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.

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.

Force velocity relations of single cardiac muscle cells: calcium dependency.

Cellular cardiac preparations in which spontaneous activity was suppressed by EGTA buffering were isolated by microdissection. Uniform and reproducible contractions were induced by iontophoretically released calcium ions. No effects of a diffusional barrier to calcium ions between the micropipette and the contractile system were detected since the sensitivity of the mechanical performance for calcium was the same regardless of whether a constant amount of calcium ions was released from a single micropipette or from two micropipettes positioned at different sites along the longitudinal axis of the preparation. Force development, muscle length, and shortening velocity of eitherisometric or isotopic contractions were measured simultaneously. Initial length, and hence preload of the preparation were established by means of an electronic stop and any additional load was sensed as afterload. Mechanical performance was derived from force velocity relations and from the interrelationship between simultaneously measured force, length, and shortening velocity. From phase plane analysis of shortening velocity vs, instantaneous length during shortening and from load clamp experiments, the interrelationship between force, shortening, and velocity was shown to be independent of time during the major portion of shortening. Moreover, peak force, shortening, and velocity of shortening depended on the amount of calcium ions in the medium at low and high ionic strength.

Nonuniformity: a physiologic modulator of contraction and relaxation of the normal heart.

Nonuniformity of mechanical performance is inherent to the multicellular nature and specific geometry and configuration of the ventricle of the heart. Although the concept of nonuniformity of the diseased heart is not new, ventricular function and the performance of the heart as a muscular pump cannot be understood unless nonuniform behavior is taken into account, even under normal conditions. Along with the loading conditions throughout the cardiac cycle and the time courses of activation and inactivation, the nonuniform behavior of load and of activation and inactivation in space and in time constitutes a third important determinant of mechanical performance and efficiency of the ventricle during both contraction and relaxation. Hence, a triad (load, activation-inactivation, nonuniformity) of controls regulates systolic function of the normal ventricle. In the diseased heart, even when loading and activation-inactivation are normal, the modulating role played by this nonuniformity can become imbalanced because of abnormal cavity size or shape or because of regional dysfunction. Such an imbalance would diminish external efficiency (the ratio of work performed to oxygen utilized) of the ventricle and result in incoordinate contraction and relaxation. These abnormalities, in turn, could exacerbate manifest cardiac failure.

Diastolic failure: pathophysiology and therapeutic implications.

Primary diastolic dysfunction or failure is a distinct pathophysiologic entity. It results from increased resistance to ventricular filling, which leads to an inappropriate upward shift of the diastolic pressure-volume relation, particularly during exercise (exercise intolerance). The causes of diastolic failure are inappropriate tachycardia, decreased diastolic compliance and impaired systolic relaxation. Impaired (incomplete or slowed) systolic relaxation must be conceptually distinguished from compensatory prolonged systolic contraction (delayed or retarded relaxation). Optimal therapy will depend on the type of disease, the phase during the course of a given disease and the coexistence and relative contribution of various (de)compensatory processes. Treatment may consist of bradycardic, remodeling and lusitropic drugs.

Influence of loading patterns on peak length-tension relation and on relaxation in cardiac muscle.

To analyze the influence of loading patterns on cardiac pump performance and cardiac relaxation [corrected], the effects of preload on peak length-tension relation [corrected] and of systolic load clamps on peak length-tension relation and on relaxation were analyzed in isolated cat papillary muscles. Preload reduction and early loading clamps induced a shift to the left of the peak length-tension relation, that is, a smaller muscle length for the same tension at peak shortening. Unloading clamps induced a shift to the right of the peak length-tension relation, that is, a larger muscle length for the same tension at peak shortening. The effects of load clamps on relaxation depended on when they were applied during isotonic shortening. Changes induced by load clamps could not be summarized in terms of enhanced or delayed relaxation, illustrating that shortening duration, isometric tension decline and isotonic lengthening have different determinants. In conclusion, not only peak or mean systolic pressure but also the entire loading pattern has to be taken into account whenever pressure-volume data or relaxation variables are interpreted.

Myocardial performance is modulated by interaction of cardiac endothelium derived nitric oxide and prostaglandins.

OBJECTIVE: The endocardial endothelium modulates the performance of the subjacent myocardium and plays an important role in regulating cardiac function. The aim of this study was to investigate the effects on cardiac function of the mutual interaction of nitric oxide (NO) and prostaglandins released from the endocardial endothelium. METHODS: The effects of NO and prostaglandin interaction were investigated in isolated cat papillary muscle (Krebs Ringer; 1.25 mM Ca2+; 35 degrees C), using substance P (1 mumol.litre-1) to release NO, L-nitroarginine (L-NOARG:30 mumol.litre-1) to inhibit NO synthase, arachidonic acid (10 mumol.litre-1) to stimulate endogenous prostaglandin (mainly prostacyclin) release, and indomethacin (1 mumol.litre-1), a cyclooxygenase inhibitor. RESULTS: Administration of substance P resulted in a negative inotropic effect. This response to substance P was abolished by arachidonic acid, while it was preserved in the presence of indomethacin. In the presence of L-NOARG, arachidonic acid induced a positive inotropic effect with prolongation of the twitch duration, while indomethacin reduced the twitch duration. CONCLUSIONS: Activation of prostaglandins abolishes the effect of NO, while prostaglandin-induced positive inotropic effect requires NO synthesis inhibition. Accordingly NO and prostaglandins interact to regulate myocardial performance.

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.

Relaxation of tetanised smooth muscle of canine saphenous vein.

Since vascular filling depends on the cross-sectional area of the venous bed and since this is determined by the state of relaxation of the mural smooth muscle, we have studied load bearing capacity during relaxation of the smooth muscle of canine saphenous vein. The effect of load on the time course of relaxation was analysed either by comparing afterloaded contractions against various loads or by imposing abrupt alterations in load (load clamps). Unlike mammalian cardiac muscle in which relaxation was reported sensitive to loading conditions, relaxation in the smooth muscle of the saphenous vein was largely independent of loading conditions. In this it resembled frog heart muscle. This type of relaxation, which is not influenced by manipulation of loading conditions, has been termed "inactivation-dependent" relaxation. It appears to operate in muscle tissue in which the calcium sequestering apparatus is poorly developed and sequestration or some process downstream to it appears to be the rate limiting step during relaxation.

Myocardial stiffness during hypoxic and reoxygenation contracture.

Isolated rat papillary muscle preparations were used to study hypoxic contracture, and cat papillary muscle preparations with ouabain to study reoxygenation contracture. Electronic analysis of the response to rapid small sinusoidal perturbations gave a continuous measurement of the elastic and viscous components of total stiffness. Increased resting force during hypoxic contracture was characterised by an increase in resting elastic and viscous stiffness relative to the control stiffness-active force relationships. During reoxygenation contracture the stiffness-force relationships followed those of active force development. The linear active force-elastic stiffness relationship (dt/dl=kT+c) was also reversibly altered during hypoxic contracture, predominantly by an increase in intercept c. These data imply that hypoxic contracture unlike reoxygenation contracture is not due solely to a rise in intracellular calcium, but is associated with a component of stiffness not participating an active force development, for example rigor.

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.

Effect of alpha-1 and beta agonists on contraction of bovine retinal resistance arteries in vitro.

Contractile responses of bovine retinal arteries (BRA) (diameter: 179 +/- 9 micron, n = 25) to high K+, circumferential stretch and adrenergic stimulation were studied in vitro. BRA could be activated by rapid circumferential stretch. Under resting conditions, phenylephrine consistently activated BRA at the highest dose of the drug used (10(-5) M). During K+- and stretch-induced activation, significant contractile responses to phenylephrine appeared at lower doses (respectively, 3.10(-8) and 10(-6) M). Isoproterenol did not relax K+- and stretch-induced contractions. Therefore, (1) BRA probably can autoregulate through a myogenic mechanism on the basis of stretch; (2) during alpha 1 adrenergic stimulation, myogenic autoregulatory responses probably increase; (3) contractile responses to alpha 1 adrenergic stimulation are masked under resting conditions; and (4) BRA may not possess functional beta adrenergic receptors.

Effects of beta-antagonists on contraction of bovine retinal microarteries in vitro.

Contractile responses of bovine retinal microarteries (BRA) (diameter: 198 +/- 5 microns, n = 49) to beta-antagonists, local anesthetics and Ca2(+)-antagonists were studied in vitro. Propranolol (10(-8)-10(-5) M) relaxed K(+)-activated BRA dose-dependently, whereas timolol (10(-8)-10(-5) M) relaxed K(+)-activated BRA only weakly at the highest doses. The relaxation by propranolol was not mediated through interaction with adrenergic nerve endings, since fluorescence histochemistry showed absence of such nerve endings in BRA. In addition, propranolol still relaxed BRA which were treated with 6-hydroxydopamine (6-OHDA), which causes chemical adrenergic denervation. Local anesthetic properties of propranolol had no part in the relaxation: lidocaine (10(-7)-10(-5) M) did not relax K(+)-activated BRA. Verapamil (10(-9)-10(-6) M) relaxed K(+)-activated BRA markedly and dose-dependently. Both verapamil and propranolol relaxed phasic K(+)-induced force more than tonic force. By contrast, they relaxed only the tonic part of serotonin-induced force, and they had no effect on stretch-induced active force. Therefore: 1) propranolol dilates BRA more than does timolol, possibly because of the Ca2(+)-antagonistic properties of the former; 2) beta- and Ca2(+)-antagonists probably spare myogenic autoregulation of blood flow and do not prevent, but could partially reverse, serotonin-induced arterial spasm.

Is stiffness increased during ischemia?

Possible sources of increased ventricular stiffness can be more easily appreciated when pressure and volume patterns are considered as a function of time. A discussion on sources of effective or apparent stiffness or stiffness changes includes viscoelastic properties and active behavior at the muscular level. Chamber geometry and coronary vascular pressure and flow are intrinsic ventricular components. Together with the pressure head and crosstalk as extraventricular components, all these properties are integrated to determine intact heart behavior in late relaxation and diastole.

Effects of encainide on myocardial contractility of cat papillary muscle.

The action of a new effective antiarrhythmic agent, encainide, was studied with respect to the mechanical performance of isolated cat papillary muscle. Encainide (0.1-10 micrograms/ml) did not alter the performance of cardiac muscle during either the contraction or relaxation phase. By contrast, lidocaine (1-5 micrograms/ml) caused a slight but statistically significant depression of myocardial contractility in terms of the force-velocity-length analysis, while it did not affect load clamp analysis, zero load clamp analysis and load dependence of relaxation.

Role of the endocardium in the inotropic action of UD-CG-212 CL.

UD-CG-212 CL is a metabolite of pimobendan (UD-CG-115 BS), a non-glycosidic, non-adrenergic positive inotropic agent. In the present study we investigated the effect of UD-CG-212 CL on cat papillary muscles in the presence or absence of an intact endocardial endothelium. The endocardium was damaged by a very short detergent treatment. We demonstrated that, in muscles with an intact endocardial endothelium, UD-CG-212 CL induced a moderate, but significant inotropic effect resembling the changes induced by adrenoceptor agonists. Addition of an alpha- and or beta-blocker reduced this positive inotropic effect. The effect induced by UD-CG-212 CL, was completely abolished after the endocardial endothelium was damaged. We conclude that the endocardium played a modulatory role in the action of UD-CG-212 CL through the release of various factors with inotropic activity.

Effects of AQA39 on contractile performance of isolated mammalian ventricular myocardium.

AQA39 is a new cardioactive agent with, at low dosages, a minute positive inotropic action on ventricular myocardial tissue probably mediated through the calcium sequestering membraneous systems. At higher concentrations AQA39 depressed myocardial performance probably due to inhibition of the slow calcium channels.

Positive inotropic effect of nitric oxide in myocardium.

Cardiac endothelium modulates underlying cardiac muscle performance probably by releasing certain regulatory factors. Nitric oxide (NO), which accounts for the biological activity of the vascular endothelium-derived relaxing factor and relaxes vascular smooth muscle by elevating intracellular cyclic GMP (cGMP), may be involved in this cardiac modulation. Many recent studies have examined inotropic effects of NO utilizing NO donors and NO-synthase inhibitors, both in vitro and in vivo, with apparently contradictory results. We examined the myocardial effects of NO-releasing nitrovasodilators (sodium nitroprusside (SNP), SIN-1 and S-nitrosoacetyl penicillamine (SNAP)), a cGMP analogue, 8-bromo-cGMP, and the cGMP phosphodiesterase inhibitor zaprinast, in isolated cat papillary muscle. A novel concentration-dependent positive inotropic effect of SNP and SIN-1 in muscles with damaged endocardial endothelium (EE) was observed which contrasted to their negative inotropic effect in muscles with intact EE. Both NO-induced positive and negative inotropic effects were attenuated by methylene blue, suggesting a role for cGMP. Concentration response curves with addition of SNAP and 8-bromo-cGMP resulted in a biphasic inotropic response. While administration of low concentrations of SNAP and 8-bromo cGMP induced a positive inotropic effect, higher concentrations induced a negative inotropic effect. Administration of zaprinast caused a monophasic concentration-dependent positive inotropic effect. We conclude that basal release of NO and consequent modest (physiological?) elevation in cGMP may preserve myocardial function, while large (pathological?) increases would depress myocardial function.