Efficacy profile of ivabradine in patients with heart failure plus angina pectoris

Objectives: In the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), slowing of the heart rate with ivabradine reduced cardiovascular death or heart failure hospitalizations among patients with systolic chronic heart failure (CHF). Subsequently, in the Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease (SIGNIFY) slowing of the heart rate in patients without CHF provided no benefit for cardiovascular death or nonfatal myocardial infarction (primary composite end point), with secondary analyses suggesting possible harm in the angina subgroup. Therefore, we examined the impact of ivabradine in the patients with CHF plus angina in SHIFT. Methods: SHIFT enrolled adults with stable, symptomatic CHF, a left ventricular ejection fraction ≤35% and a sinus rhythm with a resting heart rate ≥70 bpm. Outcomes were the SHIFT and SIGNIFY primary composite end points and their components. Results: Of 6,505 patients in SHIFT, 2,220 (34%) reported angina at randomization. Ivabradine numerically, but not significantly, reduced the SIGNIFY primary composite end point by 8, 11 and 11% in the SHIFT angina subgroup, nonangina subgroup and overall population, respectively. Ivabradine also reduced the SHIFT primary composite end point in all 3 subgroups. Conclusions: In SHIFT, ivabradine showed consistent reduction of cardiovascular outcomes in patients with CHF; similar results were seen in the subgroup of SHIFT patients with angina

Genetics of heart rate in heart failure patients (GenHRate)

BACKGROUND: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF. METHODS: Patients who met Framingham criteria for HF and had an ejection fraction \u3c 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant hits (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX). RESULTS: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 x 10(-8)). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population. CONCLUSIONS: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts

Genetics of heart rate in heart failure patients (GenHRate)

BACKGROUND: Elevated resting heart rate (HR) is a risk factor and therapeutic target in patients with heart failure (HF) and reduced ejection fraction (HFrEF). Previous studies indicate a genetic contribution to HR in population samples but there is little data in patients with HFrEF. METHODS: Patients who met Framingham criteria for HF and had an ejection fraction \u3c 50% were prospectively enrolled in a genetic HF registry (2007-2015, n = 1060). All participants donated blood for DNA and underwent genome-wide genotyping with additional variants called via imputation. We performed testing of previously identified variant hits (43 loci) as well as a genome-wide association (GWAS) of HR, adjusted for race, using Efficient Mixed-Model Association Expedited (EMMAX). RESULTS: The cohort was 35% female, 51% African American, and averaged 68 years of age. There was a 2 beats per minute (bpm) difference in HR by race, AA being slightly higher. Among 43 candidate variants, 4 single nucleotide polymorphisms (SNPs) in one gene (GJA1) were significantly associated with HR. In genome-wide testing, one statistically significant association peak was identified on chromosome 22q13, with strongest SNP rs535263906 (p = 3.3 x 10(-8)). The peak is located within the gene Cadherin EGF LAG Seven-Pass G-Type Receptor 1 (CELSR1), encoding a cadherin super-family cell surface protein identified in GWAS of other phenotypes (e.g., stroke). The highest associated SNP was specific to the African American population. CONCLUSIONS: These data confirm GJA1 association with HR in the setting of HFrEF and identify novel candidate genes for HR in HFrEF patients, particularly CELSR1. These associations should be tested in additional cohorts

Glucose metabolism in the heart

Dans ce travail, nous avons essayé de caractériser davantage les principaux points de contrôle du métabolisme glucidique cardiaque. Plus particulièrement, notre travail peut être séparé en trois parties. Dans une première partie, nous avons déterminé l’importance du fructose 2,6 bisphosphate comme régulateur de la 6-phosphofructo-1-kinase. Nous avons montré que cet activateur est particulièrement important dans la stimulation glycolytique en aérobiose. Ensuite, nous avons étudiés les effets du lactate sur le métabolisme glucidique et avons montré que le lactate inhibe considérablement la glycolyse sans affecter le captage de glucose extracellulaire par le cœur, ce qui permet au myocarde d’alimenter ses réserves de glycogène. Ensuite, nous avons montré le rôle primordial exercé par la dégradation de glycogène dans la production résiduelle d’ATP au cours de l’ischémie sans flux. Dans la deuxième partie, nous avons étudié le rôle de la voie de signalisation du GMP cyclique dans le cœur ischémique. Nous avons d’abord montré que ce second messager augmente au cours de l’ischémie, suite à une activation de la NO synthase. Nous avons ensuite montré que l’inhibition de la NO synthase par des inhibiteurs sélectifs bloque l’augmentation de GMP cyclique et améliore la fonction cardiaque post ischémique, suite à une stimulation du métabolisme glucidique dans le cœur ischémique. Nous avons enfin montré que les analogues du GMP cyclique exercent par contre un effet inhibiteur sur le mélange glucidique cardiaque. La troisième partie du travail a été consacrée à l’étude du métabolisme glucidique dans le cœur humain ischémique. Nous avons montré que dans une telle situation, une accumulation majeure de glycogène se produit, de même qu’une stimulation du captage de glucose extracellulaire dans les mêmes territoires. Ces résultats supposent que le myocarde humain soumis à des épisodes répétés d’ischémie utilise préférentiellement le glucoseIn this work, we sought to further delineate the importance of glucose in heart metabolism, by investigating the different regulatory steps of heart glycolysis and the role of glycolysis in the adaptation of the heart to ischemic conditions. Specific topics were choosed, because of th extreme diversity of potential investigations. The work is presented under the form of published or submitted articles. In the first part, we analyzed the regulation of the key steps of glucose metabolism in the heart, mainly the regulation of 6-phosphofructo-1-kinase by 2,6-biphosphate and alternate substrates. In this part, we also studied the role of glycogen in the adaptation of the heart to ischemia and anoxia. As preliminary results indicated that cyclic GMP could play a role in the ischemic heart, we investigated in the second part the role of the nitric oxide and cyclic GMP-signalling pathway in the regulation of glycolytic flux. Namely, we measured the variations of cyclic GMP in the heart submitted to ischemia, the effect of inhibitors of NO synthase on cyclic GMP content and on ischemic damage, the activation on NO synthase by ischemia and the effect of cyclic GMP analogues in the perfused heart. Finally, we were interested in the regulation of glucose metabolism in human chronic ischemic myocardial dysfunction myocardium is characterized by increased fluorodeoxyglucose uptake at positron emission tomography, we correlated this metabolic signal to the morphology of hibernating myocardium and to the expression of glucose transporters mRNAsThèse de doctorat en sciences biomédicales (biochimie) -- UCL, 199

Isolated working heart: description of models relevant to radioisotopic and pharmacological assessments.

Isolated heart preparations are used to study physiological and metabolic parameters of the heart independently of its environment. Several preparations of isolated perfused heart are currently used, mainly the retrograde perfusion system and the working heart model. Both models allow investigations of the metabolic regulation of the heart in various physiological conditions (changes in workload, hormonal influences, substrate competition). These systems may also reproduce different pathological conditions, such as ischemia, reperfusion and hypoxia. Quantitation of metabolic activity can be performed with specific radioactive tracers. Finally, the effects of various drugs on cardiac performance and resistance to ischemia can be studied as well. Heart perfusion also revealed efficient methods to determine the tracer/tracee relation for radioisotopic analogues used with Positron Emission Tomography

Inhibition of glycogenolysis by a glucose analogue in the working rat heart

The effects of BAY o 1248, an inhibitor of alpha-amylo-1, 6-glucosidase, on glycogenolysis and post-ischemic functional recovery were investigated in isolated perfused rat hearts. Working rat hearts were perfused during 30 min with 11 mm glucose (controls) and, in some hearts, with 1 microM insulin or 5 mM lactate to increase their glycogen concentration. The hearts were then submitted to 10 min of no-flow ischemia and reperfused during 15 min with 11 mM glucose alone. Glycogen content was increased by 50% in hearts perfused with insulin or lactate. During ischemia, glycogen breakdown was similar in the control and lactate groups, but was abolished in the insulin-group. At reperfusion, functional recovery was improved in glycogen-loaded hearts compared to controls. When hearts were perfused with 1 mM BAY o 1248, added before ischemia, glycogenolysis was inhibited in the three groups and functional recovery was hampered in both the control and lactate groups. In the insulin group, however, the functional recovery was barely affected by BAY o 1248. We conclude that: (i) BAY o 1248 is an inhibitor of heart glycogen breakdown; (ii) the consequences of inhibition of ischemic glycogenolysis on post-ischemic functional recovery depend on the conditions; and (iii) the protective effect of insulin does not result from ischemic glycogenolysis

Morphological analysis of atherosclerotic plaque retrieved by coronary atherectomy.

The development of atherectomy catheters and their use in clinical practice during percutaneous revascularization procedures permitted the analysis of the pathophysiology of obstructive coronary disease in vivo. The various clinical presentations of coronary disease are related to distinct morphological aspects of the culprit coronary stenosis as assessed by angiography, angioscopy or intravascular ultrasound imaging. Analysis of plaque fragments revealed the underlying histopathology. Restenotic lesions following various mechanical interventions have been studied in detail both in native coronary arteries and in bypass conduits. The biological reaction to implantation of endovascular stents involves inflammation around the stent wires as well as smooth muscle cell proliferation. Specific processes such as nitric oxide production or the activity of intramural proteases can be characterized and contribute to identify targets for future pharmacological therapy