Myocardial Gi alpha-protein levels in patients with hypertensive cardiac hypertrophy, ischemic heart disease and cardiogenic shock

OBJECTIVE: Increased inhibitory G-protein alpha-subunits (Gi alpha) have been reported to be related to adenylyl cyclase desensitization in the failing human heart. In order to investigate whether this cellular alteration occurs already at the stage of hypertensive cardiac hypertrophy or in catecholamine-refractory cardiogenic shock, Gi alpha levels were studied in myocardial samples from patients with hypertensive cardiac hypertrophy, coronary heart disease without heart failure and from patients with cardiogenic shock on high-dose catecholamine therapy as well as from patients without evidence of heart disease. METHODS: Gi alpha was quantified with pertussis-toxin-catalyzed 32P-ADP-ribosylation and with a radioimmunoassay in myocardial samples from patients within 16 h of death. The radioimmunoassay was constructed with recombinant G-protein alpha-subunits (rGi alpha 1) from transformed E. coli harbouring the full-length cDNA of Gi alpha 1, iodinated peptide 125I-KENLKDCGLF and immunoprecipitating antiserum (MB 1) raised against the synthetic peptide (KENLKDCGLF) in rabbits. RESULTS: Pertussis toxin substrates and immunochemical Gi alpha remained stable up to 80 h following storage at room temperature in myocardium obtained during cardiac transplantation. Gs alpha, adenylyl cyclase, beta-adrenoceptors and inhibitory receptors were not stable and could not be determined. Increases in myocardial Gi alpha of 65-82% of both pertussis toxin substrates and immunologically quantified Gi alpha were observed in hypertensive cardiac hypertrophy. Catecholamine therapy in patients who died of catecholamine-refractory shock increased myocardial Gi alpha by 225% compared to myocardium from patients with coronary heart disease without heart failure and without catecholamine therapy or compared to control myocardium. CONCLUSION: These findings provide evidence than an increase in myocardial Gi alpha-proteins could be of relevance in pathological conditions other than chronic heart failure. Since an increase in Gi alpha levels already occurs in hypertensive cardiac hypertrophy, it could play a role in contributing to the development of contractile dysfunction and heart failure in later stages of the syndrome. Finally, an increase in Gi alpha could be one mechanism contributing to catecholamine refractoriness in shock. This could provide a target for pharmacological treatment in this condition.     

Beta-adrenergic signal transduction in the failing and hypertrophied myocardium

A strong sympathetic activation has been observed in heart failure and is the cause of beta-adrenergic desensitization in this condition. On the receptor level there is downregulation of beta1-adrenergic receptors and uncoupling of beta2-adrenoceptors. The latter mechanism has been related to an increased activity and gene expression of beta-adrenoceptor kinase in failing myocardium, leading to phosphorylation and uncoupling of receptors. beta3-Adrenoceptors mediate negative inotropic effects, but alterations in these receptors are not known. In addition, an increase in inhibitory G protein alpha subunits (Gi alpha) has been suggested to be causally linked to adenylyl cyclase desensitization in heart failure. In contrast, the catalytic subunit of adenylyl cyclase, stimulatory G protein alpha and betagamma subunits, have been observed to be unchanged. Recent evidence shows that increases in Gi alpha also depress adenylyl cyclase in compensated cardiac hypertrophy both in monogenic and polygenic and in secondary hypertension. These increases of Gi alpha can suppress adenylyl cyclase in the absence of beta-adrenergic receptor downregulation. Since cardiac hypertrophy in pressure overload is a strong predictor of cardiac failure, these observations indicate that adenylyl cyclase desensitization by Gi alpha may be a pathophysiologically relevant mechanism contributing to the progression from compensated cardiac hypertrophy to heart failure.     

The DD genotype of the angiotensin-converting enzyme gene is associated with increased mortality in idiopathic heart failure

OBJECTIVES: The aim of the present study was to investigate the association between the homozygous DD (deletion) genotype of the angiotensin-converting enzyme gene and survival and cardiac function in patients with idiopathic congestive heart failure. BACKGROUND: The DD genotype gene is a linkage marker for an etiologic mutation at or near the angiotensin-converting enzyme gene and has been associated with increased risk for the development of coronary artery disease, left ventricular hypertrophy and left ventricular dilation after myocardial infarction. We investigated the association between this angiotensin-converting enzyme genotype and mortality in a population-based cohort of patients with idiopathic congestive heart failure. METHODS: The genotype was determined in 193 patients recruited from a large unselected population of patients with congestive heart failure (n = 2,711). The patients were studied with echocardiography, and survival data were obtained after 5 years of follow-up. A control group from the general population (n = 77) was studied by a similar procedure. RESULTS: The frequency of the D allele was not significantly different in the study and control groups (0.57 vs 0.56, p = NS). Long-term survival was significantly worse in the patients with the DD genotype than in the remaining patients (5-year survival rate 49% vs. 72%, p = 0.0011 as assessed by log rank test). The independent importance of the DD genotype for prognosis was verified by a multivariate Cox proportional hazards analysis, by which the odds ratio for mortality and the DD genotype was 1.69 (95% confidence interval 1.01 to 2.82). The only significant difference in cardiac function data between the two groups was an increase in left ventricular mass index in the DD group (153 +/- 57 vs 134 +/- 44 g/m2, p = 0.019). CONCLUSIONS: Angiotensin-converting enzyme gene DD polymorphism was associated with poorer survival and an increase in left ventricular mass in patients with idiopathic heart failure. The results suggest a possible pathophysiologic pathway between angiotensin-converting enzyme gene polymorphism, angiotensin-converting enzyme activity, myocardial hypertrophy and survival. Therefore, the DD genotype may be a marker of poor prognosis in patients with congestive heart failure.     

Effects of eprosartan on renal function and cardiac hypertrophy in rats with experimental heart failure

Activation of the renin-angiotensin system may contribute to the derangement in renal and cardiac function in congestive heart failure. The present study evaluated the effects of eprosartan, a selective angiotensin II receptor antagonist, on renal hemodynamic and excretory parameters and on the development of cardiac hypertrophy in rats with aortocaval fistula, an experimental model of congestive heart failure. Infusion of eprosartan (1.0 mg/kg) in rats with aortocaval fistula produced a significant increase (+34%) in total renal blood flow and a sustained decrease (-33%) in the calculated renal vascular resistance. These effects on renal hemodynamics were more pronounced than those observed in sham-operated control rats and occurred despite a significant fall (-12%) in mean arterial blood pressure. Moreover, eprosartan caused a preferential increase in renal cortical blood perfusion and significantly increased glomerular filtration in rats with congestive heart failure. Chronic administration of eprosartan (5.0 mg/kg per day for 7 days through osmotic minipumps inserted intraperitoneally on the day of operation) resulted in a significant enhancement of urinary sodium excretion compared with nontreated rats with heart failure. Moreover, administration of eprosartan to salt-retaining rats with congestive heart failure resulted in a progressive increase and ultimate recovery in urinary sodium excretion. Finally, early treatment with eprosartan blocked the development of cardiac hypertrophy in rats with aortocaval fistula to a larger extent than the angiotensin-converting enzyme inhibitor enalapril. These findings emphasize the importance of angiotensin II in mediating the impairment in renal function and induction of cardiac hypertrophy in heart failure and further suggest that angiotensin II receptor blockade may be a useful treatment of these consequences in severe cardiac failure.     

Decompensation of pressure-overload hypertrophy in G alpha q-overexpressing mice

BACKGROUND: Receptor-mediated activation of myocardial Gq signaling is postulated as a biochemical mechanism transducing pressure-overload hypertrophy. The specific effects of Gq activation on the functional and morphological adaptations to pressure overload are not known. METHODS AND RESULTS: To determine the effects of intrinsic myocyte G alpha q signaling on the left ventricular hypertrophic response to experimental pressure overload, transgenic mice overexpressing G alpha q specifically in the heart (G alpha q-25) and nontransgenic siblings underwent microsurgical creation of transverse aortic coarctation and the morphometric, functional, and molecular characteristics of these pressure-overloaded hearts were compared at increasing times after surgery. Before aortic banding, isolated G alpha q-25 ventricular myocytes exhibited contractile depression (depressed +dl/dt and -dl/dt) and G alpha q-25 hearts showed a pattern of fetal gene expression similar to the known characteristics of nontransgenic pressure-overloaded mice. Three weeks after transverse aortic banding, G alpha q-25 left ventricles hypertrophied to a similar extent (approximately 30% increase) as nontransgenic mice. However, whereas nontransgenic mice exhibited concentric left ventricular remodeling with maintained ejection performance (compensated hypertrophy), G alpha q-25 left ventricles developed eccentric hypertrophy and ejection performance deteriorated, ultimately resulting in left heart failure (decompensated hypertrophy). The signature hypertrophy-associated progress of fetal cardiac gene expression observed at baseline in G alpha q-25 developed after aortic banding of nontransgenic mice but did not significantly change in aortic-banded G alpha q-25 mice. CONCLUSIONS: Intrinsic cardiac myocyte G alpha q activation stimulates fetal gene expression and depresses cardiac myocyte contractility. Superimposition of the hemodynamic stress of pressure overload on G alpha q overexpression stimulates a maladaptive form of eccentric hypertrophy that leads to rapid functional decompensation. Therefore G alpha q-stimulated cardiac hypertrophy is functionally deleterious and compromises the ability of the heart to adapt to increased mechanical load. This finding supports a reevaluation of accepted concepts regarding the mechanisms for compensation and decompensation in pressure-overload hypertrophy.     

Assessment of cardiovascular perioperative risk in non-cardiac surgery

Patients with cardiovascular disease undergoing non cardiac surgery are exposed to three cardiac risks: myocardial infarction, heart failure and death. To estimate cardiac risk, clinical predictors of perioperative cardiovascular risk are classified as major, intermediate and minor and non cardiac surgery is stratified in high risk (greater than 5%), intermediate (from 1 to 5%), minor (lower than 1%) procedures. Efficient perioperative assessment of cardiac patients is obtained by teamwork and usually, indications for further cardiac investigations are the same as those in the nonoperative setting. An simplified algorithm, easier to use than original algorithm given in the guidelines of the American college of cardiology and the American heart association, may be helpful for the indication of further investigations. Five questions must be answered before using algorithm: is it an emergency surgical procedure?, was a coronary revascularization required in the past five years? has the patient had a coronary evaluation in the past two years?, are there identified clinical predictors of cardiac risk?, is it major or minor surgery? Three tests evaluate the preoperative cardiac risk: exercise testing, dipyridamole thallium scintigraphy, dobutamine stress echocardiography. Their accuracy is similar, their negative predictive value is high, their positive predictive value is low. These guidelines may be helpful to indicate further cardiac investigations which will have an impact on patient's treatment, monitoring during or after surgery and outcome.     

Effect of centrifugation on the pressure resistance of exponential phase cells of Escherichia coli 8164

OBJECTIVE: To assess the efficacy of partial left ventriculectomy as a treatment for patients with end-stage heart failure. METHODS: From February to June 1995, 7 patients with end-stage heart failure underwent partial left ventriculectomy. Subsequently, patients underwent clinical evaluation every 2 months, and 2-dimensional echocardiography at the 6th and 12th months after cardiac surgery. All patients were given digitalis and diuretics at conventional doses, and captopril or enalapril at maximal tolerated doses. RESULTS: Two (28%) patients died; 1 from cardiac arrhythmia associated with gastrointestinal hemorrhage, and the other suddenly. One (14%) patient developed an embolic cerebrovascular accident. Four (57%) patients were hospitalized for congestive heart failure; all of them had either decreased the daily dose of captopril or enalapril or discontinued the drugs by themselves. Twelve months after ventriculectomy, left ventricular ejection fraction values were greater and left ventricular diastolic dimension and functional class values lower than those found before cardiac operation. CONCLUSION: Beneficial effects of partial left ventriculectomy are observed one year after the surgical procedure. This technique, therefore, can be useful for the treatment of patients with end-stage heart failure.     

Effects of ischaemia-reperfusion and cyclosporin-A on cardiac muscle ultrastructure

The present study investigates the effects on the cardiac muscle cell of two of the determining factors for the success of organ transplant; ischaemia-perfusion and immunosuppressive treatment with cyclosporin-A (CsA). To this end an abdominal, heterotopic heart transplant model in singenic Sprague-Dawley rats was employed. Three study groups were established: Group I (control, n = 15) animals undergoing heart transplant without treatment; Group II (n = 15) animals undergoing heart transplant and subjected to a daily dose of CsA in a cremophor vehicle (Sandimun) (5 mg/kg/sc); Group III (n = 15): animals undergoing heart transplant and administered a daily dose of pure CsA (5 mg/kg/sc). Recipient animals were sacrificed 7, 14, 21, 30 and 50 days after transplant. During the post-operative period, heart function was assessed by daily abdominal palpation. Graft specimens obtained at each follow-up period were subjected to light and transmission electron microscopy. Immunohistochemical analysis of specimens was performed using the rat macrophage-specific monoclonal antibody MCA-341. The ischaemia/reperfusion process induced considerable alteration to cardiac muscle cells of control animals. Effects, apparent after the first week of transplant, included mitochondrial swelling and loss of cristae, hypertrophy of the sarcoplasmic reticulum and structural changes to sarcomeres. Two weeks after transplant, the myocardium was infiltrated by inflammatory cells. These effects diminished 30 days post-transplant. Cardiac tissues of treated animals (groups II and III) showed similar behaviour although, in the latter group, mitochondrial damage was greater and intense myocardial fibrosis took place. Infiltration of cardiac muscle by white blood cells did not take place until 3 weeks post-implant. These results indicate: a) The ultrastructural changes detected in cardiac fibres of animals of the three study groups were attributable to the ischaemia/reperfusion process rather than to treatment with CsA; b) CsA appears to augment mitochondrial damage and myocardial fibrosis; c) the inflammatory response was delayed and reduced by the immunosupressant; and d) the cremophor administration vehicle did not seem to exert an independent toxic effect on the myocardium.     

Is laparoscopic cholecystectomy minor invasive surgery?

We conducted a comparative study to investigate whether or not laparoscopic cholecystectomy is less invasive and safer than abdominal subcostal laparotomy, using findings in blood pressure, heart rate, blood gas and endocrinological functions. In laparoscopic cholecystectomy, the patients' hospitalization period and expense for surgery were markedly reduced. However, those patients who underwent laparoscopic cholecystectomy had increases in blood pressure, heart rate, plasma cortisol and norepinephrine concentrations; it was assumed that these increases might be the result of reduced venous return to the heart which accompanied increased intra-thoracic and abdominal pressures, with reduction of cardiac output. In conclusion, since laparoscopic surgery is very advantageous for patients, we consider that for the success of this surgical procedure, it will be necessary to conduct safe anesthetic managements as well as to select patients carefully.     

A review of infectious endocarditis due to Candida

OBJECTIVE: As fungal endocarditis is a serious disease, frequently requiring cardiac surgery, a review was made of the experience of our Departments in this pathology. DESIGN: A retrospective analysis of clinical, echocardiographic and surgical data. SETTING: Patients studied in a tertiary care Hospital with cardiac surgery available. PATIENTS: Between 1984 and 1994 there were ten cases of candida endocarditis in nine patients, four male and five female, mean age--45 +/- 12 years (31-65). INTERVENTIONS: The following parameters were analysed: clinical (predisposing factors, clinical evolution, complications, therapy and mortality), echocardiographic (presence of vegetations, abscesses, valvular regurgitations). Patients studied in other Centres and referred to our Department only for examination (echocardiograms) were excluded from this analysis. RESULTS: Eight cases in seven patients were prosthetic valve endocarditis and two native valve endocarditis. No patient was drug addicted. Seven cases of prosthetic valve endocarditis developed less than one year after surgery and another had a gynecological fungal infection as the cause of the endocarditis. Four patients had had previous endocarditis. There were four embolic events and three developed heart failure. There were three perivalvular infections, six valvular regurgitations and only one case with huge vegetations on echocardiography. Nine patients were treated with amphotericin B, in five fluocytosin was added and in four ketoconazol, which was replaced by flukonazol in one patient. Therapy was continued for at least eight weeks. Six patients were operated during the acute stage and one died. One patient was operated on late after the infection. Three patients died during the active stage. In a follow up of 5.2 +/- 4.8 years (8 months to 8 years) there was one fatal candida endocarditis relapse, one fatal candida sepsis, one non cardiac death, one patient developed a periprosthetic leak and one had recurrent systemic embolization. Abscesses/pseudoaneurysms were found in five out of seven patients submitted to surgery. CONCLUSION: Candida infective endocarditis has a bad prognosis, specially in those patients not operated early; it develops in patients with predisposing factors, which in our series were a previous infective endocarditis (four patients) and/or a prosthetic valve implantation less than one year before; it has important morbidity with multiple embolic events, perivalvular involvement, valvular regurgitation and heart failure.     

Indications for heart transplantation

Heart transplantation may have a considerable impact on the fate of the patient in the end stage of heart failure. A successful procedure requires the existence of a sophisticated programme combining the expertise of top departments of cardiology and cardiac surgery working in conjunction with the transplant centre directly responsible for removing the organ. One of the factors playing an important role in a favourable outcome is the correct indication for the procedure. The information on patient selection and criteria for the heart donor, presented in this paper, become increasingly important even for the practitioner in cardiology referring their patients to specialized departments. The paper also offers background information on the heart transplant programme in the Czech Republic suggesting the need for expanding the availability of the therapeutic method in this country.     

Molecular pathobiology in heart failure

Heart failure is a pathophysiological state resulting from disturbed cardiac function. It is based on complex molecular processes, many of which are not fully understood. During heart failure adaptive mechanisms, that reinstall altered cardiac function, are activated. The main mechanisms are: a) Alteration of the structure and composition of myocytes by myocardial hypertrophy, reexpression of fetal and neo-natal proteins and the expression of certain proto-oncogenes; b) Activation of the neuroendocrinal system, specifically the sympathetic nervous system, renin-angiotensin-aldosterone system and vasopressin release; c) Activation of autocrine and paracrine systems. However, when these systems are activated beyond a certain limit they contribute to heart failure aggravation. This can also be promoted by alteration of the calcium metabolism inherent in heart failure. The synthesis of the counterregulator atrial natriuretic factor is also increased.     

Fresh osteochondral allografts for treatment of articular defects in osteochondritis dissecans of the lateral femoral condyle in adults

Fresh osteochondral allografts were used to patch defects in the lateral femoral condyle in 17 patients with osteochondritis dissecans. The patients included 12 males and five females, ages 16 to 46 years. All had previously undergone other procedures including pinning (4), primary removal of osteochondral fragments (16), and abrasion arthroplasty (14). Defects up to 3 cm in diameter were treated with isotopic grafts and fixed with Herbert screws. Larger defects were treated with crescent-shaped grafts fixed with multiple Herbert screws. Follow-up time ranged from two to nine years. Pain, stiffness, swelling, buckling, and locking were ablated in 16 of the 17 patients. No graft collapse has been noted in these individuals. Verification of graft viability was achieved at periods from six weeks to six years, typically at the time of hardware removal. The only failure occurred in an individual with a 3- x 4.5-cm defect who suffered gross fragmentation which left a large crater. Osteochondritis dissecans of the lateral femoral condyle provides an ideal opportunity for evaluating osteochondral grafts. Sixteen of 17 grafts were a success at two to nine years after surgery.     

Neurohormonal activity in heart insufficiency

The maintenance of cardiac pumping ability in the presence of a primary disturbance of myocardial contractility and/or an excessive haemodynamic strain on the heart is dependent on several compensatory mechanisms. Particular attention has formerly been paid to the importance of the Frank-Starling mechanism and cardiac hypertrophy and dilatation in maintaining a blood supply sufficient to cover the metabolic needs of various tissues in heart failure. In recent years, however, it has been found that certain neurohormonal systems (the sympathetic nervous system, the renin-angiotensin-aldosterone system, atrial natriuretic peptide and several locally acting vaso-active substances) undergo considerable changes according to the degree of heart failure. These compensatory mechanisms support the circulation wholly or partially in acute heart failure, however sustained neurohormonal activation may be harmful in chronic heart failure, where several neurohormonal factors may be activated to ill-effect. The most significant neurohormonal systems and their importance in heart failure are reviewed on the basis of the available literature.     

Cyclic stretch down-regulates calcium transporter gene expression in neonatal rat ventricular myocytes

Abnormal intracellular Ca2+ handling in hypertrophied and failing hearts is partly due to changes in Ca2+ transporter gene expression, but the mechanisms responsible for these alterations remain largely unknown. We previously showed that intrinsic mechanical load (i.e. spontaneous contractile activity) induced myocyte hypertrophy, and down-regulated SR Ca2+ ATPase (SERCA2) gene expression in cultured neonatal rat ventricular myocytes (NRVM). In the present study, we examined whether extrinsic mechanical load (i.e. cyclic stretch) also induced NRVM hypertrophy, and led to down-regulation of SERCA2 and other Ca2+ transporter genes which have been associated with cardiac hypertrophy and failure in vivo. NRVM were maintained in serum-free culture medium under control conditions, or subjected to cyclic mechanical deformation (1.0 Hz, 20% maximal strain, 48 h). Under these conditions, cyclic stretch induced NRVM hypertrophy, as evidenced by significant increases in total protein/DNA ratio, myosin heavy chain (MHC) content, and atrial natriuretic factor (ANF) secretion. Cyclic stretch also induced the MHC isoenzyme "switch" which is characteristic of hemodynamic overload of the rat heart in vivo. Cyclic stretch significantly down-regulated SERCA2 and ryanodine receptor (RyR) mRNA and protein levels, while simultaneously increasing ANF mRNA. In contrast, Na+-Ca2+ exchanger and phospholamban mRNA levels were unaffected. Load-dependent SERCA2 and RyR down-regulation was independent of Ca2+ influx via voltage-gated, L-type Ca2+ channels, as cyclic stretch down-regulated SERCA2 and RyR mRNA levels in both control and verapamil-treated NRVM. These results indicate that extrinsic mechanical load (in the absence of other exogenous stimuli) induces NRVM hypertrophy and causes down-regulation of Ca2+ transporter gene expression. This in vitro model system should prove useful to dissect the intracellular signaling pathways responsible for transducing this phenotype during cardiac hypertrophy and heart failure in vivo.     

Sturge-Weber syndrome: experience with 14 cases

We report a first documented case in Senegal with simple transposition of the great arteries diagnosed in a 2 months old girl treated by Rashkind atrioseptostomy. Our patient benefited from clinical examination, ECG (15 derivations), chest X ray and standard laboratory tests. Pulsed-Doppler, two dimensional and TM echocardiography have been performed with an ATL MK 600 echocardiograph. Cardiac catheterism, angiocardiography and Rashkind procedure have been realized in our Department. These data are discussed and compared to the literature. At admission this patient presents with major cyanosis and polypnea. At examination, there is a 3/6 murmur at the left sternal border and a subclavicular continuous murmur. Laboratory tests showed metabolic acidosis and severe hypoxemia. Chest x-ray showed a cardio-thoracic ratio at 0.64 with increased pulmonary vascular markings. ECG showed right ventricular hypertrophy. Echocardiography-Doppler revealed ventriculo-arterial discordance with restrictive atrial septal defect and persistent ductus arteriosus. Rashkind procedure was followed by an increased aortic saturation. After 6 weeks there was an improvement of cyanosis and cardiac failure. Diagnosis of transposition of the great arteries is actually easier with development of ultrasonography which is useful when performed by experienced cardiologist. Spontaneous prognosis of this malformation is very poor. Rashkind atrioseptostomy is an important step for the initial treatment of transposition of the great arteries in terms of survival before open heart surgery.