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.

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.

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.

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.

First evidence of increased plasma serotonin levels in Tako-Tsubo cardiomyopathy.

BACKGROUND: There is no data about the serotonergic activity during the acute phase of Tako-Tsubo Cardiomyopathy (TTC). The objective of our study was to investigate evidence of serotonin release from patients with TTC in comparison with patients with ST elevation myocardial infarction (STEMI) and healthy control subjects (HCS). METHODS AND RESULTS: Plasma serotonin levels in 14 consecutive patients with TTC were compared with those in 14 patients with STEMI and 14 HCS. Plasma serotonin levels at admission were markedly higher in patients with TTC and STEMI as compared to HCS (3.9 ± 4.6, P = 0.02 versus control; 5.7 ± 5.6, P = 0.001 versus control; and 1 ± 0.4 ng/mL, resp.). There was no difference in serotonin levels between patients with TTC and those with STEMI (P = 0.33). CONCLUSION: This finding suggests that serotonin could participate to the pathophysiology of TTC.

Subarachnoid haemorrhage associated with midventricular Tako-Tsubo syndrome.

BACKGROUND: A new form of Tako-Tsubo cardiomyopathy has recently been described as a midventricular localisation, opposite to the apical typical form. CASE REPORT: We report the case of a patient who presented with a sudden cardiac death and an acute coronary syndrome. However, coronary arteries were normal and the left ventriculography showed a midventricular ballooning Tako-Tsubo syndrome associated with a hawk's beak. A cerebral CT scan revealed a massive subarachnoid haemorrhage in relation with a left sylvian aneurysm rupture leading to the death of the patient. CONCLUSION: This case relates for the first time, the association of a subarachnoid haemorrhage and the recently described midventricular form of Tako-Tsubo syndrome with a hawk's beak. It is an illustration of the complexity of the relationships between brain and heart.

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 the 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 literature review presents the "state of art" of this marker, detailing NT-proBNP physiological recent knowledge and its recognized or investigated clinical applications.

[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.

Treatment of heart failure with preserved systolic function.

Heart failure is a major public health problem. Heart failure with preserved systolic function (HF-PSF) is a common form, which is difficult to diagnose. Results of recent studies show that HF-PSF has a poor prognosis, with an annual survival rate similar to that of heart failure with left ventricular systolic dysfunction. Despite these findings, the therapeutic management of HF-PSF is not clearly defined. We will discuss in this review of the literature the current therapeutic management of HF-PSF, including the role of precipitating factors such as hypertension, myocardial ischaemia and supraventricular arrhythmias, and the main results of epidemiological registries and randomized controlled clinical trials in this disease. Only four large therapeutic trials have assessed the impact of different classes of drugs (digoxin, angiotensin II converting enzyme inhibitors, angiotensin II receptors type I blockers and beta-blockers) on morbidity and mortality in HF-PSF. Results of these trials are disappointing. Apart from the beta-blockers, the other three classes of drugs did not show benefit on the outcome of the disease. Moreover, the results of the beta-blocker trial are controversial as a mixed population of heart failure with and without preserved systolic function was studied. Finally, the current therapeutic management of patients with HF-PSF is still based on our pathophysiological knowledge: education, low salt diet, diuretics, slowing heart rate and controlling triggering factors. Other large randomized controlled multicenter trials, which may help us in the understanding of HF-PSP and its therapeutic management, are ongoing.

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.

Epicardial catheter ablation of ventricular tachycardia using surgical subxyphoid approach.

We report the case of a patient presenting with a previous inferior myocardial infarction complicated by incessant monomorphic ventricular tachycardia resistant to antiarrhythmic drugs. Because endocardial catheter ablation failed and because of focal endocardial activation arising from the left ventricular inferior wall, an epicardial location of the reentry circuit was suspected. Catheter mapping of the pericardial space through a surgical subxyphoid approach performed in the electrophysiological laboratory confirmed the epicardial location of the arrhythmogenic substrate and allowed us successfully to ablate and cure the patient. Surgical subxyphoid approach can be performed in the electrophysiological laboratory when epicardial ablation is needed in case of inadvisable, difficult, or failed non-surgical percutaneous access.

NMR and cDNA array analysis prior to heart failure reveals an increase of unsaturated lipids, a glutamine/glutamate ratio decrease and a specific transcriptome adaptation in obese rat heart.

Obesity is a risk factor for heart failure through a set of hemodynamic and hormonal adaptations, but its contribution at the molecular level is not clearly known. Therefore, we investigated the kinetic cardiac transcriptome and metabolome in the Spontaneous Hypertensive Heart Failure (SHHF) rat. The SHHF rat is devoid of leptin signaling when homozygous for a mutation of the leptin receptor (ObR) gene. The ObR-/- SHHF rat is obese at 4 months of age and prone to heart failure after 14 months whereas its lean counterpart ObR-/+ is prone to heart failure after 16 months. We used a set of rat pangenomic high-density macroarrays to monitor left ventricle cardiac transcriptome regulation in 4- and 10-month-old, lean and obese animals. Comparative analysis of left ventricle of 4- and 10-month-old lean rat revealed 222 differentially expressed genes while 4- and 10-month-old obese rats showed 293 differentially expressed genes. (1)H NMR analysis of the metabolome of left ventricular extracts displayed a global decrease of metabolites, except for taurine, and lipid concentration. This may be attributed to gene expression regulation and likely increased extracellular mass. The glutamine to glutamate ratio was significantly lower in the obese group. The relative unsaturation of lipids increased in the obese heart; in particular, omega-3 lipid concentration was higher in the 10-month-old obese heart. Overall, several specific kinetic molecular patterns act as a prelude to heart failure in the leptin signaling deficient SHHF obese rat.

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.

[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.

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.