Aortic valve dysfunction and aortic dilatation in adults with coarctation of the aorta

Objectif: Déterminer la prévalence de la dysfonction de la valve aortique, de la dilatation de l'aorte proximale et des interventions au niveau de la valve aortique et de l'aorte ascendante chez les adultes avec une coarctation de l'aorte. Contexte: La dysfonction de la valve aortique et la dilatation de l'aorte proximale sont rares chez les enfants et les adolescents avec une coarctation de l'aorte. A long terme, les adultes pourraient être plus à risque de développer ce type de pathologie. Méthode: Nous avons rétrospectivement passé en revue tous les adultes avec une coarctation de l'aorte corrigée ou pas suivis au « Boston Children's Hospital » entre 2004 et 2010. Résultats: 216 adultes (56 % d'hommes) avec une coarctation ont été identifiés. L'âge médian à la dernière évaluation était de 28 (de 18 à 75) ans. Une bicuspidie aortique était présente dans 66% des cas. Au dernier contrôle, 3% avaient une sténose aortique modérée ou sévère et 4% avaient une insuffisance aortique modérée à sévère. Une dilatation de la racine de l'aorte ou de l'aorte ascendante était présente dans 28%, respectivement 42% des patients. Une dilatation au moins modérée de la racine de l'aorte ou de l'aorte ascendante (score Z > 4) était présente dans 8%, respectivement 14%. Les patients avec une bicuspidie aortique étaient plus sujets à avoir une dilatation au moins modérée de la racine de l'aorte ou de l'aorte ascendante comparés à ceux sans bicuspidie (20% contre 0%; p<0.001). L'âge était associé à une dilatation de l'aorte ascendante (p=0.04). Au dernier suivi, 6% avait nécessité une intervention au niveau de la valve aortique et 3% un remplacement de la racine de l'aorte ou de l'aorte ascendante.

A CMR study of the effects of tissue edema and necrosis on left ventricular dyssynchrony in acute myocardial infarction: implications for cardiac resynchronization therapy.

ABSTRACT: BACKGROUND: In acute myocardial infarction (AMI), both tissue necrosis and edema are present and both might be implicated in the development of intraventricular dyssynchrony. However, their relative contribution to transient dyssynchrony is not known. Cardiovascular magnetic resonance (CMR) can detect necrosis and edema with high spatial resolution and it can quantify dyssynchrony by tagging techniques. METHODS: Patients with a first AMI underwent percutaneous coronary interventions (PCI) of the infarct-related artery within 24 h of onset of chest pain. Within 5-7 days after the event and at 4 months, CMR was performed. The CMR protocol included the evaluation of intraventricular dyssynchrony by applying a novel 3D-tagging sequence to the left ventricle (LV) yielding the CURE index (circumferential uniformity ratio estimate; 1 = complete synchrony). On T2-weighted images, edema was measured as high-signal (>2 SD above remote tissue) along the LV mid-myocardial circumference on 3 short-axis images (% of circumference corresponding to the area-at-risk). In analogy, on late-gadolinium enhancement (LGE) images, necrosis was quantified manually as percentage of LV mid-myocardial circumference on 3 short-axis images. Necrosis was also quantified on LGE images covering the entire LV (expressed as %LV mass). Finally, salvaged myocardium was calculated as the area-at-risk minus necrosis (expressed as % of LV circumference). RESULTS: After successful PCI (n = 22, 2 female, mean age: 57 ± 12y), peak troponin T was 20 ± 36ug/l and the LV ejection fraction on CMR was 41 ± 8%. Necrosis mass was 30 ± 10% and CURE was 0.91 ± 0.05. Edema was measured as 58 ± 14% of the LV circumference. In the acute phase, the extent of edema correlated with dyssynchrony (r2 = -0.63, p < 0.01), while extent of necrosis showed borderline correlation (r2 = -0.19, p = 0.05). PCI resulted in salvaged myocardium of 27 ± 14%. LV dyssynchrony (=CURE) decreased at 4 months from 0.91 ± 0.05 to 0.94 ± 0.03 (p < 0.004, paired t-test). At 4 months, edema was absent and scar %LV slightly shrunk to 23.7 ± 10.0% (p < 0.002 vs baseline). Regression of LV dyssynchrony during the 4 months follow-up period was predicted by both, the extent of edema and its necrosis component in the acute phase. CONCLUSIONS: In the acute phase of infarction, LV dyssynchrony is closely related to the extent of edema, while necrosis is a poor predictor of acute LV dyssynchrony. Conversely, regression of intraventricular LV dyssynchrony during infarct healing is predicted by the extent of necrosis in the acute phase.

Benznidazole biotransformation in rat heart microsomal fraction without observable ultrastructural alterations: comparison to Nifurtimox-induced cardiac effects

Benznidazole (Bz) and Nifurtimox (Nfx) have been used to treat Chagas disease. As recent studies have de-monstrated cardiotoxic effects of Nfx, we attempted to determine whether Bz behaves similarly. Bz reached the heart tissue of male rats after intragastric administration. No cytosolic Bz nitroreductases were detected, although microsomal NADPH-dependent Bz nitroreductase activity was observed, and appeared to be mediated by P450 reductase. No ultrastructurally observable deleterious effects of Bz were detected, in contrast to the overt cardiac effects previously reported for Nfx. In conclusion, when these drugs are used in chagasic patients, Bz may pose a lesser risk to heart function than Nfx when any cardiopathy is present.

Immunological imbalance between IFN-³ and IL-10 levels in the sera of patients with the cardiac form of Chagas disease

The immune response is crucial for protection against disease; however, immunological imbalances can lead to heart and digestive tract lesions in chagasic patients. Several studies have evaluated the cellular and humoral immune responses in chagasic patients in an attempt to correlate immunological findings with clinical forms of Chagas disease. Moreover, immunoglobulins and cytokines are important for parasitic control and are involved in lesion genesis. Here, cytokine and IgG isotype production were studied, using total epimastigote antigen on sera of chagasic patients with indeterminate (IND, n = 27) and cardiac (CARD, n = 16) forms of the disease. Samples from normal, uninfected individuals (NI, n = 30) were use as controls. The results showed that sera from both IND and CARD patients contained higher levels of Trypanosoma cruzi-specific IgG1 (IgG1) antibodies than sera from NI. No difference in IgG2 production levels was observed between NI, IND and CARD patients, nor was a difference in IL-10 and IFN-³ production detected in the sera of IND, CARD and NI patients. However, IND patients displayed a positive correlation between IL-10 and IFN-³ levels in serum, while CARD patients showed no such correlation, indicating an uncontrolled inflammatory response in CARD patients. These findings support the hypothesis that a lack of efficient regulation between IFN-³ and IL-10 productions in CARD patients may lead to cardiac immunopathology.

Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease.

Introduction. Fibromyalgia is a chronic pain syndrome with unknown etiology. Recent studies have shown some evidence demonstrating that oxidative stress may have a role in the pathophysiology of fibromyalgia. However, it is still not clear whether oxidative stress is the cause or the effect of the abnormalities documented in fibromyalgia. Furthermore, the role of mitochondria in the redox imbalance reported in fibromyalgia also is controversial. We undertook this study to investigate the role of mitochondrial dysfunction, oxidative stress, and mitophagy in fibromyalgia. Methods. We studied 20 patients (2 male, 18 female patients) from the database of the Sevillian Fibromyalgia Association and 10 healthy controls. We evaluated mitochondrial function in blood mononuclear cells from fibromyalgia patients measuring, coenzyme Q10 levels with high-performance liquid chromatography (HPLC), and mitochondrial membrane potential with flow cytometry. Oxidative stress was determined by measuring mitochondrial superoxide production with MitoSOX™ and lipid peroxidation in blood mononuclear cells and plasma from fibromyalgia patients. Autophagy activation was evaluated by quantifying the fluorescence intensity of LysoTracker™ Red staining of blood mononuclear cells. Mitophagy was confirmed by measuring citrate synthase activity and electron microscopy examination of blood mononuclear cells. Results. We found reduced levels of coenzyme Q10, decreased mitochondrial membrane potential, increased levels of mitochondrial superoxide in blood mononuclear cells, and increased levels of lipid peroxidation in both blood mononuclear cells and plasma from fibromyalgia patients. Mitochondrial dysfunction was also associated with increased expression of autophagic genes and the elimination of dysfunctional mitochondria with mitophagy. Conclusions. These findings may support the role of oxidative stress and mitophagy in the pathophysiology of fibromyalgia.

Frequency of Fabry disease in male and female haemodialysis patients in Spain

BACKGROUND: Fabry disease (FD), an X-linked lysosomal storage disorder, is caused by a reduced activity of the lysosomal enzyme alpha-galactosidase A. The disorder ultimately leads to organ damage (including renal failure) in males and females. However, heterozygous females usually present a milder phenotype with a later onset and a slower progression. METHODS: A combined enzymatic and genetic strategy was used, measuring the activity of alpha-galactosidase A and genotyping the alpha-galactosidase A gene (GLA) in dried blood samples (DBS) of 911 patients undergoing haemodialysis in centers across Spain. RESULTS: GLA alterations were found in seven unrelated patients (4 males and 3 females). Two novel mutations (p.Gly346AlafsX347 and p.Val199GlyfsX203) were identified as well as a previously described mutation, R118C. The R118C mutation was present in 60% of unrelated patients with GLA causal mutations. The D313Y alteration, considered by some authors as a pseudo-deficiency allele, was also found in two out of seven patients. CONCLUSIONS: Excluding the controversial D313Y alteration, FD presents a frequency of one in 182 individuals (0.55%) within this population of males and females undergoing haemodialysis. Moreover, our findings suggest that a number of patients with unexplained and atypical symptoms of renal disease may have FD. Screening programmes for FD in populations of individuals presenting severe kidney dysfunction, cardiac alterations or cerebrovascular disease may lead to the diagnosis of FD in those patients, the study of their families and eventually the implementation of a specific therapy.

Protective role of amantadine in mitochondrial dysfunction and oxidative stress mediated by hepatitis C virus protein expression.

Amantadine is an antiviral and antiparkinsonian drug that has been evaluated in combination therapies against hepatitis C virus (HCV) infection. Controversial results have been reported concerning its efficacy, and its mechanism of action remains unclear. Data obtained in vitro suggested a role of amantadine in inhibiting HCV p7-mediated cation conductance. In keeping with the fact that mitochondria are responsible to ionic fluxes and that HCV infection impairs mitochondrial function, we investigated a potential role of amantadine in modulating mitochondrial function. Using a well-characterized inducible cell line expressing the full-length HCV polyprotein, we found that amantadine not only prevented but also rescued HCV protein-mediated mitochondrial dysfunction. Specifically, amantadine corrected (i) overload of mitochondrial Ca(2+); (ii) inhibition of respiratory chain activity and oxidative phosphorylation; (iii) reduction of membrane potential; and (iv) overproduction of reactive oxygen species. The effects of amantadine were observed within 15 min following drug administration and confirmed in Huh-7.5 cells transfected with an infectious HCV genome. These effects were also observed in cells expressing subgenomic HCV constructs, indicating that they are not mediated or only in part mediated by p7. Single organelle analyzes carried out on isolated mouse liver mitochondria demonstrated that amantadine induces hyperpolarization of the membrane potential. Moreover, amantadine treatment increased the calcium threshold required to trigger mitochondrial permeability transition opening. In conclusion, these results support a role of amantadine in preserving cellular bioenergetics and redox homeostasis in HCV-infected cells and unveil an effect of the drug which might be exploited for a broader therapeutic utilization.

Chagas heart disease: pathophysiologic mechanisms, prognostic factors and risk stratification

Chagas heart disease (CHD) results from infection with the protozoan parasite Trypanosoma cruzi and is the leading cause of infectious myocarditis worldwide. It poses a substantial public health burden due to high morbidity and mortality. CHD is also the most serious and frequent manifestation of chronic Chagas disease and appears in 20-40% of infected individuals between 10-30 years after the original acute infection. In recent decades, numerous clinical and experimental investigations have shown that a low-grade but incessant parasitism, along with an accompanying immunological response [either parasite-driven (most likely) or autoimmune-mediated], plays an important role in producing myocardial damage in CHD. At the same time, primary neuronal damage and microvascular dysfunction have been described as ancillary pathogenic mechanisms. Conduction system disturbances, atrial and ventricular arrhythmias, congestive heart failure, systemic and pulmonary thromboembolism and sudden cardiac death are the most common clinical manifestations of chronic Chagas cardiomyopathy. Management of CHD aims to relieve symptoms, identify markers of unfavourable prognosis and treat those individuals at increased risk of disease progression or death. This article reviews the pathophysiology of myocardial damage, discusses the value of current risk stratification models and proposes an algorithm to guide mortality risk assessment and therapeutic decision-making in patients with CHD.

Current status and perspectives of cell therapy in Chagas disease

One century after its discovery, Chagas disease, caused by the protozoan, Trypanosoma cruzi, remains a major health problem in Latin America. Mortality and morbidity are mainly due to chronic processes that lead to dysfunction of the cardiac and digestive systems. About one third of the chronic chagasic individuals have or will develop the symptomatic forms of the disease, with cardiomyopathy being the most common chronic form. This is a progressively debilitating disease for which there are no currently available effective treatments other than heart transplantation. Like in other cardiac diseases, tissue engineering and cell therapy have been investigated in the past few years as a means of recovering the heart function lost as a consequence of chronic damage caused by the immune-mediated pathogenic mechanisms elicited in individuals with chronic chagasic cardiomyopathy. Here we review the studies of cell therapy in animal models and patients with chronic Chagas disease and the perspectives of the recovery of the heart function lost due to infection with T. cruzi.

Intracoronary injection of bone marrow-derived mononuclear cells early or late after acute myocardial infarction: effects on global left ventricular function.

BACKGROUND: Intracoronary administration of autologous bone marrow-derived mononuclear cells (BM-MNC) may improve remodeling of the left ventricle (LV) after acute myocardial infarction. The optimal time point of administration of BM-MNC is still uncertain and has rarely been addressed prospectively in randomized clinical trials. METHODS AND RESULTS: In a multicenter study, we randomized 200 patients with large, successfully reperfused ST-segment elevation myocardial infarction in a 1:1:1 pattern into an open-labeled control and 2 BM-MNC treatment groups. In the BM-MNC groups, cells were administered either early (ie, 5 to 7 days) or late (ie, 3 to 4 weeks) after acute myocardial infarction. Cardiac magnetic resonance imaging was performed at baseline and after 4 months. The primary end point was the change from baseline to 4 months in global LV ejection fraction between the 2 treatment groups and the control group. The absolute change in LV ejection fraction from baseline to 4 months was -0.4±8.8% (mean±SD; P=0.74 versus baseline) in the control group, 1.8±8.4% (P=0.12 versus baseline) in the early group, and 0.8±7.6% (P=0.45 versus baseline) in the late group. The treatment effect of BM-MNC as estimated by ANCOVA was 1.25 (95% confidence interval, -1.83 to 4.32; P=0.42) for the early therapy group and 0.55 (95% confidence interval, -2.61 to 3.71; P=0.73) for the late therapy group. CONCLUSIONS: Among patients with ST-segment elevation myocardial infarction and LV dysfunction after successful reperfusion, intracoronary infusion of BM-MNC at either 5 to 7 days or 3 to 4 weeks after acute myocardial infarction did not improve LV function at 4-month follow-up. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00355186.

Urinary aminopeptidase activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats

This study analyzes the fluorimetric determination of alanyl- (Ala), glutamyl- (Glu), leucyl-cystinyl- (Cys) and aspartyl-aminopeptidase (AspAp) urinary enzymatic activities as early and predictive biomarkers of renal dysfunction in cisplatin-treated rats. Male Wistar rats (n = 8 each group) received a single subcutaneous injection of either saline or cisplatin 3.5 or 7 mg/kg, and urine samples were taken at 0, 1, 2, 3 and 14 days after treatment. In urine samples we determined Ala, Glu, Cys and AspAp activities, proteinuria, N-acetyl-β-D-glucosaminidase (NAG), albumin, and neutrophil gelatinase-associated lipocalin (NGAL). Plasma creatinine, creatinine clearance and renal morphological variables were measured at the end of the experiment. CysAp, NAG and albumin were increased 48 hours after treatment in the cisplatin 3.5 mg/kg treated group. At 24 hours, all urinary aminopeptidase activities and albuminuria were significantly increased in the cisplatin 7 mg/kg treated group. Aminopeptidase urinary activities correlated (p<0.011; r(2)>0.259) with plasma creatinine, creatinine clearance and/or kidney weight/body weight ratio at the end of the experiment and they could be considered as predictive biomarkers of renal injury severity. ROC-AUC analysis was made to study their sensitivity and specificity to distinguish between treated and untreated rats at day 1. All aminopeptidase activities showed an AUC>0.633. We conclude that Ala, Cys, Glu and AspAp enzymatic activities are early and predictive urinary biomarkers of the renal dysfunction induced by cisplatin. These determinations can be very useful in the prognostic and diagnostic of renal dysfunction in preclinical research and clinical practice.

Assessment of coronary vasoreactivity by multidetector computed tomography: feasibility study with rubidium-82 cardiac positron emission tomography.

BACKGROUND: Positron emission tomography (PET) during the cold pressor test (CPT) has been used to assess endothelium-dependent coronary vasoreactivity, a surrogate marker of cardiovascular events. However, its use remains limited by cardiac PET availability. As multidetector computed tomography (MDCT) is more widely available, we aimed to develop a measurement of endothelium-dependent coronary vasoreactivity with MDCT and similar radiation burden as with PET. METHODS AND RESULTS: A study group of 18 participants without known cardiovascular risk factor (9F/9M; age 60±6 years) underwent cardiac PET with (82)Rb and unenhanced ECG-gated MDCT within 4h, each time at rest and during CPT. The relation between absolute myocardial blood flow (MBF) response to CPT by PET (ml·min(-1)·g(1)) and relative changes in MDCT-measured coronary artery surface were assessed using linear regression analysis and Spearman's correlation. MDCT and PET/CT were analyzed in all participants. Hemodynamic conditions during CPT at MDCT and PET were similar (P>0.3). Relative changes in coronary artery surface because of CPT (2.0-21.2%) correlated to changes in MBF (-0.10-0.52ml·min(-1)·g(1)) (ρ=0.68, P=0.02). Effective dose was 1.3±0.2mSv for MDCT and 3.1mSv for PET/CT. CONCLUSIONS: Assessment of endothelium-dependent coronary vasoreactivity using MDCT CPT appears feasible. Because of its wider availability, shorter examination time and similar radiation burden, MDCT could be attractive in clinical research for coronary status assessment.

Relation of cardiac troponin I measurements at 24 and 48 hours to magnetic resonance-determined infarct size in patients with ST-elevation myocardial infarction.

Levels of circulating cardiac troponin I (cTnI) or T are correlated to extent of myocardial destruction after an acute myocardial infarction. Few studies analyzing this relation have employed a second-generation cTnI assay or cardiac magnetic resonance (CMR) as the imaging end point. In this post hoc study of the Efficacy of FX06 in the Prevention of Mycoardial Reperfusion Injury (F.I.R.E.) trial, we aimed at determining the correlation between single-point cTnI measurements and CMR-estimated infarct size at 5 to 7 days and 4 months after a first-time ST-elevation myocardial infarction (STEMI) and investigating whether cTnI might provide independent prognostic information regarding infarct size at 4 months even taking into account early infarct size. Two hundred twenty-seven patients with a first-time STEMI were included in F.I.R.E. All patients received primary percutaneous coronary intervention within 6 hours from onset of symptoms. cTnI was measured at 24 and 48 hours after admission. CMR was conducted within 1 week of the index event (5 to 7 days) and at 4 months. Pearson correlations (r) for infarct size and cTnI at 24 hours were r = 0.66 (5 days) and r = 0.63 (4 months) and those for cTnI at 48 hours were r = 0.67 (5 days) and r = 0.65 (4 months). In a multiple regression analysis for predicting infarct size at 4 months (n = 141), cTnI and infarct location retained an independent prognostic role even taking into account early infarct size. In conclusion, a single-point cTnI measurement taken early after a first-time STEMI is a useful marker for infarct size and might also supplement early CMR evaluation in prediction of infarct size at 4 months.

Guidelines for specialized nutritional and metabolic support in the critically-ill patient. Update. Consensus SEMICYUC-SENPE: Cardiac patient

Patients with cardiac disease can develop two types of malnutrition: cardiac cachexia, which appears in chronic congestive heart failure, and malnutrition due to the complications of cardiac surgery or any other type of surgery in patients with heart disease. Early enteral nutrition should be attempted if the oral route cannot be used. When cardiac function is severely compromised, enteral nutrition is feasible, but supplementation with parenteral nutrition is sometimes required. Sustained hyperglycemia in the first 24 hours in patients admitted for acute coronary syndrome, whether diabetic or not, is a poor prognostic factor for 30-day mortality. In critically-ill cardiac patients with stable hemodynamic failure, nutritional support of 20-25 kcal/kg/day is effective in maintaining adequate nutritional status. Protein intake should be 1.2-1.5 g/kg/day. Routine polymeric or high protein formulae should be used, according to the patient's prior nutritional status, with sodium and volume restriction according to the patient's clinical situation. The major energy source for myocytes is glutamine, through conversion to glutamate, which also protects the myocardial cell from ischemia in critical situations. Administration of 1 g/day of omega-3 (EPA+DHA) in the form of fish oil can prevent sudden death in the treatment of acute coronary syndrome and can also help to reduce hospital admission for cardiovascular events in patients with chronic heart failure.