESULTS: Twenty-three patients with stable CHF due to coronary artery disease (CAD, n=12) or idiopathic dilated cardiomyopathy (IDCM, n=11) were trained for 4 months. Blood sampling for measurement of plasma concentrations (ELISA) of interleukin (IL)-6, tumour necrosis factor (TNF)-alpha, soluble TNF receptor 1 (sTNFR1) and 2 (sTNFR2), as well as cardiopulmonary exercise testing were performed at baseline and after 4 months. Training induced a significant decrease in sTNFR1 (P=0.02) for the total population, and in both sTNFR1 (P=0.01) and sTNFR2 (P=0.02) concentrations for the CAD group only. IL-6 and TNF-alpha levels were not altered. Cytokine concentrations remained unchanged in an untrained age- and sex-matched control group. NYHA functional class, submaximal and maximal workrate were significantly improved in both patient groups. Oxygen uptake at the anaerobic threshold (P=0.002) and at peak exercise increased in the CAD patients only (P=0.008). CONCLUSION: Besides an overall beneficial effect on exercise capacity, combined endurance/resistance exercise training has an anti-inflammatory effect in patients with CHD and CAD.

Distribution and role of Na(+)/K(+) ATPase in endocardial endothelium.

OBJECTIVE: In mammalian cardiomyocytes, alpha isoforms of Na(+)/K(+) ATPase have specific localisation and function, but their role in endocardial endothelium is unknown. METHODS: Different alpha isoforms in endocardial endothelium and cardiomyocytes of rabbit were investigated by measuring contractile parameters of papillary muscles, by RT-PCR, by Western blots and by immunocytochemistry. RESULTS: Inhibition of Na(+)/K(+) ATPase by decreasing external K(+) from 5.0 to 0.5 mmol/l caused biphasic inotropic effects. The maximal negative inotropic effect at external K(+) of 2.5 mmol/l was significantly larger in +EE muscles (with intact endocardial endothelium) than in -EE muscles (with endocardial endothelium removed) (-22.5+/-2.4% versus -5.9+/-4.0%, n=7, P<0.05). Further decrease of K(+) to 0.5 mmol/l caused endothelium-independent positive inotropy (27.8+/-11.8% for +EE versus 18.6+/-11.3% for -EE, n=7, P>0.05). Inhibition of Na(+)/K(+) ATPase either by dihydro-ouabain (10(-9) to 10(-4) mol/l, n=4) or by K(+) decrease following inhibition of Na(+)-H(+) exchanger by dimethyl-amiloride (50 micromol/l, n=6) caused endothelium-independent positive inotropic effects only. RT-PCR and Western Blot demonstrated alpha(1) and alpha(2) Na-K-ATPase isoforms in cardiomyocytes, but only alpha(1) in cultured endocardial endothelial cells. Immunohistochemistry showed that alpha(1) in endocardial endothelium was predominantly present at the luminal side of the cell (n=7) and that alpha(1) and alpha(2) displayed different localisation in cardiomyocytes. CONCLUSIONS: These results suggested that negative and positive inotropic effects of Na(+)/K(+) ATPase inhibition in +EE muscles could be attributed to inhibition of endocardial endothelial alpha(1) and muscle alpha(2) isoform, respectively. Accordingly, the endocardial endothelial alpha(1) isoform of Na(+)/K(+) ATPase may contribute to blood-heart barrier properties of this endothelium and may control cardiac performance via endothelial Na(+)/H(+) exchange.

Activation of cardiac endothelium as a compensatory component in endotoxin-induced cardiomyopathy: role of endothelin, prostaglandins, and nitric oxide.

BACKGROUND: In view of growing evidence of an important endothelial paracrine regulation of cardiac function, the present study investigated the role of cardiac endothelium-derived endothelin-1 (ET-1), prostaglandins, and nitric oxide (NO) during endotoxin-induced cardiomyopathy in rabbits. METHODS AND RESULTS: Immunohistochemical studies showed a marked transient coinduction of the inducible isoforms of NO synthase (NOS-2) and cyclooxygenase (COX-2) in endocardial endothelium and coronary arteriolar endothelium of hearts 12 hours after intravenous administration of lipopolysaccharide (LPS+12h); staining for both isoforms was much weaker 24 hours later (LPS+36h). Nitrotyrosine localization was similar to that of NOS-2, suggesting a NOS-2-related endothelial formation of peroxynitrite in septic hearts. Contractile performance of papillary muscles was depressed in both LPS-treated groups. In the LPS+12h group, however, isometric twitches were significantly prolonged (482+/-14 versus 420+/-14 ms in the saline-treated group, P<0.005). This twitch prolongation was completely reversed by simultaneous administration of BQ-123 and indomethacin to block endogenous ET-1 and prostaglandins, respectively. In addition, in the LPS+12h group, myocardial inotropic responsiveness to exogenous ET-1 was enhanced (P<0.01). CONCLUSIONS: Cardiac endothelial activation and myocardial sensitization to endothelium-derived mediators may be part of an adaptive response in the early (12 hours) stages of septic cardiomyopathy.

Reducing emotional distress improves prognosis in coronary heart disease: 9-year mortality in a clinical trial of rehabilitation.

BACKGROUND: The impact of treating emotional distress on prognosis in coronary heart disease (CHD) has not been documented convincingly. We tested the hypothesis that treatment-related changes in emotional distress may explain the beneficial effect of rehabilitation on prognosis. METHODS AND RESULTS: In this nonrandomized clinical trial, 150 men with CHD participated in rehabilitation (n=78) or received standard medical care (n=72). There were no differences between rehabilitation and control patients with regard to left ventricular ejection fraction (LVEF) or standard care. End points were reduction in distress after 3 months and mortality after 9 years. At the end of the 3-month trial, 64 patients (43%) reported improvement and 22 (15%) reported deterioration in negative affect. Rehabilitation patients improved more (P=0.004) and deteriorated less (P=0.001) than control patients; rehabilitation was effective in reducing distress. After 9 years of follow-up, 15 patients had died (13 cardiac and 2 cancer deaths). Mortality was associated with LVEF

Inadequate response to treatment in coronary heart disease : adverse effects of type D personality and younger age on 5-year prognosis and quality of life.

BACKGROUND: Improvement in treatment of patients with coronary heart disease (CHD) has caused longer survival but also an increase in the number of patients at risk for subsequent cardiac events and impaired quality of life (QOL). We hypothesized that chronic emotional distress confers an increased risk of poor outcome despite appropriate treatment. METHODS AND RESULTS: This prospective study examined the 5-year prognosis of 319 patients with CHD. Baseline assessment included symptoms of depression/anxiety and distressed personality type (type D-ie, high negative affectivity and social inhibition). The main end points were cardiac death or nonfatal myocardial infarction and impaired QOL. There were 22 cardiac events (16 nonfatal); they were related to left ventricular ejection fraction (LVEF)

Improvement of endocardial and vascular endothelial function on myocardial performance by captopril treatment in postinfarct rat hearts.

Background-Endocardial (EE) and myocardial capillary vascular endothelial (myocap VE) cells have been shown to modulate the contractile characteristics of myocardium in a calcium-dependent manner. We evaluated the endothelial-myocardial interaction in the rat postinfarction myocardial infarction (MI) model and the effects of captopril. Methods and Results-Wistar rats were divided into 4 groups treated for 4 weeks: (1) control; (2) infarcted controls (left anterior coronary artery ligation); (3) infarcted+captopril 2 g/L in drinking water; and (4) infarct+captopril+triton intracoronary injection. Coronary VE function was evaluated by infusion of serotonin in Langendorff preparations (n=31), and the myocardial contractile characteristics were investigated by use of isolated papillary muscles (n=44). Cardiac mRNA for endothelial constitutive nitric oxide synthase (ecNOS) was measured, and its cellular location was evaluated by immunohistochemistry. Serotonin-induced increase in coronary flow was decreased in infarct controls compared with controls (4.6% versus 53.4%, P<0.01) but not in the 2 infarct+captopril groups. Intracoronary triton injection decreased serotonin-induced coronary flow in the infarct+captopril+triton group. All MI groups had decreased total tension in isolated papillary muscles. EE removal by triton immersion decreased total tension in all groups except for infarct controls (3.3 versus 3.2 g/mm(2)). Cardiac ecNOS mRNA decreased in the control infarct group but remained normal in the infarct+captopril group. Conclusions-Chronic postinfarction endothelium-induced coronary vasodilatation is impaired, and both EE and myocap VE dysfunction contribute to myocardial depression. Captopril use prevents these abnormalities and the reduction of cardiac ecNOS mRNA.

Dilated cardiomyopathy: changing pathophysiological concepts and mechanisms of dysfunction.

Experimental observations made over the past two decades have led to a profound shift in the conceptual paradigms about the syndrome of heart failure and dilated cardiomyopathy. As a consequence, heart failure is currently considered a complex disease and is not merely characterized by hemodynamic disturbances. It is now believed that the syndrome is governed and impelled by neurohormonal imbalances and intracardiac paracrine processes. The latter processes are mediated by activated cardiac endothelial cells and cytokines, creating a state of cardiac maladaption and leading to disease progression. Therapeutic interventions such as operative left ventricular volume reduction or mitral valve reconstruction should therefore no longer be solely interpreted in terms of hemodynamics (i.e., symptomatic improvements). Effects on neurohormonal, endothelial, and cytokine activities should be taken equally into account.

Pathogenesis of heart failure. Changing conceptual paradigms.

Experimental observations, made over the past two decades, have led to a profound shift in the conceptual paradigms about the syndrome of heart failure. As a consequence, heart failure is nowadays considered as a complex disease, not merely characterized by haemodynamic disturbances. Instead, it is now believed that the syndrome is governed and impelled by neurohumoral imbalances and by intracardiac paracrine processes. The latter processes are mediated by activated cardiac endothelial cells and by cytokines, creating a state of cardiac maladaption and leading to disease progression. The clinical benefit of several therapeutic interventions that could not be satisfactorily clarified by improvements in the haemodynamic status, may, therefore, be explained by an unexpected impact on cytokines and endothelial dysfunction. Further extension of these insights will form the basis for the future treatment of heart failure.

Cardiac endothelium and myocardial function.

Endocardial endothelium and vascular endothelium of myocardial capillaries share common features as modulators of cardiac performance, rhythmicity and growth. Growing evidence suggests differences between these two cardiac endothelial cell types with regard to developmental, morphological and functional properties. A major difference probably resides in the way and extent by which these endothelial cells perceive and transmit signals.

Nonuniformity of endothelial constitutive nitric oxide synthase distribution in cardiac endothelium.

Endocardial endothelium and endothelium of coronary vessels produce NO. Histochemical methods have suggested that coronary arterial endothelial cells contain more endothelial constitutive NO synthase (ecNOS) than does coronary venous endothelium. We have further investigated the distribution of ecNOS in cardiac endothelium using immunofluorescence and en face confocal microscopy of rat heart. In endocardial endothelium, confocal microscopy revealed distinct ecNOS labeling of peripheral cell borders, cytoplasmic labeling, and labeling of the Golgi complexes. Labeling of the cell borders and of the Golgi complexes was confirmed by double staining for ecNOS and for platelet and endothelial cell adhesion molecule or Golgi 58k protein, respectively. Cytoplasmic labeling was strongest in coronary arterial endothelium. The size of the ecNOS-labeled Golgi complexes decreased from coronary arterial endothelial cells (8.63 +/- 0.39 microm2, mean +/- SE of 5 rats) to endocardial endothelium (7.07 +/- 0.61 microm2) and to coronary venous endothelium (3.65 +/- 0.20 microm2). In addition, pixel intensity of ecNOS labeling was higher in arterial endothelial cells than in venous endothelial cells. Endothelium of myocardial capillaries also contained small ecNOS-labeled Golgi complexes. No correlation was observed between endothelial cell surface area and Golgi complex size. Caveolin-1 labeling was strongest in capillaries and did not coincide completely with ecNOS labeling in endocardial and venous endothelium. These results suggest that endocardial and coronary arterial endothelium in the rat have a higher synthetic activity and might express more ecNOS than is expressed by cardiac venous and capillary endothelium. The observed heterogeneity in ecNOS distribution might be related to the specific mechanochemical environment and function of each endothelial compartment.

Personality, disease severity, and the risk of long-term cardiac events in patients with a decreased ejection fraction after myocardial infarction.

BACKGROUND: Patients with myocardial infarction (MI) with a decreased left ventricular ejection fraction (LVEF) have a poor prognosis, but the role of emotional stress in prognosis is not known. We hypothesized that emotional stress in these patients (1) is unrelated to the severity of cardiac disorder, (2) predicts cardiac events, and (3) is a function of basic personality traits. METHODS AND RESULTS: Eighty-seven patients with MI (age, 41 to 69 years) with an LVEF of < or =50% underwent psychological assessment at baseline. Patients and their families were contacted after 6 to 10 years (mean, 7.9 years); cardiac events were defined as cardiac death or nonfatal MI. Emotional distress was unrelated to the severity of cardiac disorder. At follow-up, 21 patients had experienced a cardiac event (13 fatal events). These events were related to LVEF of < or =30%, poor exercise tolerance, previous MI, anxiety, anger, and depression (all P< or =.02). Patients with a distressed personality (type D; ie, the tendency to suppress negative emotions) were more likely to experience an event over time compared with non-type D patients (P=.00005). Cox proportional hazards analysis yielded LVEF of < or =30% (relative risk, 3.0; 95% confidence interval, 1.2 to 7.7; P=.02) and type D (relative risk, 4.7; 95% confidence interval, 1.9 to 11.8; P=.001) as independent predictors. Anxiety, anger, and depression did not add to the predictive power of type D; these negative emotions were highly correlated and reflected the personality domain of negative affectivity. CONCLUSIONS: Personality influences the clinical course of patients with a decreased LVEF. Emotional distress in these patients is unrelated to disease severity but reflects individual differences in personality. Clinical trials should take a broad view of the target of intervention; assessment of LVEF and personality may identify patients at risk.

Reappraisal of the multicellular preparation for the in vitro physiopharmacological evaluation of myocardial performance.

In order to evaluate myocardial performance, single cardiomyocytes suffer from technical problems and from the fact that some basic functional properties vanish when one moves down the hierarchic scale from multicellularity to single cells. The isolated papillary muscle has at present proven to be superior to the isolated intact cardiomyocyte. A large number of major intra- and extracellular features required to describe myocardial performance can be derived from analyzing twitch contraction and relaxation in the multicellular isolated papillary muscle. In addition, the present paper illustrates the possibility to differentiate between effects of inotropic interventions on activating Ca2+ and Ca2+ sensitivity in multicellular preparations, from a grid analysis of isometric twitches in a coordinate system of peak rate of force development (+dF/dt; reflecting the time pattern of twitch contraction) versus time to half relaxation (tHR; reflecting the time pattern of twitch relaxation). The abundance of information about myocardial performance that can be derived from the easily accessible multicellular preparation reflects its physiological kinship with the intact ventricle.

Endocardial endothelial dysfunction and heart failure.

Like vascular endothelium, the EE plays a role in transendothelial transport, in coagulant and thrombotic processes, and in interactions with inflammatory cells. In addition, EE is involved in the modulation of cardiac performance of subjacent myocardium. EE dysfunction includes insufficient as well as excessive performance of any of its multiple functions. Dysfunction can progress from a disturbed modulation of myocardial performance and an imbalance in the release of growth factors to changes in EE cytoskeletal organization, with concomitant changes in transendothelial permeability, and in extreme cases, to loss of endothelial integrity and frank denudation. Structural and functional impairment of EE and of endocardial interstitial cells may be primary or secondary to the disease. Mechanical stress, various hormones and cytokines can initiate EE dysfunction. EE dysfunction may influence the development of cardiac failure in endo(myo)cardial fibrosis (Loeffler's endocarditis and carcinoid syndrome) and in dilated cardiomyopathy. Although Bouillaud, in 1836, was referring to endocarditis when stating: (quote: see text) his statement may presently find a much broader field of applicability in cardiology.