Role of endothelium-derived nitric oxide in the regulation of cardiac oxygen metabolism: implications in health and disease.

Endothelium-derived NO is considered to be primarily an important determinant of vascular tone and platelet activity; however, the modulation of myocardial metabolism by NO may be one of its most important roles. This modulation may be critical for the regulation of tissue metabolism. Several physiological processes act in concert to make endothelial NO synthase-derived NO potentially important in the regulation of mitochondrial respiration in cardiac tissue, including (1) the nature of the capillary network in the myocardium, (2) the diffusion distance for NO, (3) the low toxicity of NO at physiological (nanomolar) concentrations, (4) the fact that low PO(2) in tissue facilitates the action of NO on cytochrome oxidase, and (5) the formation of oxygen free radicals. A decrease in NO production is involved in the pathophysiological modifications that occur in heart failure and diabetes, disease states associated with altered cardiac metabolism that contributes to the evolution of the disease process. In contrast, several drugs (eg, angiotensin-converting enzyme inhibitors, amlodipine, and statins) can restore or maintain endogenous production of NO by endothelial cells, and this mechanism may explain part of their therapeutic efficiency. Thus, the purpose of this review is to critically evaluate the role of NO in the control of mitochondrial respiration, with special emphasis on its effect on cardiac metabolism.

Recurrence of dilated cardiomyopathy after re-introduction of a tricyclic antidepressant.

A causal relationship between treatment with tricyclic antidepressant (TCA) at therapeutic doses and cases of dilated cardiomyopathy has been suspected, but not definitely evidenced. We present a case of a dilated cardiomyopathy, which seemed idiopathic, but occurred during treatment with imipramine and recovered after its withdrawal. For the first recorded time, the cardiomyopathy recurred 9 years later, after a 2-year period of treatment with amitriptyline and lithium, and recovered again 1 year after both psychotropic drugs withdrawal. New arguments for the existence of TCA-induced dilated cardiomyopathy are brought.

Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study.

OBJECTIVES: The study investigated the potential role of eight candidate genes in the susceptibility to idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Idiopathic dilated cardiomyopathy has a familial origin in 20% to 25% of cases, and several genetic loci have been identified in rare monogenic forms of the disease. These findings led to the hypothesis that genetic factors might also be involved in sporadic forms of the disease. In complex diseases that do not exhibit a clear pattern of familial aggregation, the candidate gene approach is a strategy widely used to identify susceptibility genes. All genes coding for proteins involved in biochemical or physiological abnormalities of cardiac function are potential candidates for IDC. METHODS: We studied 433 patients with IDC and 401 gender- and age-matched controls. Polymorphisms investigated were the I/D polymorphism of the angiotensin I-converting enzyme (ACE) gene, the T174M and M235T polymorphisms of the angiotensinogen (AGT) gene, the A-153G and A+39C polymorphisms of the angiotensin-II type 1 receptor (AGTR1) gene, the T-344C polymorphism of the aldosterone synthase (CYP11B2) gene, the G-308A polymorphism of the tumor necrosis factor-alpha (TNF) gene, the R25P polymorphism of the transforming growth factor beta1 (TGFB1) gene, the G+11/in23T polymorphism of the endothelial nitric oxide synthase (NOS3) gene and the C-1563T polymorphism of the brain natriuretic peptide (BNP) gene. RESULTS: None of the polymorphisms were significantly associated with the risk or the severity of the disease. CONCLUSIONS: We did not find evidence for an involvement of any of the 10 investigated polymorphisms in the susceptibility to IDC.

Genetic testing and genetic counselling in hypertrophic cardiomyopathy: the French experience.

AIMS: A major breakthrough in the molecular genetics of hypertrophic cardiomyopathy (HCM) has made genetic testing now available in clinical practice, raising new questions about its implications, potential benefits, and the organisation of the procedure. The aim of this work was (1) to discuss the different questions related to genetic testing in HCM, and propose guidelines for the different situations, (2) to report our preliminary experience with a specific procedure. METHODS AND RESULTS: The main questions asked by patients and relatives concern presymptomatic diagnosis and prenatal counselling/diagnosis, while clinicians sometimes discuss diagnostic and prognostic testing. To take into account the complex medical and psychological implications of this new approach, we developed a specific, multidisciplinary, and multiple step procedure, including a cardiologist, a geneticist, and a psychologist. Seventy subjects were examined, including (1) 29 adults for presymptomatic diagnosis (of whom 10 left the procedure after the first visit and 19 continued, among whom six had a mutation and two experienced negative psychological impact, observed during follow up), (2) nine couples of parents for presymptomatic diagnosis in their children (the procedure was stopped after the first visit in eight and continued in one), (3) 22 couples for prenatal counselling (no prenatal genetic testing was asked for after the first visit), and (4) 10 subjects for diagnostic testing. We decided to perform no prognostic testing. CONCLUSION: Our preliminary experience confirms the complexity of the situation and suggests the necessity for a specific procedure to ensure good practice in genetic testing of HCM.

The management of patients with heart failure in France.

Heart failure is becoming, in France as in other countries, a major public health problem, occurring in elderly patients with concurrent disease. A general overview of the current care of heart failure patients in France is provided in this article, and some ideas about possible ways of improving the present management of heart failure.

Ambulatory heart failure management in private practice in France.

UNLABELLED: Management of ambulatory heart failure was assessed in a group of 600 patients, mean age 73, 64% males, NYHA I: 9%; II: 52%; III: 33%; IV: 6%; followed up by a representative sample of private cardiologists. Fifty-two percent of patients had been previously hospitalised for worsening heart failure with a mean duration of stay of 13.1 days, for those hospitalised in the year preceding the survey (26%). First diagnosis of heart failure had been performed by a cardiologist (57%), a general practitioner (37%) or another category of physician (6%). Seventy percent of patients received three or more different classes of heart failure medications. Diuretics were prescribed to 71%, angiotensin converting enzyme inhibitors to 54% and digitalis to 35% of the population. Beta-blockers were given to only 14% of the patients. In patients aged over 80 years, only 45% received angiotensin converting enzyme inhibitors. CONCLUSION: This survey of ambulatory heart failure patients confirms that the disease is predominantly observed in elderly patients, and associated with prolonged and recurrent hospitalisations. The underuse of recommended therapeutic classes including angiotensin converting enzyme inhibitors and beta-blockers deserves further investigation.

Accuracy of European diagnostic criteria for familial hypertrophic cardiomyopathy in a genotyped population.

BACKGROUND: Since the sensitivity of conventional diagnostic criteria for familial hypertrophic cardiomyopathy (HCM) is low, new diagnostic criteria were proposed by a European collaboration. However, their diagnostic value remains unknown. The aim of the study was to evaluate the accuracy of these new criteria, using the genetic status as the criterion of reference. METHODS: We studied 109 genotyped adults (54 genetically affected, 55 unaffected) from 7 families (mutations in 3 genes). Major European echographic criteria were a maximal wall thickness >or=13 mm or >or=15 mm according to the segment involved, or the presence of SAM. Major European ECG criteria were abnormal Q waves, left ventricular hypertrophy, or marked ST-T changes. Combined major/minor European criteria were also evaluated. RESULTS: Sensitivity and specificity of major European criteria (72 and 92%, respectively) were similar to those of major conventional criteria (70 and 94%) and were not improved by combined major/minor European criteria (72 and 90%). When all the minor European criteria were considered, sensitivity increased to 87% but specificity dramatically decreased to 51%. However, one of these minor ECG criteria, deep S V2, was of interest and when added to major European criteria, sensitivity increased to 76% and specificity remained good (90%). CONCLUSIONS: The diagnostic value of new European criteria for HCM was evaluated for the first time. We found that it was not different from that of conventional criteria, with a good specificity but a low sensitivity. Additional criteria should be studied to improve the early identification of HCM.

Panic disorder and idiopathic cardiomyopathy.

OBJECTIVE: This study investigated whether, among a population of cardiac patients, there is a preferential association between idiopathic cardiomyopathy (CMP) and Panic Disorder (PD). METHODS: A total of 93 patients with cardiac failure, 50 of them with CMP, 43 with other cardiac diseases, underwent a standard psychiatric examination using the MINI neuropsychiatric interview. RESULTS: While half of the subjects met the criteria for a psychiatric disorder, PD was no more prevalent in the CMP group compared to other patients. CONCLUSION: This study confirms the high prevalence of psychiatric pathology, particularly anxiety, mood, and alcohol-related disorders, in patients with cardiac failure. However, previous findings on the specific association between CMP and PD could not be replicated.

Penetrance of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant cardiac disease for which the penetrance remains a much-debated issue. Since the recent identification of the genes involved in the disease, the penetrance of FHC has not been reassessed in a large genotyped population. The aim of our study was therefore to evaluate it, according to age and sex, in ten families with previously identified mutations. Among 178 individuals we studied, 90 were genetically affected (9 different mutations in 3 genes). We found that penetrance, assessed by classical echocardiographic and electrocardiographic criteria, was (1) incomplete: 69%; (2) age-related: 55% between 10 and 29 years old, 75% between 30 and 49 y. and 95% over 50 y.; (3) greater in males than in females: 77% vs 58%, age-adjusted odds ratio: 3.98, CI 95%: 1.34 to 11,48; (4) similar for the genes analyzed. The consequences of these results for genetic counseling and linkage analyses are discussed.

[Education of patients with heart failure]. / Education des patients insuffisants cardiaques.

Chronic cardiac failure is a common complication of coronary artery disease and hypertension. It is observed above all in the elderly and represents a high public health cost, mainly due to hospital admissions. The education of patients with cardiac failure, and their families', will contribute to an improved cost/efficacy ratio of the management of this pathology. This educative process comprises a simple description of cardiac failure, its symptoms and aetiologies. Dietary advice is very important (salt intake, drinks...). Physical exercise, which is not contraindicated, should be adapted to the degree of functional impairment and the same applies to travelling and voyages. Medical treatment should be clearly explained, mode of action, dosage, expected benefit, side effects... Finally, the possible progression of the disease should be explained if arrangements have to be made. The possibility of cardiac transplantation should be discussed if the subject is young. Although the risk of sudden death is not usually spoken about, this common complication of cardiac failure justifies consideration and widespread instruction of cardiopulmonary ressuscitation.

[Digitalis and beta-blockers: what treatment, what dose and for which patient?]. / Digitaliques et bêtabloquants: quel traitement, à quelle dose et pourquel patient?

The aim of this update is to review the role of digitalis and betablockers in the treatment of chronic cardiac failure. The role of digitalis is unquestioned in the treatment of chronic cardiac failure complicated by atrial fibrillation resistant to attempts at reduction. Digoxin, with a shorter half-life, is preferred to digitalis. When in sinus rhythm, digoxin is indicated in association with diuretics and angiotensin converting enzyme inhibitors, to improve the quality of life without demonstrable effects on survival. Betablockers now have a recognised place in the treatment of chronic cardiac failure in association with diuretics and angiotensin converting enzyme inhibitors. The compilation of the US-Carvedilol HF Trial have shown a 67% reduction in mortality at 6 months. Carvedilol has been officially approved for use in this indication. Some betablockers are under evaluation, regarding positive results in term of mortality, some clinical trials have been stopped. This review emphasises the changes in prescribing habits of digitalis, and mostly betablockers, in chronic cardiac failure.

[Left ventricular systolic dysfunction in cardiomyopathies]. / Dysfonction ventriculaire systolique dans les myocardiopathies.

Of the three physiopathological types of cardiomyopathy, dilated, hypertrophic and restrictive, it is the first which characteristically shows major left ventricular systolic dysfunction. The left ventricular volumes are increased, the ventricle becomes spherical and global ejection fraction decreases with diffuse or segmental wall motion abnormalities. The left ventricular mass is increased in an excentrical fashion with wall thinning. Isovolumic contraction is slower, the ejection time is shorter and, above all, the indices of contractility such as maximal velocity of the contractile elements ... are very abnormal and do not improve after positive inotropic stimulation.

[Experimental study of the subacute toxicity of mitoxantrone and doxorubicin in rats (subcutaneous and/or intraperitoneal route)]. / Etude expérimentale de la cardiotoxicité subaiguë de la mitoxantrone et la doxorubicine chez le rat. (voie sous-cutanée et/ou intrapéritonéale).

The aims of this study were to compare experimentally the subacute cardiotoxicity of a new anthracycline, mitoxantrone (MIT) with doxorubicin (ADM), the reference anthracycline drug. Seventy nine male rats were divided into 5 groups receiving one of the drugs or a placebo by subcutaneous (SC) or intraperitoneal (IP) injection, each week for 13 weeks. The surviving rats were sacrificed at the 21st week. Group I comprised 16 rats which received 2 mg/kg AMD-IP. The mortality rate was 50% between the 14th and 18th week. Twelve of the 16 cases had a haemorrhagic ascites. The heart was normal macroscopically and on light microscopy. However, electro microscopy showed moderate myocytic degeneration. Group II comprised 16 rats which received 0.6 mg/kg MIT-IP. Morality was 100% at the 11th week. Groups III and IV comprised 32 rats; half of the animals were given 0.6 mg/kg MIT-SC and the other half 0.4 mg/kg MIT-SC. The results were identical: good clinical tolerance, normal macroscopy. Three cases of lymphocytic myocarditis and in 4 out of 8 cases very mild myocardial degeneration on electron microscopy. Group V comprised 15 rats which were given NaCl 9% SC or IP; there were no complications. These results show that mitoxantrone given IP produced major peritoneal toxicity. On the other hand, it was well tolerated when given SC and only produced mild myocardial degenerative changes.

[Fatal form of pericardo-myocarditis in Wissler-Fanconi syndrome]. / Forme mortelle de péricardo-myocardite au cours d'un syndrome de Wissler-Fanconi.

The Wissler-Fanconi syndrome is an inflammatory disease of unknown origin, similar to Still's disease, a systemic form of juvenile arthritis. The long-term evolution is marked by recurrent febrile exacerbations, sometimes complicated by pericardo-myocarditis which usually resolves without sequellae. The authors report a case with chronic pericardo-myocarditis progressing over a 7 year period to refractory congestive cardiac failure.

[Strategy of the medical treatment of angina pectoris]. / Stratégie du traitement médical de l'angine de poitrine.

The first objective is to correct any existing coronary risk factors but this must be achieved with discrimination. Smoking should be strictly forbidden, hypertension reduced and a more active life style encouraged. However, a more nuanced approach should be adopted towards dietetic problems, obesity and disorders of lipid metabolism. It is also very important to teach the patient to use glyceryl trinitrate correctly in the double objective of relieving pain as quickly as possible and of preventing pain by using it in certain critical situations. Clinical practice shows that patients often use glyceryl trinitrate too sparingly. When these general measures have been settled, treatment must be adapted to each particular situation. The patient's age, the frequency of attacks, trigger factors, the repercussions of the disease on the patient's life all have to be considered before deciding on the individual's treatment. In younger patients, a controlled exercise ECG is essential for selecting patients for surgery. The drugs of choice for stable angina are the betablockers which have been shown to be effective and well tolerated. When this group of drugs cannot be used or is ineffective, other major anti-anginal drugs may be chosen according to the individual terrain and their known secondary effects.

[What are the indications for ambulatory mechanical hart-assist devices for the left ventricle?]. / Quelles indications pour l'assistance mécanique ambulatoire du ventricule gauche?

Ambulatory mechanical left ventricular assistance has become a reality but clinical experience of long-term tolerance is limited for setting up a randomised trial comparing this technique with cardiac transplantation. On the other hand, it is justified in proposing this long-term circulatory assistance to a subgroup of patients on the waiting list for transplantation but who have little chance of being transplanted before irreversible multivisceral failure sets in. Some specific contraindications to left ventricular mechanical assistance should be respected. After implantation of a portable system, the possibility of being reinscribed on the waiting list for cardiac transplantation should be envisaged if the patient so wishes.

[Ventricular rhythms with normal heart rate in the acute stage of myocardial infarction]. / Rythmes ventriculaires á fréquence normale au stade aigu de l'infarctus du myocarde

In relation with 25 personal cases, a general review of ventricular rhythms with normal rate observed during the acute stage of myocardial infarction is undertaken. More commonly called "slow VT", this transient and benign arrhythmia occurs within the first 48 hours of infarction. Presence of numerous fusion beats and His potential recordings make it possible to demonstrate its ventricular origin. Its mechanism is variable: in most cases it results from the discharge of an automatic, non-parasystolic, intermittently active focus, more rarely from the discharge of a parasytolic focus and in many cases, the focus is not apparent. Treatment of this arrhythmia should be careful: its benign character often justifies therapeutic abstention.

[Study of the association between aortic coarctation and congenital mitral insufficiency (excluding atrioventricular canals)]. / Etude de l'association coarctation de l'aorte-insuffisance mitrale congénitale (à l'exclusion des canaux atrio-ventriculaires)

Coarctation of the aorta is accompanied by congenital mitral incompetence in 3% of cases, and this combination worsens the prognosis. A series of 23 cases is reported, and the treatment analysed. In 6 cases only medical treatment was used, either because death was rapid or, on the contrary, satisfactory progress made it possible to wait for the normal age for resection and suture of the coarctation. In one case the severity of the mitral incompetence required early valvular replacement, while the minimal coarctation was ignored. Usually (16 cases) a Crafoord operation is carried out as a first stage, and of the 13 children still alive, 8 had their mitral incompetence improved or stabilised; but in 5 it became worse, requiring mitral valve surgery from 1 to 7 years later. Post mortem study showed the multiplicity of mitral lesions present, and explains the difficulty of mitral 'plasty' operations, which are the best solution in children.

[Medical treatment of hypertrophic myocardiopathy. Comparison of propranolol and verapamil]. / Traitement médical de la myocardiopathie hypertrophique. Comparaison entre le propranolol et le vérapamil.

It remains difficult to make a reasoned choice between betablockers and calcium antagonists in the medical treatment of hypertrophic cardiomyopathy. In order to help in making this choice, we compared the effects of 320 mg of propranolol and 480 mg of verapamil, prescribed in a random order for an average period of 2.5 months in 24 patients. In 15 patients the two therapeutic sequences were preceded and followed by a clinical examination and an exercise stress test after withdrawal of all treatment. The overall functional status correlated to oxygen consumption was unchanged by the two drugs, but patients felt better more often with verapamil. These was no significant change in maximal power developed during exercise testing although verapamil increased it by 9 p. 100 throughout with a corresponding increase in oxygen consumption. Two parameters were significantly changed by both drugs: the maximal heart rate fell from 161 +/- 22 to 122 +/- 18 with propranolol, and to 145 +/- 28 with verapamil; the oxygen pulse (equivalent to the systolic index) increased from 10.9 +/- 2.2 to 14.8 +/- 3.9 with propranolol, and to 13.7 +/- 2.4 with verapamil. There were no changes in the blood pressure profiles during exercise. Side effects were observed with both drugs; muscular weakness was the biggest problem with propranolol and sinus node dysfunction with verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)

[Effect of cardioversion of atrial fibrillation on left ventricular function in dilated cardiomyopathy. A multicenter study]. / Effet de la réduction de la fibrillation auriculaire sur la fonction ventriculaire gauche des cardiomyopathies dilatées. Etude multicentrique.

A group of 73 patients with idiopathic dilated cardiomyopathy were followed up for an average of 22 +/- 7 months to assess the medium term evolution of echocardiographic parameters of left ventricular function and, in particular, the consequences of cardioversion of atrial fibrillation. Seventy nine per cent of patients presented with cardiac failure. Left bundle branch block was observed in 20% and ventricular arrhythmias were frequent in 31%, complex in 62% with episodes of non-sustained ventricular tachycardia in 10% of cases. Left ventricular dilatation was greater in patients with complete left bundle branch block (p less than 0.003). Atrial fibrillation was present in 14 patients (19%) who were generally older than the rest of the study population (p less than 0.02) and was associated with less severe left ventricular dysfunction (p less than 0.01). Return to sinus rhythm was obtained in 9 patients. Echocardiographic data was obtained in 64 patients after an average of 6.2 +/- 1.7 months. Left ventricular function improved during the follow-up period and returned to normal in 12% of cases. Reduction of atrial fibrillation to sinus rhythm was the only predictive factor of normalisation of left ventricular function (p less than 0.02). The changes in left ventricular end diastolic dimension and fractional shortening was less marked in the group of 56 patients in sinus rhythm or chronic atrial fibrillation (normalisation of left ventricular function in 8% of cases) than in the group of 8 patients in which atrial fibrillation was converted to sinus rhythm (normalisation of left ventricular function in 50% of cases).(ABSTRACT TRUNCATED AT 250 WORDS)