Sarcoplasmic reticulum Ca2+ATPase and phospholamban mRNA and protein levels in end-stage heart failure due to ischemic or dilated cardiomyopathy.

Abnormalities in intracellular Ca2+ handling play a crucial role in the pathogenesis of heart failure. The reduced capacity of failing human myocardium to restore low resting Ca2+ levels during diastole has been explained by the impairment of Ca2+ uptake into the sarcoplasmic reticulum (SR) via the SR Ca2+ATPase. It is unclear whether Ca2+ATPase function, protein levels, and mRNA steady-state levels correspond to one other, and whether the cause of heart failure, namely idiopathic dilated or ischemic cardiomyopathy, produces different changes. The present study examined SR Ca2+ATPase activity and both mRNA and protein levels of SR Ca2+ATPase, phospholamban, and Gi alpha 2 in left ventricular myocardium from eight nonfailing hearts, from eight hearts of patients with idiopathic dilated cardiomyopathy (DCM), and from six hearts from patients with ischemic cardiomyopathy (ICM). Compared to nonfailing myocardium, the activity of the SR Ca2+ATPase was significantly reduced in failing myocardium from patients with DCM (36%, P < 0.01) and from patients with ICM (37%, P < 0.001). Significantly lower levels of SR Ca2+ATPase mRNA levels (55% and -56%, P < 0.001 for DCM and ICM, respectively) and phospholamban mRNA (45%, P < 0.001 for DCM; 31%, P < 0.05 for ICM) were observed in failing than in nonfailing myocardium. In contrast, no significant changes were observed at the level of proteins, Gi alpha 2 mRNA and protein levels were both significantly increased in failing myocardium. There were no differences between idiopathic dilated and ischemic cardiomyopathy concerning the examined parameter. It is concluded that reduced SR Ca2+ATPase activity contributes to an altered intracellular Ca2+ handling by the SR in both dilated and ischemic cardiomyopathic hearts. However, changes in SR Ca2+ATPase and phospholamban steady-state protein levels do not contribute to these alterations. The dissociation between protein and mRNA levels provides evidence for a posttranscriptional or post-translational regulation of these proteins. The observed alterations are not dependent on the underlying cause of end-stage heart failure.

Effects of angiotensin II type 1 receptor blockade and angiotensin-converting enzyme inhibition on cardiac beta-adrenergic signal transduction.

Inhibition of the renin-angiotensin system has been shown to improve symptoms and prognosis in heart failure. We compared the effects of inhibition of angiotensin-converting enzyme or blockade of angiotensin II type 1 (AT1) receptors in a model with renin-induced hypertension that is known to exhibit similar changes in sympathetic activation and beta-adrenergic desensitization, as observed in heart failure. Treatment with captopril (100 mg/kg of feed) or the AT1-antagonist Bay 10-6734 (100 mg/kg of feed) was performed in transgenic rats harboring the mouse renin 2d gene [TG(mREN2)27]. Neuropeptide Y and angiotensin II levels, adenylyl cyclase activity, beta-adrenergic receptors, G(salpha), and G(ialpha) were investigated. TG(mREN2)27 showed a depletion of myocardial neuropeptide Y stores and an increase in myocardial angiotensin II concentrations. Isoprenaline- and guanylylimidodiphosphate-stimulated adenylyl cyclase activities and beta-adrenergic receptor density were reduced, whereas the catalyst and G(salpha)-function were unchanged. G(ialpha) protein and mRNA concentrations were increased. All alterations were normalized by both treatments. Systolic left ventricular pressures, plasma atrial natriuretic peptide, and myocardial steady state atrial natriuretic peptide mRNA concentrations and heart weights were similarly reduced by both treatments. Sympathetic neuroeffector defects are similarly reversed by angiotensin-converting enzyme inhibition or AT1 antagonism. The data support the concept that pharmacological interventions in the myocardial renin-angiotensin system significantly reverse local sympathetic neuroeffector defects. This could be important for the beneficial effects of these agents.

Chamber-specific alterations of norepinephrine uptake sites in cardiac hypertrophy.

The present study investigated local differences of sympathetic activation and sympathetic neuroeffector defects in nonhypertrophied right and hypertrophied left ventricles in a rat model with renin-induced pressure overload [TG(mREN2)27]. As judged from the depletion of myocardial norepinephrine stores, sympathetic activation was more pronounced in the left than in the right ventricles. In addition, norepinephrine uptake1 carrier sites were reduced in left but unchanged in right ventricles. Gene expression of the carrier was unchanged in stellate ganglia. An increase of Gialpha expression and a heterologous adenylyl cyclase desensitization occurred only in the left but not in the right ventricles, whereas a reduction of beta-adrenergic receptors was observed in both chambers. We concluded that general sympathetic activation can lead to beta-adrenoceptor downregulation but that pressure overload further increases sympathetic activation involving norepinephrine uptake mechanisms in the left ventricles, resulting in heterologous beta-adrenergic desensitization.

Contractile systolic and diastolic dysfunction in renin-induced hypertensive cardiomyopathy.

The present study investigated whether functional, molecular, and biochemical alterations occurring in chronic heart failure can already be detected in compensated hypertensive cardiac hypertrophy. Force of contraction (isolated papillary muscle strip preparations), sarcoplasmic reticulum (SR) protein and myosin heavy chain isoform expression (Northern and Western blot analysis), myocardial fibrosis (collagen stains, hydroxyproline quantification), myocardial renin mRNA (RT-PCR), and angiotensin II levels and plasma aldosterone concentrations (radioimmunoassay) were studied in hypertrophied myocardium from transgenic rats harboring the mouse Ren-2d gene. Contraction and relaxation velocities of isolated papillary muscle strips were significantly reduced in cardiac hypertrophy. The beta-/alpha-myosin heavy chain ratio was significantly increased in the hypertrophied left ventricles, whereas SR Ca2+-ATPase (SERCA 2a) and phospholamban mRNA and protein levels were significantly decreased. The decrease in SERCA 2a was more pronounced than the decrease in phospholamban levels. There was no increased myocardial fibrosis. Left ventricular myocardial renin mRNA and angiotensin II concentrations, as well as plasma aldosterone levels, were higher in transgenic than in control rats. In hypertensive cardiac hypertrophy, myosin heavy chain isoform shift and reduction of SR protein levels are related to systolic and diastolic dysfunction, respectively. These alterations precede the development of myocardial fibrosis. Increased myocardial renin mRNA and angiotensin II concentrations suggest that an activated tissue renin-angiotensin system might contribute to these alterations. Since the alterations in compensated cardiac hypertrophy apparently precede those in chronic heart failure, they might accelerate the transition from hypertrophy to failure and could therefore be targets for pharmacological interventions.

Angiotensin receptor antagonism and angiotensin converting enzyme inhibition improve diastolic dysfunction and Ca(2+)-ATPase expression in the sarcoplasmic reticulum in hypertensive cardiomyopathy.

BACKGROUND: Hypertensive cardiomyopathy is a major risk factor for the development of chronic heart failure. OBJECTIVE: To investigate whether treatment with an angiotensin converting enzyme inhibitor (ACEI) or with an angiotensin type 1 receptor antagonist (AT1-RA) is sufficient to prevent the development of hypertensive cardiomyopathy and cardiac contractile dysfunction. Special emphasis was placed on the effects of both treatments on sarcoplasmic reticulum Ca(2+)-ATPase (SERCA 2a) gene expression as a major cause of impaired diastolic cardiac relaxation. METHODS AND RESULTS: Eight-week-old rats harboring the mouse renin 2d gene [TG(mREN2)27] were treated for 8 weeks with 100 mg/kg captopril (Cap) in their food and 100 mg/kg of the AT1-RA Bay 10-6734 (Bay) in their food. Untreated TG(mREN2)27 and Sprague-Dawley rats (SDR) were used as controls. Both treatment regimens normalized the left ventricular weight, which was increased significantly (P < 0.001) in TG(mREN2)27. Both treatments normalized the left ventricular end-systolic and end-diastolic pressures, which were significantly (P < 0.001) higher in TG(mREN2)27 than they were in SDR, and they improved the velocity of the decrease in pressure [P < 0.05, Bay and Cap versus TG(mREN2)27]. Decreased left ventricular SERCA 2a mRNA and protein levels and increased atrial natriuretic peptide messenger RNA levels were normalized by Bay and Cap treatments (P < 0.05, Bay and Cap versus TG(mREN2)27, by Northern and Western blotting). According to radioimmunoassay and an enzyme assay, respectively, Bay, but not Cap, increased plasma angiotensin I concentrations and the renin activity above normal levels (P < 0.05), whereas myocardial angiotensin II concentrations (determined by radioimmunoassay), which were significantly (P < 0.05) increased in TG(mREN2)27, were normalized equally by Bay and Cap. CONCLUSIONS: In renin-induced hypertensive cardiomyopathy, left ventricular diastolic dysfunction occurs at the stage of compensated myocardial hypertrophy. The decreased left ventricular relaxation velocity might be due to reduced SERCA 2a gene expression. In this model of hypertensive cardiomyopathy, AT1-RA and ACEI treatments are similarly effective at reducing the arterial pressure, preventing myocardial hypertrophy and diastolic contractile dysfunction. Normalization of SERCA 2a gene expression, either by AT1-RA or by ACEI treatment, might contribute to the improvement in diastolic function.

The quiz electrocardiogram: a new diagnostic and research technique for evaluating the relation between emotional stress and ischemic heart disease.

To evaluate possible cardiovascular effects of emotional stress, a specially designed 12 minute tape-recorded stress quiz was administered to 43 subjects while blood pressure and the electrocardiogram were monitored. For the entire group, the heart rate and blood pressure rose from respective control levels of 76 beats/min and 136/87 mm Hg to a mean during the quiz of 87 beats/min and 158/94 mm Hg. This difference was highly significant. Of the 43 subjects, 33 were classified as executives and 10 as nonexecutives. There were three groups of executives: control and angina with and without a history of hypertension. Both groups of executives with angina responded with a significantly higher heart rate than that of the executive control group. Blood pressure response was significantly greater in executives with angina and hypertension than in the other groups. Heart rate and systolic blood pressure responses to the quiz were lower in nonexecutives with angina than in executives with angina. During the quiz, 10 of 14 executives with angina had S-T segment depression greater than 0.5 mm; of these, 7 evidenced greater than 1.0 mm depression, andin 3 of these the depression was greater than 1.5 mm and in 2 greater than or equal to 2.0 mm. None of the executive control subjects had S-T depression greater than 0.5 mm Among nonexecutives, 2 had S-T depression greater than 0.5 mm but none greater than 1.0 mm S-T depression. Seventeen of the patients also were given a bicycle exercise tolerance test. There was a significant correlation between S-T depression in response to exercise and to the quiz (r = 0.63; P less than 0.01). The quiz electrocardiogram is presented as a new research technique and diagnostic test for evaluating the relation of emotional stress to ischemic heart disease.

Cognitive activity of the right hemisphere: possible contributions to psychological function.

This paper reviews evidence from split-brain and other, more recent studies that have enriched and advanced our understanding of the cognitive and emotional abilities and characteristics of the right hemisphere. The more recent work includes research on intact subjects (employing Wada tests, unilateral videos, and functional imaging) and neurophysiological studies on dissociated states such as multiple personality disorder and hypnosis. The literature continues to support the view that in intact persons, the right hemisphere has significant mental faculties that can operate with some independence from those of the left hemisphere. The paper also reviews relevant psychodynamic literature and discusses the theoretical and therapeutic implications of the existence of these partially autonomous right hemispheric mental faculties.

Psychotherapy of nine successfully treated cocaine abusers: techniques and dynamics.

The author reviews a series of nine cocaine abusers successfully treated with long-term, in-depth, dynamic psychotherapy begun on an inpatient drug abuse unit and continued after hospitalization. He finds his patients to have been victims of unrecognized psychological trauma in childhood. He argues that the cocaine abuse, in addition to functioning as a form of self-medication, was functioning as a component of a repetition compulsion in which old psychological traumas were symbolically recreated in the post-drug dysphoria. In a retrospective assessment, the author delineates four steps he used in the treatment process: 1) he looked for traumatic or abusive conditions; 2) he established emotional contact; 3) he helped the patient to appreciate how the abuse had affected him; 4) he helped the patient to master the traumatic experiences. A clinical vignette and the relevant literature on the psychodynamics of cocaine abuse are discussed.

Affect changes observed with right versus left lateral visual field stimulation in psychotherapy patients: possible physiological, psychological, and therapeutic implications.

Seventy psychotherapy patients were given two pairs of goggles each taped over to allow vision from only the left or the right lateral visual field (LVF and RVF). Sixty percent reported at least a one-point difference between visual fields on a five-point anxiety scale; 23% reported at least a two-point difference. Among 21 patients with major depression, 11 reported greater anxiety through the LVF, four reported greater anxiety through the RVF, and six reported no difference. Among 18 with posttraumatic stress disorder (PTSD), 10 reported greater anxiety from the RVF and four from the LVF, and four reported no difference. The absolute difference in anxiety ratings was significantly greater (P < .001) between the two pairs of experimental goggles than between two pairs of control goggles allowing monocular vision among 40 patients in whom the four pairs were tested. During a subsequent psychiatric interview, 40 of 49 patients who were responsive while using the experimental goggles manifested an intensification of their usual symptoms on one side and an alleviation on the other. The possible physiological, psychological, and therapeutic implications of these findings are discussed.

Evoked potential evidence for right brain activity during the recall of traumatic memories.

Auditory probe evoked potential attenuation was measured as an index of hemispheric activity in 10 subjects with a history of childhood trauma and 10 matched subjects without such history while they recalled a neutral memory and then a traumatic memory. There were prominent group differences in degree of cerebral laterality between memory tasks (P = 0.02). The trauma group had a significant left dominant asymmetry during the neutral memory (P = 0.02), which markedly shifted to the right during the unpleasant memory (P = 0.007 for degree of shift). Normal control subjects did not display a significant asymmetry during either task, nor did they show a significant shift between tasks.

Different psychological status in the two hemispheres of two split-brain patients.

Questions of a psychological nature were presented to two split-brain patients from the California series encouraging each hemisphere to respond simultaneously and independently. The responses of both patients indicated that their hemispheres were responding independently. For the first patient, his right hemisphere appeared to be more disturbed than his left by childhood memories of being bullied. The right hemisphere of the second patient seemed to regard himself more positively, but it also seemed to feel more negative emotions such as loneliness and sadness. We discuss the possible significance of the findings.

Electroencephalogram, bilateral ear temperature, and affect changes induced by lateral visual field stimulation.

Fifteen subjects evaluated while wearing, in random order, four pairs of glasses, two limiting vision to either the left or right lateral visual field (LVF) and two monocular glasses (MGs) limiting vision to either eye, manifested significant differences in laterality indices in the predicted direction for the theta electroencephalogram (EEG) (P < .003) and ear canal temperature (P < .02) between the LVF glasses, but not the MGs. There was a significant correlation between lateral shifts in the theta EEG and ear canal temperature (r2 = .47, F(1,10) = 8.72, P < .015). The LVF glasses induced an absolute difference in anxiety greater (P < .05) than that induced by the MGs. LVF glasses appear to induce a shift in affect and hemispheric dominance.

Evidence for emotionally-induced coronary arterial spasm in patients with angina pectoris.

Twelve executives with typical angina pectoris, given a 12-minute quiz, designed to be psychologically stressful, responded with ST depressions of greater than or equal to 1.0 mm. Each of these patients was given an exercise tolerance test on an upright bicycle to induce an amount of ST depression equivalent to that observed during the quiz. A statistical analysis was made of the products of the heart rate and the systolic blood pressure (rate-pressure product), at the onset of equivalent ST depression on both tests. At the maximal ST depression during the quiz, the mean rate-pressure product was 181 +/- 64 (SD) X 10(2), and at an equivalent ST depression during exercise it was 225 +/- 54 X 10(2); the mean difference was 44 +/- 40 X 10(2). Inasmuch as the rate-pressure product is an index of myocardial oxygen consumption, the differences in rate-pressure product suggest that myocardial ischaemia occurred at a lower myocardial oxygen consumption during emotional stress than during exercise. If equivalent degrees of ST depression during exercise and the quiz are indicative of equivalent ischaemia, than a relative reduction in coronary blood flow during emotional stress, probably by coronary spasm, may be postulated as the most reasonable explanation for these observations.

Evidence for functional relevance of an enhanced expression of the Na(+)-Ca2+ exchanger in failing human myocardium.

BACKGROUND: The present study aimed at investigating the expression of the Na(+)-Ca2+ exchanger and its functional role in human failing myocardium. METHODS AND RESULTS: Na(+)-Ca2+ exchanger mRNA and protein levels were examined in nonfailing (NF, n = 8) and failing human myocardium (New York Heart Association functional class IV) with idiopathic dilated cardiomyopathy (DCM, n = 8) or ischemic heart disease (ICM, n = 6). The inotropic effect of the Na+ channel activator BDF 9148 was determined in electrically driven left ventricular papillary muscle strip preparations (1 Hz, 37 degrees C) from nonfailing (n = 8) and failing (n = 8) human hearts. Na(+)-Ca2+ exchanger mRNA levels were significantly increased, by 79% (P < .001) in DCM and by 58% (P < .01) in ICM compared with NF; protein levels increased by 36% (P < .001) and by 20% (P < .05), respectively. BDF 9148 increased the force of contraction concentration dependently, with a similar maximal effect in NYHA class IV and NF, but was more potent in NYHA class IV as demonstrated by a significantly smaller (P < .01) EC50 value (NYHA class IV, 0.18 [0.16 to 0.22] mumol/L; NF, 1.65 [1.3 to 3.0] mumol/L). In NYHA class IV, BDF 9148 (0.1 mumol/L) restored the positive force-frequency relationship and reduced the frequency-dependent increase in diastolic tension in relation to force of contraction. CONCLUSIONS: The increased expression of the Na(+)-Ca2+ exchanger is a possible explanation for the increased inotropic potency of the Na+ channel activator BDF 9148 in failing human myocardium. The increase in exchanger molecules could be of functional relevance for the modulation of cardiac contractility by agents that increase the intracellular Na+ concentration. Enhancement of Na(+)-Ca2+ exchanger activity might be a powerful mechanism for increasing cardiac contractility in chronic heart failure.