Identification of the first homozygous intragenic deletion in the YY1AP1 gene in a consanguineous family: New insights into the phenotypic variability associated with Grange syndrome.

Grange syndrome (GRNG-MIM#135580) is a rare recessive disorder associating variable features including diffuse vascular stenosis, brachysyndactyly, osteopenia with increased bone fragility, cardiac malformations, and variable developmental delay. Since its first description in 1998, only 15 individuals from 10 families have been reported, carrying homozygous or compound heterozygous frameshift or nonsense variants in YY1AP1. In a patient with cutaneous and bone syndactyly and a hemorrhagic stroke at the age of 16 months, consistent with a clinical diagnosis of GRNG, we performed exome sequencing after negative array-CGH and congenital limb malformation panel results. Copy number variant analysis from exome data identified a homozygous intragenic out-of-frame deletion of 1.84 kb encompassing exons seven and eight of YY1AP1, confirming a molecular diagnosis of GRNG. Genetic counseling led to the identification of additional family members compatible with GRNG. Here, we provide new insights into the phenotypic variability associated with GRNG and highlight the utility of the detection of small copy number variants to identify the molecular causes of heterogeneous malformative genetic disorders.

DBH deficiency in an elderly patient: efficacy and safety of chronic droxidopa.

We describe the effects of chronic droxidopa in a patient with Dopamine beta-hydroxylase deficiency diagnosed at the age of 73. Investigations were performed to assess sympathetic activity (MIBG scintigraphy, catecholamines) and cardiovascular droxidopa safety.

[NT-proBNP in practice: from chemistry to medicine]. / NT-proBNP en pratique "de la biologie à la clinique".

Since introduction of routine assay for natriuretic peptides, there are a growing number of clinical applications for those new tests. Numerous studies have defined analytical characteristics and clinical interest of NT-proBNP assay. Originally limited to acute heart failure diagnosis in the emergency room, NT-proBNP assay has now a wide number of applications. This review presents the "state of art" of this marker, detailing NT-proBNP physiological recent knowledge and its recognized or investigated clinical applications.

Predictive criteria for acute heart failure in emergency department patients with acute dyspnoea: the PREDICA study.

OBJECTIVES: The early identification of patients with Acute Heart Failure Syndrome (AHFS) among patients admitted to the Emergency Department (ED) with dyspnoea can facilitate the introduction of appropriate treatments. The objectives are to identify the predictive factors for AHFS diagnosis in patients with acute dyspnoea (primary objective) and the clinical 'gestalt' (secondary objective) in ED. METHODS: PREDICA is an observational, prospective, multicentre study. The enrolment of patients admitted to the ED for nontraumatic acute dyspnoea and data collection on admission were recorded by the patient's emergency physician. The AHFS endpoints were assessed following a duplicate expert evaluation by pairs of cardiologists and emergency physicians. Step-by-step logistic regression was used to retain predictive criteria, and the area under the receiver operating characteristic (ROC) curve of the model was constructed to assess the ability of the selected factors to identify real cases. The probability of AHFS was estimated on a scale from 1 to 10 based on the emergency physician's perception and understanding (gestalt). RESULTS: Among 341 patients consecutively enrolled in three centres, 149 (44%) presented AHFS. Eight predictive factors of AHFS were detected with a performance test showing an area under the model ROC curve of 0.86. Gestalt greater than or equal to five showed sensitivity of 78% and specificity of 90% (AUC 0.91) and diagnosed 88% of AHF in our population. CONCLUSIONS: We identified several independant predictors of final AHFS diagnosis. They should contribute to the development of diagnostic strategies in ED. However, unstructured gestalts seem to perform very well alone.

Is the gap between guidelines and clinical practice in heart failure treatment being filled? Insights from the IMPACT RECO survey.

BACKGROUND: Recent registries have shown that recommended drugs for the treatment of chronic heart failure (CHF) are under-prescribed in daily practice. AIMS: To determine prescription rates of CHF drugs, and to assess predictive factors for drug prescription using data from a large panel of French cardiologists. METHODS AND RESULTS: We included 1919 outpatients, with NYHA class II-IV heart failure and a left ventricular ejection fraction <40%. The most frequently prescribed drugs were diuretics (83%), angiotensin converting enzyme inhibitors (ACE-I) (71%), beta-blockers (65%), spironolactone (35%) and angiotensin receptor blockers (ARB) (21%); 61% of patients received a combination of a beta-blocker and an ACE-I or ARB. Target doses were reached in 49% of the patients for ACE-I, but in only 18% for beta-blockers and in 9% for ARBs. Multivariate analyses showed that age >75 years was an independent factor associated with under-prescription of ACE-I-ARBs, beta-blockers or spironolactone. Renal failure was associated with a lower prescription of ACE-I-ARB and spironolactone, and asthma was a predictor of under-prescription of beta-blockers. CONCLUSIONS: In this contemporary survey, prescription rates of CHF drugs were higher than previously reported. However, dosages were lower than those recommended in guidelines. Age remained an independent predictor of under-prescription of CHF drugs.

[Late complications of a pseudo aneurysm of the left ventricle: thrombus infection and purulent pericarditis]. / Complications tardives d'un faux anévrisme du ventricule gauche: infection du thrombus et péricardite purulente.

Pseudoaneurysm is a rare complication of left ventricle myocardial infarction. Rupture with tamponade and sudden death is the usual outcome. Surgical intervention remains the treatment of choice. Long term survival cases without surgery are rare. Infection of the thrombus is also a possible event. We report the case of a patient with postinfarction left ventricular pseudoaneurysm complicated by infection of the thrombus and purulent pericarditis involving a peptostreptococcus. Infection must be considered a potential complication of left ventricular pseudoaneurysms.

Research of predictive factors for cardiac resynchronization therapy: a prospective study comparing data from phase-analysis of gated myocardial perfusion single-photon computed tomography and echocardiography : Trying to anticipate response to CRT.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in chronic systolic heart failure. About 20% of implanted patients are considered as "non-responders". This study aimed to evaluate gated myocardial perfusion single-photon emission computed tomography (GMPS) phase parameters as compared to echocardiography in the assessment of predictors for response to CRT before and after CRT activation. METHODS: Forty-two patients were prospectively included during 15 months. A single injection of 99mTc-tetrofosmin was used to acquire GMPS phase pre- and post-CRT activation. Indicators of positive CRT response were improvement of functional status and 15% reduction in left ventricular end-systolic volume at 3 months. RESULTS: Phase parameters at baseline were similar in the two groups with no influence of perfusion data. Phase parameters after CRT activation were significantly improved in the responders' group (Δ Bandwidth -19° ± 24° vs. 13° ± 31°, p = 0.001; Δ SD -20° ± 30° vs. 26° ± 46°, p = 0.001; Δ Entropy -11 ± 12 vs. 2 ± 6%, p = 0.001). Feasibility and reproducibility were higher for GMPS. CONCLUSION: Acute phase modifications after CRT activation may predict response to CRT immediately after implantation, but not at baseline, even when adjusted to perfusion data.

Management of heart failure in the elderly: recommendations from the French Society of Cardiology (SFC) and the French Society of Gerontology and Geriatrics (SFGG).

Heart failure, a frequent disease in the elderly, has a pejorative prognosis. Clinical diagnosis is complicated by atypical or difficult-to-interpret symptoms and by the concomitant presence of other diseases, particularly cognitive impairment, neurological disorders and diseases of the musculoskeletal system. Among the additional investigations, echocardiography remains underused. Impairment of diastolic left ventricular function is frequent. The usual laboratory tests must include calculation of the creatinine clearance, which is indispensable for dosage adjustment of certain drugs (ACE inhibitors, digoxin, spironolactone). The value of plasma natriuretic peptide assays as diagnostic tools has not been determined in elderly or very elderly populations and the plasma B-type natriuretic peptide increases with age. Comprehensive geriatric assessment is essential in order to screen for concomitant diseases and determine the patient's degree of dependence. The general objectives of treatment remain applicable to the elderly subject: improvement in the quality of life, reduction of mortality and the number and duration of hospitalisations, and slowing disease progression. In the frail elderly subject, symptom alleviation is to be the primary objective. In the absence of specific studies on elderly or very elderly subjects, most of the recommendations have been extrapolated from the data based on the evidence generated in younger populations. The dietary rules are to be more flexible than those used for younger subjects, particularly in order to prevent the risk of denutrition induced by strict salt-free diets. Special precautions for the use of heart failure drugs are due to comorbidities and the pharmacokinetic and pharmacodynamic changes related to aging. Drugs dosage increase is to be cautious and carefully monitored for adverse reactions. The therapeutic programmes in which multidisciplinary teams are involved reduce the number and duration of hospitalisations and the costs generated by the disease.

[Angiotensin receptor blockers and cardiac rhythm disorders]. / Antagonistes des récepteurs de l'angiotensine II et troubles du rythme.

Angiotension Receptor Blockers (ARB) are able to prevent the occurrence of atrial fibrillation (AF) through various mechanisms among them: neurhumoral antagonism and hemodynamic control. This occurs during arterial hypertension and chronic heart failure both diseases known to be associated with left atrial dysfunction. In the CHARM program, candesartan reduced by 20% the incidence of AF and thus also mortality and the incidence of hospitalisation for heart failure related to AF This beneficial effect is also observed with ACE inhibitors but is more important and potentated by ARB. In the Val-Heft study, valsartan on the top of standard treatment including ACE inhibitors, significantly lowered the cases of AF In hypertensive patients, ARB are more powerful than ACE inhibitors for the prevention of AF In the LIFE study, patients in the losartan arm had 33% less AF than patients from the other arm, despite treatment with atenolol and similar blood pressure reduction. Moreover ARB beside their specific effects are also able to increase efficiency of anti-arrhythmic agent; since after cardioversion patients treated with amiodarone plus irbesartan had a lower rate of recurrence of atrial fibrillation than patients treated with amiodarone alone. Finally ARB may reduce the risk of sudden death by ventricular arrhythmias in patients with diabetes mellitus.

Heart failure with preserved systolic function: a diagnostic algorithm for a pragmatic definition.

Heart failure is a major health problem which often concerns the elderly. Prevalence of heart failure with preserved systolic function is increasing and varies from 40 to 50%. In the literature, and in the large epidemiological studies, it is commonly designed with the term of "diastolic heart failure", even if a precise analysis of diastolic function is not performed. A diagnostic algorithm is proposed in order to better define the concept of heart failure with preserved systolic function. It consists of seven steps from symptoms and clinical signs to the echocardiographic analysis of diastolic function, in order to confirm the definition of heart failure with preserved systolic function.

[Cardiac asystole during acute anterior myocardial infarction: a consequence of endocardiac reflexes]. / Asystolie en phase aiguë d'infarctus du myocarde antéroseptal: une manifestation de la mise en jeu de réflexes endocardiaques.

The authors report a case of paroxysmal, complete atrioventricular block during an anterior acute myocardial infarction, leading to asystolia. The different possible physiopathological mechanisms are discussed, suggesting a paroxysmal nodal conduction defect, secondary to transient parasympathetic stimulation, triggered by a Bezold-Jarish type of cardiac reflex. This reflex is frequently involved in various pathologic situations or diagnostic procedures, usual in cardiology. Although it is frequently observed in inferior myocardial infarction, it can occur during an anterior acute myocardial infarction.

Intramyocardial transplantation of mesenchymal stromal cells for chronic myocardial ischemia and impaired left ventricular function: Results of the MESAMI 1 pilot trial.

BACKGROUND: The MESAMI 1 trial was a bicentric pilot study designed to test the feasibility and safety of intramyocardially injected autologous bone marrow-derived mesenchymal stromal cells (MSCs) for the treatment of ischemic cardiomyopathy. METHODS AND RESULTS: The study included 10 patients with chronic myocardial ischemia, left ventricular (LV) ejection fractions (EFs) of ≤35%, and reversible perfusion defects who were on stable optimal medical therapy and were not candidates for revascularization. MSCs (mean: 61.5×10(6) cells per patient) were injected into 10-16 viable sites at the border of the LV scar via a NOGA-guided catheter. Both primary endpoints, feasibility (successful harvest, expansion, and injection of autologous MSCs) and safety (absence of severe adverse events [SAEs]) were met in all 10 patients at the 1-month follow-up time point, and none of the SAEs reported during the full 2-year follow-up period were attributable to the study intervention. The results of secondary efficacy endpoint analyses identified significant improvements from baseline to Month 12 in LVEF (29.4±2.0% versus 35.7±2.5%; p=0.003), LV end-systolic volume (167.8±18.8mL versus 156.1±28.6mL; p=0.04), 6-min walk test and NYHA functional class. CONCLUSIONS: Our results suggest that autologous MSCs can be safely administered to the hearts of patients with severe, chronic, reversible myocardial ischemia and impaired cardiac function and may be associated with improvements in cardiac performance, LV remodeling, and patient functional status. A randomized, double blind, multicenter, placebo-controlled clinical trial (MESAMI 2) will evaluate the efficacy of this treatment approach in a larger patient population. CLINICAL TRIAL REGISTRATION: Unique identifier: NCT01076920.

[Obesity and cardiac failure]. / Obésité et insuffisance cardiaque.

Obesity alone is the cause of 11% of cases of cardiac failure in men and 14% of cases in women in the United States. The frequency of obesity continues to rise in our country, 41% of our compatriots being obese or overweight. It is expected that obesity will become an important cause of cardiac failure in the coming years. The Framingham study showed that, after correction for other risk factors, for every point increase in body mass index, the increase in risk of developing cardiac failure was 5% in men and 7% in women. There are three physiopathological mechanisms to explain the adverse effects of obesity on left ventricular function: an increase in ventricular preload secondary to increased plasma volume induced by the high fatty mass; an increase in left ventricular afterload due to the common association of hypertension generated by activation of the sympathetic nervous system by hyperinsulinism; and systolic and diastolic dysfunction due to changes in the myocardial genome and coronary artery disease induced by risk factors of atherosclerosis aggravated by obesity. The adipocyte also secretes a number of hormones which act directly or indirectly on the myocardium: angiotensin II, leptin, resistin, adrenomedulin, cytokines. These haemodynamic and hormonal changes profoundly modify the genetic expression of the myocardium in obesity, favourising hypertrophy of the myocyte and the development of interstitial fibrosis. Whether it be eccentric in the absence of hypertension or concentric when hypertension is associated with obesity, left ventricular hypertrophy, although normalising left ventricular wall stress, has adverse consequences causing abnormal relaxation and decreased left ventricular compliance. Therefore, in obese patients, two forms of cardiac failure may be observed. The more common is due to diastolic dysfunction, obesity being one of the principal causes of cardiac failure with preserved systolic function. Cardiac failure due to systolic dysfunction is less common and may be observed in cases with inappropriate left ventricular hypertrophy which does not normalise abnormal left ventricular wall stress leading to cardiomyopathy, and in cases with associated coronary artery disease. Whatever the underlying mechanism, the diagnosis of cardiac failure is made more difficult by obesity. From the prognostic point of view, in the global population of patients with cardiac failure, obesity improves survival because it counteracts the adverse effect of cachexia; however, obesity increases the risk of sudden death. In fact, obesity is associated with dynamic change in QT interval. In cases of cardiac failure secondary to obesity-related cardiomyopathy, loss of weight leads to an improved functional status and a reduction of left ventricular remodelling and an increase of the ejection fraction.

[Prescriptions following acute coronary syndrome]. / Ordonnance de sortie après syndrome coronaire aigu.

Each year in France, 150,000 to 180,000 new patients are the subject of prescriptions following acute coronary syndrome with or without ST segment elevation. There are two targets of the treatment, atherosclerosis, a diffuse, evolving trouble which, in this situation, is coming out of an unstable phase, and the myocardium, which has often been revascularised and has suffered deterioration of its contractile and electrophysiological characteristics to a greater or lesser extent. Prescriptions, based on proven factors and always centred on hygiene and dietary advice and the use of a combination of statins and aspirin, are adapted to suit the atherosclerotic and myocardial risk assessed for the individual patient. The prescription starts off the secondary preventive phase. It marks the first stage of the follow up, which is inevitable though of variable duration, for a disease which may evolve. It is the first step in the accompaniment of an attentive, informed patient whose confidence has been restored and who must now avoid falling into the double trap of not taking the treatment sufficiently seriously or of obsessively over-reacting.

[Evaluation of therapeutic strategies for myocardial infarction: the ESTIM Midi-Pyrénées survey]. / Evalualion des stratégies thérapeutiques dans l'infarctus du myocarde: le registre ESTIM Midi-Pyrénées.

UNLABELLED: The aim of the ESTIM Midi-Pyrénées survey was to monitor the management of acute coronary syndrome with ST segment elevation by cardiologists and emergency departments in the Midi-Pyrénées region. Over a period of 2 years between June 2001 and June 2003, 1287 patients presenting with acute coronary syndrome within the first 24 hours were recruited prospectively. The initial management of these patients was undertaken either by a mobile medical team in the pre-hospital phase, or in a hospital emergency department, non-interventional cardiology department or an interventional cardiology department in 51.8%, 28.8%, 9.6% et 9.9% of cases respectively. Depending on these four modes of initial management, the median time for initial management was 1h30, 2h45, 4h30 et 4h respectively. Emergency coronary reperfusion was proposed in 89.6% of cases. Of the patients in whom reperfusion was attempted within the first 12 hours, 33.7% underwent pre-hospital thrombolysis (median delay of 1h48), 35.8% underwent thrombolysis in hospital (median delay 3h), and 30.4% underwent primary angioplasty (median delay 4h40). Thrombolysis was followed by angioplasty in 80% of cases. A combined approach with thrombolysis and angioplasty was applied in 41% of patients. At one month the rate of major cardiac events, death, and/or subsequent myocardial infarction was 12%. Multivariate analysis revealed that the only significant adverse prognostic features were: not offering reperfusion [Odds ratio (OR) 4, confidence interval (CI) 2.3-3.7] and age [OR 3.8, CI 2.3-6.2]. The method of reperfusion did not influence the subsequent outcome in this regional survey. CONCLUSION: pre-hospital management allows early revascularisation. In our region there was no significant prognostic difference between pre-hospital thrombolysis and primary angioplasty. It shows that the logistic and therapeutic potentials of prehospital care are not being sufficiently exploited.

[Identification of viable myocardium in ischemic heart disease with severe left ventricular contractile dysfunction: comparison of myocardial scintigraphy with 99mTc-sestamabi and with 201-thallium]. / Identification du myocarde viable dans les cardiopathies ischémiques avec atteinte sévère de la fonction contractile du ventricule gauche: comparaison de la scintigraphie myocardique <> au 99mtechnétium-sestamibi et de la scintigraphie myocardique au 201thallium.

The aim of this study was to compare quantitatively uptake of 99mTc-Sestamibi at rest and that of late redistribution of 201Tl in the same patients with severe ischaemic left ventricular dysfunction, and to correlate the uptake of the tracer to regional ventricular dysfunction studied by ECG grated 99Tc-Sestamini. A double isotope myocardial scintigraphy, 201 Thallium at rest/redistribution and 99Tc-Sestamibi at rest and on exercise, was performed in 28 patients with severe postinfarction ischaemic cardiomyopathy (EF= 29 +/- 4%). Quantitative analysis for each patient and each isotope were performed with respect to the number of hits expressed in percentage of the activity of a normal zone in 17 circumferential profiles distributed in 4 zones, that is to say in 476 segments. A score allowed counting of viable and non-viable segments and evaluation of contractile function of the 17 segments with respect to wall motion and systolic thickening. Total concordance of global uptake of the two isotopes was observed in 430 of the 476 segments (90.3%) (r= 0.814, p< 0.0001), but the 99mTc-Sestamibi uptake was less than 201 Th (71 +/- 23% vs 73 +/- 21%, p= 0.0001). With respect to left ventricular wall motion, uptake of 99mTc-Sestamibi was greater than that of 201Tl in normal or hypokinetic segments but less in akinetic and dyskinetic segments. The difference between the two isotopes was most marked in segments with very severe contractile dysfunction. The authors conclude that the uptake of 99mTc-Sestamibi is correlated with that of late distribution of 201Tl when left ventricular contraction is not too poor and should no longer be considered as only a marker of perfusion but can also be useful in the investigation of myocardial viability.

[Cardiac cellular therapy: from cells to the first clinical uses]. / Thérapie cellulaire cardiaque: des cellules aux premières indications cliniques.

Despite the improvement in revascularisation techniques, coronary artery disease remains the principal aetiology of cardiac failure in developed countries. The therapeutic management of cardiac failure has been improved over recent years, yet cardiac failure is still associated with significant morbidity and mortality. As cardiac transplantation lacks donors, techniques that allow myocardial regeneration represent an attractive alternative. To date, several types of cells are under study and are suitable for implantation into infarcted myocardium (myoblasts, medullary stem cells...). Following good preclinical study results, the first human cell therapy trials, using the intramyocardial route, have begun, in the course of aorto-coronary bypass surgery in patients with chronic ischaemic cardiopathy and little altered left ventricular function, and then in those with ventricular dysfunction. Different modes of administration of these cell therapy products are under study and could be envisaged in clinical situations such as just after infarction in order to improve ventricular remodelling with an intracoronary injection technique. As for every new treatment, there are numerous problems to resolve, from understanding the relevant mechanisms of cellular transplantation, to the secondary effects that it could entail. Nevertheless, cardiac cellular transplantation is expanding rapidly and with the evolution of techniques it allows a glimpse of a new field of treatment for cardiac failure.

[Long-term follow-up after primary angioplasty: is stenting beneficial?]. / Angioplastie primaire a long-terme: quel bénéfice des endoprothèses?

BACKGROUND: Primary stenting leads to a better short-term outcome than balloon angioplasty for acute myocardial infarction in randomised trials. However few data are available about the long-term outcome of primary stenting in acute myocardial infarction (AMI). OBJECTIVES: The aim of this study was to compare the three-year outcome after primary stenting versus balloon angioplasty in patients with acute myocardial infarction. METHODS: We conducted a retrospective study including 157 patients with AMI in a single center. Patients underwent balloon angioplasty (N = 48) or primary stenting (N = 109) within six hours after the onset of chest pain. We looked at the outcome during three years focusing on global mortality, major adverse cardiac events (MACE), reinterventions and target vessel revascularization (TVR). RESULTS: The two groups are similar for their baseline characteristics. No difference was noted for in-patient mortality in the balloon angioplasty group and the primary stenting group (2.1 vs 2.8%; P = ns). The three-year mortality was not significantly different in the two groups. Regarding MACE (27.8 vs 31.7; P = 0.95), reinterventions (20.4 vs 24.7%; P = 0.98) and TVR (18.6 vs 17.8%; P = 0.69), both groups were statistically not different. CONCLUSION: In the long-term patients treated with stent placement have similar rates of MACE, reinterventions or TVR than patients undergoing balloon angioplasty. If few studies noted a benefit in short-term outcomes, primary stenting doesn't improve the prognosis of acute myocardial infarction on long-term follow-up, which is dependent on atherosclerosis.

Prognostic value of ventricular arrhythmias in systemic hypertension.

OBJECTIVE: Hypertensive left ventricular hypertrophy is associated with an increased risk of arrhythmias and mortality. However, no clinical study has demonstrated a significant relationship between ventricular arrhythmias and mortality in systemic hypertension. DESIGN AND METHODS: To evaluate the prognostic value of arrhythmogenic markers, we included, prospectively, 214 hypertensive patients aged (mean+/-SD) 59.1+/-12.8 years, without symptomatic coronary disease, myocardial infarction, systolic dysfunction or electrolyte disturbances. At inclusion, a 12-lead electrocardiogram (ECG) with QT dispersion calculation, a 24 h Holter ECG (204 patients) with Lown classification of ventricular arrhythmias, echocardiography (reliable in 187 patients) and a signal-averaged ECG (125 patients) with ventricular late potentials were recorded. RESULTS: At baseline, echocardiographic left ventricular hypertrophy was found in 63 patients (33.7%). Non-sustained ventricular tachycardia (Lown class IVb) was recorded in 33 patients (16.2%) and late potentials in 27 patients (21.6%). After a mean follow-up of 42.4+/-26.8 months, all-cause mortality was 11.2% (24 patients); 17 patients died of cardiac causes (7.9%); of these, nine (4.2%) died suddenly. In univariate analysis, age, Lown class IVb and a QT dispersion > 80 ms were significantly related to global, cardiac and sudden death (P < 0.01). The left ventricular mass index was related to cardiac mortality (P= 0.002). In multivariate analysis, only Lown class IVb was an independent predictor of global and cardiac mortality, increasing the risk of global death 2.6-fold (95% confidence interval 1.2-6.0) and cardiac death 3.5-fold (95% confidence interval 1.2-9.7). CONCLUSION: In hypertensive patients the presence of non-sustained ventricular tachycardia has prognostic value.