Tumor necrosis factor alpha and glutathione interplay in chronic heart failure.

The pro-inflammatory cytokine, tumor necrosis factor alpha (TNF alpha), in concert with neurohormones, contributes to chronic heart failure (CHF) progression. This implies that TNF a antagonism may constitute an important target for CHF therapy. However, clinical trials in CHF patients using compounds that trap TNF alpha, comprising infliximab, an antibody directed to TNF alpha, and etanercept, a soluble recombinant receptor of TNF alpha, gave disappointing results bringing back to light the dual, short-term beneficial and long-term harmful effect of TNF alpha. This review focuses on the dual, concentration- and time-related effects of TNF alpha, the yin and yang action of TNF alpha in cardiac ischemia/reperfusion and contraction. Importantly, the harmful effects of TNF a are related to glutathione deficiency, a common hallmark to several other chronic inflammatory diseases. Recently, in rat models of CHF, oral administration of the glutathione precursor, N-acetylcysteine (NAC), was shown to hinder pathways of TNF alpha harmful signalling and to rescue cardiac structure and function. These results suggest that glutathione deficiency in association with TNF alpha activation may play a role in the pathophysiology of CHF and that NAC may represent a potential therapy in CHF.

[Pathology and dental care in the context of cardiovascular conditions: myths, beliefs and realities]. / Pathologies et soins dentaires dans le cadre des affections cardiovasculaires: mythes, croyances et réalités.

The knowledge regarding the links between dental and cardiac affections are generally based on empirical concepts and lead to unjustified clinical practices. Infectious endocarditis (IE) is the principal cardiac diseases concerned with dental procedures. Although in France, the incidence of IE is stable, the incidence of oral bacteria at the origin of IE is diminishing. The risk of IE and thus the indication of antibioprophylaxis depend upon the subjacent cardiopathy and dental treatment. Antibioprophylaxis has to be very strict in patients with high or moderate risks of IE but is not necessary in low risk patients. In all cases, a good oral and dental hygiene and a regular dentist follow up are the most effective methods of preventing IE. Coronary artery disease and dental affections are associated because they present similar risk factors (i.e. smoking, excessive sugar consumption) and also because inflammation increases the risk of acute coronary syndrome. Today, dental cares are not contraindicated in patients with recent coronary syndrome if precise protocols are followed. Concerning the hemorrhagic risk during dental care in patients treated by anticoagulants and/or antithrombotics, dental cares and extractions are possible if INR or heparinemy are within the therapeutic limits and local haemostasis is meticulous. In addition, aspirin does not require to be stopped before minor dental treatments. Finally a better collaboration between dentists and cardiologists would allow an optimum management of patients with cardiac disease requiring dental cares.

[Left ventricular functional imagery by magnetic resonance. Applications and developments]. / Imagerie fonctionnelle du ventricule gauche par résonance magnétique. Applications et développements.

Technical developments have considerably reduced the acquisition time and have improved the quality of magnetic resonance imaging. The recent recommendations of the European Society of Cardiology place MRI in the front line of investigations for the diagnosis and evaluation of congenital heart disease, cardiac tumours and pathology of the pericardium and great vessels. With the possibility of obtaining oblique planes in all 3 dimensions, MRI is the reference for the measurement of left ventricular mass, volumes, and ejection fraction, with the major advantage of not depending on hypotheses of left ventricular geometry. In addition to these known applications, the development of functional cardiac MRI has led to significant advances in the study of regional myocardial function and perfusion. The aim of this article is to discuss present indications and the potential developments of functional cardiac MRI, focusing on the quantitative evaluation of myocardial function and perfusion.

[Hospital mortality in cardiology. Analysis of deaths occurring in the Federation of Cardiology of a university hospital center]. / Mortalité hospitalière en cardiologie. Analyse des décès survenus au sein de la fédération de cardiologie d'un centre hospitalo-universitaire.

The aim of this study was to examine the nature of cardiovascular deaths occurring in a University Hospital. All the hospital files of 1999 of the Federation of Cardiology of Henri Mondor Hospital, Creteil, of patients who died in the department or after transfer to the intensive care unit or cardiac surgery department, were analysed. Myocardial ischaemia was the leading cause of death, occurring either in the acute phase of transmural infarction or in patients with chronic cardiac failure. Deaths occurring during acute myocardial infarction were associated with late treatment and/or non-reperfusion of the culprit artery. The delay of diagnosis seemed to be secondary to late consultation or difficulty in diagnosis. This resulted in severe left ventricular dysfunction and, in a quarter of cases, mechanical complications. They led to the early death of the patients (2.9 +/- 3.5 days after admission). Campaigns of patient information and education of doctors who see these patients would seem to be the most appropriate approach to reduce the delay before hospital admission in order to reduce mortality related to myocardial infarction. Cardiac failure is a common cause of death in cardiology departments. The deaths of patients occurred after a long follow-up and several days after hospital admission (11 +/- 10 days). Optimisation of the treatment of cardiac failure, the investigation of ischaemic heart disease, the search for new therapeutic strategies of acute cardiac failure and information of patients about their disease, seem to be the principal measures to take to improve the poor prognosis of this disease.

[Coronary microcirculation. Physiologic and pathologic aspects]. / Microcirculation coronaire. Aspects physiologique et pathologique.

The coronary circulation has a protective regulation system which, in extreme haemodynamic conditions, compensates increased myocardial oxygen demand. The coronary reserve, based on this concept defines the capacity of the system to increase flow temporally, and, thereby, myocardial oxygen supply. The introduction of new methods of investigating the coronary microcirculation has enabled the study of this phenomenon in several cardiovascular pathologies. Two types of investigation are used currently for studying the coronary microcirculation: 1) invasive methods, especially the recently developed intracoronary Doppler and pressure guide, 2) non-invasive methods, and, in particular, contrast echocardiography, position emission tomography and magnetic nuclear resonance. These investigations allow measurement of the coronary reserve or the assessment of the myocardial consequences of abnormalities of the microcirculation. Some workers use these methods to investigate pathological coronary microcirculation in different cardiomyopathies, in the presence of different cardiovascular risk factors (hypertension, diabetes, smoking, hypercholesterolaemia) and after cardiac transplantation.

Coronary vascular morphology in pressure-overload left ventricular hypertrophy.

To attempt to explain the loss of subendocardial coronary reserve in chronic pressure-overload cardiac hypertrophy on a morphologic basis, we measured capillary capacity and coronary artery and arteriole medial wall area in dogs with moderately severe chronic (1 year) left ventricular hypertrophy (LVH). Aortic bands were placed on the ascending aorta of 8-10-week-old puppies of either sex, and hearts were perfusion fixed with 2% glutaraldehyde 8-16 months later after hemodynamic study while fully conscious. Left ventricular (LV) mass/body weight ratio in 11 banded dogs with LV end-diastolic pressure < 12 mmHg was 72% greater than in 15 controls (C). There was a decrease in subendocardial coronary reserve during adenosine-induced vasodilation with a shift away from the subendocardium (endo/epi flow ratio: C = 0.68 +/- 0.05; LVH = 0.34 +/- 0.06; P < 0.05). In spite of the extensive hypertrophy, image analysis revealed capillary density to be equally reduced by only 10-15% in endo, mid and epicardial LV regions compared to control dogs, while increased capillary cross-sectional area resulted in no change in capillary surface area/myocyte volume or volume percentage capillary space. In addition to these data suggesting capillary angiogenesis, there was no reduction in arteriolar density, indicating transmural increase in arteriolar number, and, as a consequence, increased total length of the resistance vessels. Medial area of arterioles and arteries showed a graduated increase according to size. We concluded that due to the lack of transmural difference in vascular morphology in chronic (1 year) moderately severe LVH, these anatomic bases do not play a major role as a cause for the loss of coronary reserve. Regional functional differences as a consequence of the morphologic alterations, however, cannot be excluded.

Hemodynamic mechanisms responsible for reduced subendocardial coronary reserve in dogs with severe left ventricular hypertrophy.

BACKGROUND: Reduced subendocardial coronary reserve is a hallmark of left ventricular hypertrophy (LVH). The goal of this study was to determine whether hemodynamic, as opposed to structural, mechanisms were responsible for the reduced subendocardial coronary reserve. METHODS AND RESULTS: The effects of near-maximal vasodilation with adenosine were examined in 10 conscious dogs with LVH (79% increase in ratio of LV weight to body weight) induced by aortic banding in puppies with and without preload reduction. At baseline, LV end-diastolic pressure, LV end-diastolic circumferential and compressive radial wall stresses, and LV myocardial blood flow were similar in dogs with LVH and sham-operated controls, while LV end-systolic circumferential wall stress tended to be greater in the LVH group compared with the control group. In control dogs, adenosine reduced LV circumferential end-systolic and end-diastolic wall stresses and compressive radial subendocardial wall stress; LV subendocardial blood flow increased (from 1.41 +/- 0.16 to 3.58 +/- 0.27 mL.min-1.g-1) and the ratio of subendocardial to subepicardial blood flow decrease from 1.30 +/- 0.07 to 0.69 +/- 0.05. In dogs with LVH, during adenosine infusion, LV circumferential end-systolic and end-diastolic wall stresses and LV radial subendocardial wall stresses remained elevated, the increase in LV subendocardial blood flow was significantly smaller (from 1.11 +/- 0.11 to 2.27 +/- 0.24 mL.min-1.g-1, P < .05), and the subendocardial/epicardial ratio fell to a lower level (from 1.22 +/- 0.17 to 0.35 +/- 0.03, P < .05). When LV wall stresses during adenosine were reduced in a subgroup of 5 dogs with LVH, the endocardium/epicardium ratio during adenosine infusion was no longer different from that in control dogs (0.63 +/- 0.11), nor was the level of subendocardial blood flow different (3.42 +/- 0.60 mL.min-1.g-1). CONCLUSIONS: These data suggest that hemodynamic factors, eg, compressive forces, are an important component of the reduced subendocardial coronary reserve as opposed to structural alterations, even in the presence of severe LVH.

Enhanced postischemic dysfunction selective to subendocardium in conscious dogs with LV hypertrophy.

The effects of a 15-min coronary arterial occlusion (CAO) and reperfusion (CAR) for 24 h were compared in 11 normal dogs and in 13 conscious dogs with left ventricular (LV) hypertrophy (H) induced by ascending aortic banding, which increased the LV weight-to-body weight ratio by 69%. The dogs were studied 2-4 wk after recovery from instrumentation for measurement of global LV dynamics and regional wall motion. During CAO, heart rate and LV end-diastolic pressure increased similarly in both groups; however, LV systolic pressure decreased (-38 +/- 6 mmHg; P < 0.01) only in LVH. At 1 h of CAR, all measurements of systemic hemodynamics and global LV function returned to baseline levels in normal dogs; however, sustained depression (P < 0.01) in LV systolic pressure (-18 +/- 4 mmHg) and mean velocity of circumferential fiber shortening corrected for heart rate (-0.17 +/- 0.06) were observed in LVH. The recovery in regional myocardial dysfunction was significantly prolonged in the subendocardium (Endo) of LVH, e.g., at 1 h of CAR, Endo wall thickening was depressed more in dogs with LVH compared with normal dogs (-69 +/- 3% vs. -53 +/- 5%; P < 0.01), but not in the subepicardium (Epi). Coronary flow reserve, assessed by intravenous adenosine, was depressed in Endo of LVH compared with normal dogs, but not altered further by CAR. In conclusion, myocardial stunning after a brief period of CAO in dogs with LVH was not enhanced in Epi but was modestly increased in Endo. This regional dysfunction was, however, sufficiently powerful to induce modest impairment of global LV function.

Changes in diastolic cardiac function in developing and stable perinephritic hypertension in conscious dogs.

The effects of developing perinephritic hypertension (2-3 weeks) and a more stable period of perinephritic hypertension (approximately 14 weeks) were examined on indexes of left ventricular (LV) diastolic function in conscious, chronically instrumented dogs. The complete period of diastole was studied using indexes of isovolumic relaxation (tau), early filling (LV +dD/dt), and stiffness (myocardial stiffness and chamber stress/diameter ratio). During developing hypertension, increased LV end-diastolic pressure, LV end-diastolic stress, peak filling rate, myocardial stiffness, and the stress/diameter ratio increased (p less than 0.05); the time constant tau was not changed. These changes were associated with preserved baseline levels of coronary blood flow (radioactive microspheres) but an impaired coronary vasodilator response to adenosine. Acute administration of phenylephrine in the normotensive dogs caused increases in systolic and diastolic stress and resulted in increases in myocardial stiffness and in the stress/diameter ratio similar to values observed in developing hypertension. During stable hypertension, LV end-diastolic stress, peak filling rate, and both parameters of late-diastolic function (myocardial stiffness and stress/diameter ratio) returned toward control values, but the isovolumic relaxation time constant was increased. Quantitative histological evaluation revealed no increase in stainable connective tissue in dogs with stable hypertension compared with control dogs, and hydroxyproline concentration was not increased in the subendomyocardium, midmyocardium, or subepimyocardium of the dogs with chronic perinephritic hypertension. Thus, in developing hypertension, major alterations in diastolic function were observed that were not structurally related, since these changes 1) could be induced in normal dogs by increasing preload and afterload acutely with phenylephrine and 2) were improved during the ensuing stable period of hypertension.

Subendomyocardial exhaustion of blood flow reserve and increased fibrosis in conscious dogs with heart failure.

The effects of near-maximal coronary vasodilation were examined in conscious dogs with left ventricular (LV) failure after pressure overload hypertrophy induced by either aortic banding alone or aortic banding plus a peripheral arteriovenous shunt. The findings were compared with results in littermates with compensated LV hypertrophy and with a third group of normal dogs. At rest, there was a marked difference in the intramyocardial distribution of coronary flow, measured with radiolabeled microspheres. The endocardial/epicardial (endo/epi) flow ratio in the LV failure dogs was 0.96 +/- 0.08 as compared with control dogs (1.28 +/- 0.06, p less than 0.05) or dogs with compensated LV hypertrophy (1.23 +/- 0.08, p less than 0.05). During near-maximal coronary vasodilation with adenosine, all groups showed similar increases in subepimyocardial (epi) flow. While significant increases in subendomyocardial (endo) flow during adenosine infusion were seen in the control group (0.88 +/- 0.10 to 3.53 +/- 0.24 ml/min/g) and in dogs with compensated LV hypertrophy (1.12 +/- 0.14 to 3.60 +/- 0.16 ml/min/g), there was no change in endo flow in the LV failure dogs (1.55 +/- 0.20 to 1.71 +/- 0.47 ml/min/g) and a further significant reduction in the endo/epi flow ratio was observed (0.30 +/- 0.06, p less than 0.01). These hemodynamic changes were associated with chronic multifocal interstitial or discrete areas of fibrosis observed preferentially in endo layers. Thus, endo flow reserve is nearly exhausted in dogs with decompensated pressure overload LV hypertrophy, which may induced periodic episodes of endo ischemia resulting in myocyte necrosis and fibrosis, which in turn results in exacerbation of LV failure.

Mechanical adaptation to chronic pressure overload.

According to Meerson, the adaptation to cardiac overload can be divided into three periods: the first stage, immediately after the initiation of the defect during which hypertrophy develops, followed by the stable hypertrophy phase (SHP), and a third phase of myocardial failure. Ventricular muscle contraction during SHP has been extensively studied both in vivo and in vitro with conflicting results. In isolated papillary muscles, most studies showed a normal or depressed contractility during chronic volume overload and a depressed inotropic state in pressure overload with a reduced maximal velocity of shortening which has been related to a myosin isozyme shift. In contrast, in conscious animals, haemodynamic status is usually described as preserved during SHP with a ventricular hyperfunction and a normal contractile function per unit of muscle. This was the basis of the concept of preload reserve and afterload mismatch described by Ross. However, mechanisms other than preload reserve may play a role during cardiac adaptation to pressure or volume overload. For instance, we recently showed in the early phase of pressure overload an increased inotropic state of the in situ heart with a change of the excitation contraction coupling evidenced by a modification of the force-frequency relations. Changes in the adrenergic receptors (density and/or affinity) may also contribute to the adaptation of the in situ heart to cardiac overload. They represent an important research area because they may explain, along with species and model differences, the discrepancies between in vivo and in vitro studies.