Inhibition of cardiac leptin expression after infarction reduces subsequent dysfunction.

Leptin is known to exert cardiodepressive effects and to induce left ventricular (LV) remodelling. Nevertheless, the autocrine and/or paracrine activities of this adipokine in the context of post-infarct dysfunction and remodelling have not yet been elucidated. Therefore, we have investigated the evolution of myocardial leptin expression following myocardial infarction (MI) and evaluated the consequences of specific cardiac leptin inhibition on subsequent LV dysfunction. Anaesthetized rats were subjected to temporary coronary occlusion. An antisense oligodesoxynucleotide (AS ODN) directed against leptin mRNA was injected intramyocardially along the border of the infarct 5 days after surgery. Cardiac morphometry and function were monitored by echocardiography over 11 weeks following MI. Production of myocardial leptin and pro-inflammatory cytokines interleukin (IL)-1ß and IL-6 were assessed by ELISA. Our results show that (1) cardiac leptin level peaks 7 days after reperfused MI; (2) intramyocardial injection of leptin-AS ODN reduces early IL-1ß and IL-6 overexpression and markedly protects contractile function. In conclusion, our findings demonstrate that cardiac leptin expression after MI could contribute to the evolution towards heart failure through autocrine and/or paracrine actions. The detrimental effect of leptin could be mediated by pro-inflammatory cytokines such as IL-1ß and IL-6. Our data could constitute the basis of new therapeutic approaches aimed to improve post-MI outcome.

Left ventricular diastolic dysfunction is linked to severity of obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) has been linked to increased cardiovascular risk. The present study examined the relationships between respiratory parameters and left ventricular abnormalities in OSA. 150 newly diagnosed OSA patients without any known cardiovascular disease were included in the study (mean ± sd age 49 ± 11 yrs, body mass index 27.1 ± 3.3 kg·m⁻², respiratory disturbance index 41 ± 18 h⁻¹). Haemodynamic, biological, respiratory, cardiac and arterial parameters were assessed at inclusion. 34 (22.7%) patients had a grade 1 left ventricular diastolic dysfunction. Patients with an abnormal diastole were older (p < 0.001) and 81% of them were hypertensive. The only respiratory parameter independently associated with the peak flow velocity in early diastole/peak flow velocity at atrial contraction ratio was mean nocturnal oxygen saturation. 17 (13%) patients had left ventricular hypertrophy. A multivariate analysis showed that clinic systolic blood pressure and mean nocturnal oxygen saturation were independently associated with left ventricular hypertrophy. In a logistic regression model, age ≥ 58 yrs (OR 3.29, 95% CI 1.78-5.64) and mean nocturnal oxygen saturation < 92% (OR 2.76, 95% CI 1.45-4.91) were associated with left ventricular diastolic dysfunction. Our findings demonstrate that left ventricular diastolic dysfunction frequently occurs in patients with OSA and that it is related to the severity of oxygen desaturation.

Resistance to platelet antiaggregants: an important cause of very late thrombosis of drug eluting stents? Observations from five cases.

BACKGROUND: Very late thrombosis of drug eluting stents is a rare complication that might be triggered by resistance to platelet antiaggregants (PAAs). AIM: Following an initial case where clinical data strongly suggested resistance to PAAs, we carried out a prospective systematic analysis of platelet aggregation in four subsequent cases of late thrombosis. METHODS: Resistance to aspirin was investigated with the PFA-100 test employing a collagen-epinephrine cartridge (Platelet Function Analyzer; Dade Behring). Resistance to clopidogrel was determined by flow cytometry of intraplatelet vasodilator-stimulated phosphoprotein (VASP) phosphorylation. RESULTS: All four cases showed resistance to either aspirin or clopidogrel, and two cases showed dual resistance to both of these PAAs. CONCLUSION: Analysis of platelet function in a patient with late stent thrombosis is useful and may allow adaptation of subsequent patient management. The value of monitoring platelet function after implantation of a drug eluting stent should be evaluated in prospective studies.

Effects of a myocardial ischaemia-guided therapeutic program on survival and incidence of coronary events in asymptomatic patients with diabetes: the ARCADIA study.

AIM: To assess the prognostic impact of a therapeutic program based on bioclinical risk-stratification and myocardial-perfusion-imaging (MPI) data on survival and the occurrence of coronary events (CE=death+myocardial infarction) in asymptomatic patients with diabetes. METHOD: Five hundred twenty one consecutive asymptomatic diabetic outpatients were prospectively enrolled and clinically classified as being at either low or high cardiac risk. All high-risk patients (n=245, age 61+/-9 years) underwent MPI and an intensive multifactorial medical therapeutic program, including anti-ischaemic agents in cases of moderate ischemia; a coronary angiography was performed in all high-risk patients with severe ischaemia (n=38), followed by immediate revascularization if necessary (n=21). Low-risk patients (n=276, age 57+/-9 years) underwent medical management of their risk factors. RESULTS: At the 19-month (median) follow-up (range, 12-36 months), both high- and low-risk patients showed similarly low CE rates (2.3% and 1.5% per year, respectively; age- and gender-adjusted log-rank P=NS). None of the patients who underwent myocardial revascularization experienced any CEs, and none of the low-risk patients died during follow-up. The negative predictive value of first-line bioclinical stratification was 0.98 for the occurrence of CEs, and 0.95 when low-risk patients were combined with high-risk patients who had normal MPI findings. CONCLUSIONS: Bioclinical first-line stratification allows identification of diabetic patients who have a good medium-term cardiac prognosis. The CE rate is similar in selected high-risk asymptomatic patients with diabetes using an intensive MPI-guided program that combines medical therapy, coronary angiography in the 16% of cases with severe ischemia and, if appropriate, revascularization.

[Study of a detection strategy for silent ischemia in diabetic patients: 18 month follow-up of the ARCADIA register]. / Etude d'une stratégie de détection de l'ischémie silencieuse chez les patients diabétiques: suivi à 18 mois du registre ARCADIA.

BACKGROUND: The prognostic impact of a myocardial ischemia-based therapeutic program in asymptomatic diabetic patients remains controversial. We prospectively assessed the benefit of a stratification algorithm based upon clinical and myocardial perfusion imaging (MPI) data on cardiovascular events in such patients in a non-randomized register. METHOD: 701 consecutive asymptomatic diabetic patients were classified to be at low or intermediate-to-high cardiac risk according to 13 simple boil-clinical parameters. Intermediate-to-high risk patients were scheduled for MPI and underwent either a conventional (Group 1, n=180) or an intensive multifactorial (Group 2, n=245) therapeutic program. Low risk patients (Group 3, n=276) underwent no specific management. RESULTS: At the end of the survey and as a consequence of intensive management, lipid lowering therapy, antiplatelet drugs, and beta-blockers were more often prescribed in Group 2 than in Group 1 (55, 31 and 17% versus 36, 23, and 8% respectively, p<0.01). Planned coronary angiography in case of severe ischemia on MPI and revascularization were more frequent in Group 2 (16.2 and 8.9%) than in Group 1 (8.0 and 2.8% - p<0.01). At 19-month follow-up (96.7% completed), major event rate in Group 2 was significantly lower than in Group 1 (3.9 versus 9.8%, p<0.01) and similar to that of Group 3 (2.2%, NS). CONCLUSION: Easy-to-perform risk stratification is able to select diabetic patients with good medium-term prognosis. In clinically selected higher risk patients, an intensive medical therapy combined with coronary angiography +/- revascularization in case of large ischemia on MPI is effective to improve prognosis.

Association of eNOS Glu298Asp gene polymorphism with circadian blood pressure rhythm.

Hypertensive patients with altered circadian blood pressure (BP) profile experience greater repercussion of hypertension on target organs and a higher risk of cardiovascular events, compared with those with physiological variations in BP. It has been demonstrated in animal models, that circadian variations in BP depend on several regulatory systems, in particular the nitric oxide-cGMP pathway. eNOS298 Glu/Asp polymorphism is a functional variant and may alter the amount of NO generated or eNOS activity. The objective of the present study was to find out whether eNOS298 gene polymorphism affects circadian BP regulation in 110 healthy subjects and 155 never-treated hypertensive patients recruited at Hypertension Units in Grenoble, Toulouse and Lille (France).

[Significance of the exercise test in hypertensives]. / Intérêt de l'épreuve d'effort chez l'hypertendu.

The presence of hypertension is responsible for an increase in cardiovascular morbidity and mortality. The significance of evaluating variations of blood pressure on exercise in actual or potential hypertensives warrants further consideration. The modes of physiological blood pressure variation on effort and the practical methods of performing an exercise test are well documented and have been the subject of guidelines. Within this framework must be included dynamic exercise tests on ergometric bicycles or with treadmills. From numerous studies it is now possible to better define the predictive and prognostic values of the various modes of blood pressure changes with exercise. Blood pressure measurement on exercise represents an additional investigation in cardiovascular morbidity and mortality (coronary or cerebrovascular events). The diagnostic applications of this exercise measurement reveal these prognostic data, and exercise blood pressure measurement is to be recommended in subjects who experience regular significant physical effort.

Oxidative stress and baroreflex sensitivity in healthy subjects and patients with mild-to-moderate hypertension.

Decreased baroreflex sensitivity (BRS) is a prognostic marker in essential hypertension. Animal experiments suggest that decreased BRS is related to increased oxidative stress. Our study was aimed at testing whether oxidative stress, estimated by isoprostane 15-F(2t)-IsoP urinary levels, is correlated to BRS variation in healthy subjects as well as in patients suffering from essential hypertension. Urinary 15-F(2t)-IsoP levels and BRS were evaluated in two groups of subjects: healthy volunteers (n=64) and patients with untreated mild-to-moderate hypertension (n=33). Data were analysed in 61 and 31 subjects, respectively, BRS analysis being impossible in three and two subjects, respectively. 15-F(2t)-IsoP levels were measured using gas chromatography/mass spectrometry. BRS was measured using the sequence method [PS+/RR+ and PS-/RR-] and crossspectral analysis (CSP) (MF gain) at rest, lying down. No significant correlation was found between basal urinary 15-F(2t)-IsoP levels and BRS (sequence method and CSP) in either healthy controls or hypertensive patients. Our study shows that oxidative stress is not involved in interindividual variations of BRS in healthy subjects and patients suffering from mild-to-moderate hypertensionJournal of Human Hypertension (2004) 18, 517-521. doi:10.1038/sj.jhh.1001684 Published online 12 February 2004

[Which coronary tests to use in asymptomatic diabetics?]. / Quelles explorations à visée coronaire chez le diabétique asymptomatique?

Coronary artery disease is a common, serious and insidious complication of diabetes. Myocardial ischaemia is often silent. All diabetics do not have the same coronary risk and, therefore, it is important to determine which investigations to perform and which patients. This strategy is justified because it allows identification of these cases which require a medical or an invasive (angioplasty, surgical revascularisation) approach, as these interventions may improve the prognosis. The first stage is clinical (investigation of cardiovascular risk factors). When more than two risk factors are found, further investigations are justified. Exercise stress testing provide reassuring diagnostic and prognostic data when maximal and negative. When sub-maximal, impossible or significantly ischaemic, a second investigation is useful. Holter ECG recording with analysis of ST variation lacks sensitivity and, above all, specificity. The diagnostic value of perfusion myocardial scintigraphy in the diabetic is not as good as that observed in the general population, but its prognostic value remains good. Ischaemia involving over 20% of the myocardium justifies therapeutic investigation. Stress echocardiography has been validated in the diagnosis and prognosis of coronary artery disease and its sensitivity and specificity are probably the same as those of scintigraphy. The authors conclude that the asymptomatic diabetic requires clinical and staged paraclinical investigation to assess prognosis and, depending on the results, the adoption of a beneficial therapeutic strategy.

Long-term additive prognostic value of thallium-201 myocardial perfusion imaging over clinical and exercise stress test in low to intermediate risk patients : study in 1137 patients with 6-year follow-up.

BACKGROUND: The exercise treadmill test (ETT) and Tl201 single proton emission computed tomography (SPECT) are of short- to medium-term prognostic value in coronary heart disease. We assessed the long-term prognostic value of these tests in a large population of patients with low- to intermediate risk of cardiac events. METHODS AND RESULTS: One thousand one hundred thirty-seven patients (857 men, age 55+/-9 years) referred for typical (62.1%) or atypical (22.4%) chest pain, or suspected silent ischemia (15.5%), were followed up for 72+/-18 months. Overall mortality was higher after strongly positive (ST depression >2 mm, or >1 mm for a workload /=3 abnormal segments on SPECT, respectively (P<0.002). An abnormal SPECT was predictive of MI (P<0.001), whereas ETT was not. In multivariate analysis, SPECT was of incremental prognostic value over clinical and ETT data for predicting overall mortality and major cardiac events. CONCLUSIONS: The incremental predictive value of SPECT is maintained over 6 years and is particularly relevant after positive, strongly positive, and nondiagnostic ETT.

[Evaluation of a clinical and scintigraphic management strategy for cardiac risk before abdominal aorta surgery. Apropos of 982 surgical patients]. / Evaluation d'une stratégie clinique et scintigraphique de prise en charge du risque cardiologique avant chirurgie de l'aorte abdominale. A propos de 982 patients opérés.

The incidence of major cardiac events (death, infarction) is over 5% after programmed aortic vascular surgery. The aim of this study was to evaluate a management strategy of this risk based on the clinical status and targeted indication of myocardial scintigraphy, coronary angiography and myocardial revascularisation. A first phase (1991-1993, 451 patients) confirmed the prognostic value of clinical (age, previous cardiac history, diabetes, hypertension, electrocardiogrammes) and scintigraphic features: the cardiac mortality was 1.25% in patients with a low clinical risk (70.3% of cases) and 4.5% in patients with a high clinical risk (2 factors, 29.3% of cases) (p < 0.01). In the latter group, the mortality was zero after normal myocardial scintigraphy and 7.2% after abnormal myocardial scintigraphy (p < 0.01) and 12.5% in cases with reversible defects (p < 0.01). During the second phase of the study (1994-1997, 531 patients) coronary angiography was performed in patients with a high clinical risk and abnormal scintigraphy (10.9% of cases). This led to a myocardial revascularisation in 3.6% of patients. The cardiac mortality was then the same in the low and high a priori clinical risk: 2.3 and 2.8% (NS). The use of simple clinical criteria enables surgery in the majority of candidates for aortic vascular surgery, scintigraphy being reserved for about one patient in ten with myocardial revascularisation in less than 4% of cases. The operative cardiac mortality then decreases to under 2.5%.

[A rare cause of inappropriate shocks of an implantable automatic defibrillator. Twiddler syndrome]. / Une cause rare de chocs inappropriés d'un défibrillateur automatique implantable. Le Twiddler's syndrome.

The authors report the case of a patient with an automatic defibrillator implanted by an endocavitary approach. The device emitted a series of inappropriate shocks. They were triggered by the detection of myopotentials resulting from lesions of the lead due to Twiddler's syndrome. This was reproduced by telemetry in real time and confirmed by chest and abdominal X-ray and the peroperative findings. Treatment consisted of ablation of all implanted material which was replaced by a new retropectoral model.

[Left ventricular diastolic function: value of its study with mitral and pulmonary venous Doppler phonocardiography and apexography]. / La fonction diastolique ventriculaire gauche: intérêt de son étude par le doppler mitral, le doppler veineux pulmonaire, le phonocardiogramme et l'apexogramme.

The study of mitral flow and pulmonary venous flow by Doppler provides a non-invasive method of assessing diastolic function. But there are difficulties in differentiating normal pattern from "pseudo-normal" (Appleton Type II) (E/A Mitral > 1). Phonocardiography enables the recording of early (B3) and late (B4) diastolic gallops. The apexogramme enables calculation of the a/H and D/H ratios (amplitude of the "D" wave resulting from rapid early diastolic filling to the total amplitude of the apexogramme). These two techniques record pulsatile phenomena ("pulse waves") arising from variations in intra-left ventricular pressure. They may complete the interpretation of Doppler recordings of velocities of blood flow ("flow waves"). To evaluate the value of each technique, the authors studied left ventricular diastolic function by Doppler phonocardiography and apexography in 60 subjects (38 patients of which 30 with ischaemic heart disease, and 22 healthy subjects). The results showed that increase in velocity and deceleration slope of the Doppler mitral E wave was associated with the presence of a B3 and correlated (r = 0.60; p = 0.0001) with the D/H ratio of the apexogramme. On the other hand, the absence of correlation between the mitral A wave velocity and a B4 associated with an increased a/H ratio enables the differentiation of normal Doppler mitral flow (absence of B4, Doppler a/H ratio < 12%) from pseudo-normal appearances (B4, a/H ratio > 12%). Therefore, the evaluation of diastolic function by Doppler mitral and pulmonary venous flow analysis may be usefully completed by phonocardiography and apexography.