Spontaneous Right Ventricular Pseudoaneurysms and Increased Arrhythmogenicity in a Mouse Model of Marfan Syndrome.

Patients with Marfan syndrome (MFS), a connective tissue disorder caused by pathogenic variants in the gene encoding the extracellular matrix protein fibrillin-1, have an increased prevalence of primary cardiomyopathy, arrhythmias, and sudden cardiac death. We have performed an in-depth in vivo and ex vivo study of the cardiac phenotype of Fbn1mgR/mgR mice, an established mouse model of MFS with a severely reduced expression of fibrillin-1. Using ultrasound measurements, we confirmed the presence of aortic dilatation and observed cardiac diastolic dysfunction in male Fbn1mgR/mgR mice. Upon post-mortem examination, we discovered that the mutant mice consistently presented myocardial lesions at the level of the right ventricular free wall, which we characterized as spontaneous pseudoaneurysms. Histological investigation demonstrated a decrease in myocardial compaction in the MFS mouse model. Furthermore, continuous 24 h electrocardiographic analysis showed a decreased heart rate variability and an increased prevalence of extrasystolic arrhythmic events in Fbn1mgR/mgR mice compared to wild-type littermates. Taken together, in this paper we document a previously unreported cardiac phenotype in the Fbn1mgR/mgR MFS mouse model and provide a detailed characterization of the cardiac dysfunction and rhythm disorders which are caused by fibrillin-1 deficiency. These findings highlight the wide spectrum of cardiac manifestations of MFS, which might have implications for patient care.

Ambulatory Electrocardiographic Monitoring and Ectopic Beat Detection in Conscious Mice.

Ambulatory electrocardiography (AECG) is a primary diagnostic tool in patients with potential arrhythmic disorders. To study the pathophysiological mechanisms of arrhythmic disorders, mouse models are widely implemented. The use of a technique similar to AECG for mice is thus of great relevance. We have optimized a protocol which allows qualitative, long-term ECG data recording in conscious, freely moving mice. Automated algorithms were developed to efficiently process the large amount of data and calculate the average heart rate (HR), the mean peak-to-peak interval and heart rate variability (HRV) based on peak detection. Ectopic beats are automatically detected based on aberrant peak intervals. As we have incorporated a multiple lead configuration in our ECG set-up, the nature and origin of the suggested ectopic beats can be analyzed in detail. The protocol and analysis tools presented here are promising tools for studies which require detailed, long-term ECG characterization in mouse models with potential arrhythmic disorders.

Human Plasmacytoid and Monocyte-Derived Dendritic Cells Display Distinct Metabolic Profile Upon RIG-I Activation.

Recent advances reveal that metabolic reprogramming is required for adequate antiviral responses of dendritic cells (DCs) that possess the capacity to initiate innate and adaptive immune responses. Several reports indicate that Toll-like receptor (TLR) stimulation of DCs is accompanied by a rapid induction of glycolysis; however, the metabolic requirements of retinoic-acid inducible gene I (RIG-I)-like receptor (RLR) activation have not defined either in conventional DCs (cDCs) or in plasmacytoid DCs (pDCs) that are the major producers of type I interferons (IFN) upon viral infections. To sense viruses and trigger an early type I IFN response, pDCs rely on endosomal TLRs, whereas cDCs employ cytosolic RIG-I, which is constitutively present in their cytoplasm. We previously found that RIG-I is upregulated in pDCs upon endosomal TLR activation and contributes to the late phase of type I IFN responses. Here we report that TLR9-driven activation of human pDCs leads to a metabolic transition to glycolysis supporting the production of type I IFNs, whereas RIG-I-mediated antiviral responses of pDCs do not require glycolysis and rather rely on oxidative phosphorylation (OXPHOS) activity. In particular, TLR9-activated pDCs show increased extracellular acidification rate (ECAR), lactate production, and upregulation of key glycolytic genes indicating an elevation in glycolytic flux. Furthermore, administration of 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, significantly impairs the TLR9-induced secretion of type I IFNs by human pDCs. In contrast, RIG-I stimulation of pDCs does not result in any alterations of ECAR, and type I IFN production is not inhibited but rather promoted by 2-DG treatment. Moreover, pDCs activated via TLR9 but not RIG-I in the presence of 2-DG are impaired in their capacity to prime allogeneic naïve CD8+ T cell proliferation. Interestingly, human monocyte-derived DCs (moDC) triggered via RIG-I show a commitment to glycolysis to promote type I IFN production and T cell priming in contrast to pDCs. Our findings reveal for the first time, that pDCs display a unique metabolic profile; TLR9-driven but not RIG-I-mediated activation of pDCs requires glycolytic reprogramming. Nevertheless, the metabolic signature of RIG-I-stimulated moDCs is characterized by glycolysis suggesting that RIG-I-induced metabolic alterations are rather cell type-specific and not receptor-specific.

[Coxiella burnetii endocarditis: long-term clinical course in 20 patients]. / Endocarditis por Coxiella burnetii: evolución a largo plazo de 20 pacientes.

INTRODUCTION AND OBJECTIVES: Coxiella burnetii is a causative agent of increasingly frequent subacute infective endocarditis, and is associated with elevated morbimortality. Our aim in the present study was to assess the clinical, serological and therapeutic long-term evolution of 20 patients with Coxiella burnetii endocarditis. METHODS: Twenty patients (13 male and 7 female, age 42 +/- 10 years) admitted between 1982 and 1996 were retrospectively studied. All of them fulfilled the Duke criteria modified by Raoult for Q fever endocarditis. RESULTS: Endocarditis involved prosthetic and native valves in 14 and 6 patients, respectively. All patients except one received antibiotic treatment. Patients treated with doxycycline in monotherapy showed worse evolution than those treated with doxycycline in combination with other antibiotics. Valve replacement was performed in 15 patients, due to prosthetic dysfunction in most of them. The overall mortality was 40% (8 patients). At follow-up of 74 months (range 19-156) (mean 74 +/- 47) all patients showed persistent high levels of phase I antibodies. At follow-up of 15 to 65 months (32 +/- 30) antibiotic treatment was suspended in five patients because they were asymptomatic and without microbiologic findings of valvular endocarditis. CONCLUSIONS: Q fever endocarditis was associated with severe complications, which often required valve replacement. All patients showed persistent high serological titers of Coxiella burnetii endocarditis without other signs of active infection. This finding raises the issue of suspending antibiotic treatment in patients with negative microbiologic findings and questions the persistence of abnormal serology as a monitor of treatment efficacy.

Phrenic nerve conduction study in demyelinating neuropathies and open-heart surgery.

OBJECTIVES: The aim of this study was to determine normal values of phrenic nerve conduction (PNC) in healthy individuals; to evaluate the subclinical extent of phrenic nerve involvement in Guillain-Barré syndrome (G-B) and hereditary motor and sensory neuropathy-I (HMSN-I), and to evaluate phrenic nerve damage after cardiac surgery. MATERIALS AND METHODS: PNC was performed by transcutaneous stimulation in the neck and recording the diaphragmatic potential from surface electrodes placed at the seventh and eight intercostal spaces. PNC was performed bilaterally in 25 healthy volunteers and 25 patients before and after open-heart surgery. Right PNC was also performed in 5 cases with G-B and 5 patients with HMNS-I. RESULTS: Latency and amplitude of the diaphragmatic potential were the same in controls and in patients with cardiac disease before surgery. After surgery, 28% of patients had left phrenic nerve inexcitability, and 8% had reduced amplitude of the response. These 9 patients demonstrated elevation of the left hemidiaphragm on chest radiography. Left PNC performed 1 year after the operation showed improvement in latency and amplitude of the responses in all except one patient. PNC was prolonged in 4 out of 5 cases with G-B and in all patients with HMNS-I. CONCLUSIONS: PNC is an easy and reliable method in evaluating phrenic nerve damage due to hypothermia or primary stretch injury in patients after cardiac surgery. PNC may be helpful in detecting diaphragmatic involvement before clinical ventilatory insufficiency in demyelinating neuropathies such as G-B and HMNS-I.

Successful treatment of prosthetic aortic valve mucormycosis.

Mucor endocarditis after cardiovascular surgery is rare and usually fatal. We report the first known case of prosthetic aortic valve mucormycosis in a patient without predisposing risk factors who was successfully treated using a combination of early antifungal drug therapy and surgical removal of infected material.

Distribution of IgA subclass response to Coxiella burnetii in patients with acute and chronic Q fever.

The progression of Coxiella burnetii infection to acute or chronic Q fever has been attributed to biological characteristics of the bacterium and to the host immune response. We measured whether serum levels of total and specific subclasses IgA1 and IgA2 could be correlated with the course of disease in acute and chronic Q fever infections, and with the occurrence of endocarditis. In patients with chronic infection, total IgA2 levels were significantly increased. Q-fever-specific IgA1 antibodies were detectable in both acute and chronic infections, but only patients with endocarditis had IgA2 antibodies to C. burnetii phase II antigens. These findings indicate that the measurement of IgA subclasses may be a useful aid in the serological diagnosis of Q fever. Our results reinforce the idea that immunologically mediated host factors are important in the pathogenesis of Q fever and in the disease outcome of this infection.

[Indications and surgical techniques in the acute phase of infective endocarditis]. / Indicaciones y técnicas quirúrgicas en la fase aguda de la endocarditis infecciosa.

Infectious endocarditis is increasingly resistant to antibiotic therapy, due to the increasing number of patient with cardiovascular prostheses or those who are severely immunosuppressed. Frequently, this syndrome and its complications can only be solved with surgery. In this article, which is based on the international literature plus own observations in 77 patients, the indications for surgery and the different technical approaches during the acute phase of infectious endocarditis are reviewed. Surgery to control infectious endocarditis is indicated when there is one of the following situations: a) persistence of infection despite an adequate antibiotic treatment, usually due to a specific pathogen (Staphylococcus aureus, fungus, etc.) or to a low antibiotic penetration into the infected issues (abscess); b) progressive hemodynamic deterioration due to tissular destruction and development of valvular incompetence or fistulous communications or c) development of other complications (repetitive embolism, cardiovascular aneurysms, conduction blocks, etc.). Hemodynamic deterioration due to heart failure refractory to medical treatment is the most frequent indication for cardiovascular surgery, and this was present in 61% of our patients. The timing for surgery is still controversial, although scheduling it at an early stage is generally preferred. The specific surgical technique is chosen according to the degree of tissular destruction and is aimed to remove the infected tissue and to repair the damaged structures or, if this is not feasible, to implant cardiovascular prosthesis.

Selective interaction of homophtalazine derivatives with morphine.

Homophtalazines show specific binding sites in the nigrostriatal system and to find their target of action the interactions between these derivatives, nerisopam and girisopam, and chlorpromazine, chlordiazepoxide and morphine were assessed. The compounds did not influence the chlorpromazine induced decrease in motility and catalepsy, nor did they alter the antiaggressive and anticonvulsive action of chlordiazepoxide. However, nerisopam and girisopam augmented the agonist potency of morphine to induce catalepsy or analgesia; they also altered the opioid antagonist potency of naloxone. The naloxone-induced decrease in sucrose consumption in drinking water was augmented by nerisopam and girisopam. It is suggested that a possible target of action of homophtalazines is the opioid signal transduction.

Apparent antinociceptive and anti-inflammatory effects of GYKI 52466.

GYKI 52466 (1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine) was examined in a battery of analgesia and anti-inflammatory tests in rats and mice, respectively. Its 3-N-acetyl (GYKI 53773) and 3-N-methylcarbamoyl (GYKI 53784) derivatives were also examined in some assays. These 2,3-benzodiazepines, known as prototypic non-competitive antagonists of AMPA receptors, showed a peculiar profile in some routinely used antinociceptive tests. They were found fairly potent in rat tail flick and mouse phenylquinone writhing assays but the dose-response curves were rather shallow as compared to that of morphine. Their action is stereoselective, i.e., the (+) isomers were found inactive, in agreement with the previous in vitro studies. Their antinociceptive effect could not be reversed by naloxone and the GYKI compounds did not potentiate significantly the morphine-induced analgesia. In the mouse hot plate assay the 2,3-benzodiazepines were active only in doses inducing visible motor incapacitation. In rats, GYKI 52466 weakly reduced the hypersensitivity accompanying acute carrageenan edema. However, it potently inhibited the hyperalgesia during Freund adjuvant-induced chronic arthritis. In the latter assay GYKI 52466 also attenuated the body weight loss without altering the paw edema. The present findings confirm reports in the literature which indicate AMPA receptors may contribute to certain forms of pathological hyperalgesia, e.g., to that detectable in inflamed tissues.

Unusual expression of Gaucher's disease: cardiovascular calcifications in three sibs homozygous for the D409H mutation.

Three sisters suffering from an unusual form of Gaucher's disease are described. These patients had cardiovascular abnormalities consisting of calcification of the ascending aorta and of the aortic and mitral valves. Neurological findings included ophthalmoplegia and saccadic eye movements in two patients, and tonic-clonic seizures in the third. The three patients died, two of them after having undergone aortic valve replacement. Tissue was obtained from one of the sibs and fibroblast and liver beta-glucocerebrosidase activity was reduced to 4% and 11% of mean normal values. Genotype analysis indicated that the patient was homozygous for the D409H mutation. It is tempting to relate the phenotype of severe cardiac involvement to the D409H/D409H genotype, although further cases will be needed before this association can be confirmed.

[Aortic prosthetic endocarditis and periprosthetic abscess caused by Staphylococcus aureus]. / Endocarditis protésica aórtica y absceso periprotesico por Staphylococcus aureus.

Prosthetic endocarditis with annular abscess formation is a severe complication of cardiac valve replacement fortunately uncommon, though highly lethal. Increasing surgical experience and the high mortality with medical management have led to a widespread recommendation for early prosthetic replacement. We report a case of a 49 year old man with infective endocarditis due to Staphylococcus aureus in aortic ascendens prosthetic and aortic valve prosthetic complicated with periaortic abscess which was as successful treatment by drain of abscess without prosthetic replacement.

Percutaneous balloon valvuloplasty for concurrent mitral, aortic and tricuspid rheumatic stenosis.

Percutaneous balloon valvuloplasty has been used with good results to treat rheumatic mitral stenosis. However, its use in degenerative aortic stenosis has shown many limitations. There is little information about balloon valvuloplasty in tricuspid and aortic rheumatic stenosis. This article describes two patients with combined rheumatic mitral, aortic and tricuspid stenosis in which triple percutaneous valvuloplasty was performed in a single procedure.

Delayed papillary muscle rupture following mild chest trauma.

A case of delayed papillary muscle rupture is reported, which developed 24 hours following a mild chest trauma. Transthoracic echocardiography established the diagnosis; immediate mitral valve replacement was carried out. The postoperative course was uneventful.

[The return to work after coronary revascularization]. / Retorno al trabajo después de la revascularización coronaria.

INTRODUCTION: Work resumption after a therapeutical intervention has been considered as a sensitive indicator of its success. There are some reports analyzing working status after coronary artery revascularization in western countries. However, to our knowledge, similar studies have not been published in Spain. PATIENTS AND METHODS: We studied 210 patients after coronary artery revascularization surgery or percutaneous transluminal coronary angioplasty. Exclusion criteria were age of 65 or more years and female sex gender (n = 64). RESULTS: Working patient rate before and after coronary revascularization was respectively 63.2% and 28.9% for surgery, and 57.1% and 41.4% for percutaneous angioplasty (p = 0.11). None of the former inactive patients, with the exception of one in the surgery group, went back to work after the revascularization procedure. Asymptomatic patients after percutaneous angioplasty had a higher postprocedure working rate than symptomatic ones (58.1% vs 11.1%, p < 0.0001). Patients in the surgery group did not show this relation (30% vs 25%, p = 0.69). CONCLUSIONS: Surprisingly, coronary artery revascularization interventions, mainly coronary surgery, seems to behave in our environment as important determinants of working cessation.

[The clinical and echocardiographic factors predictive of bioprosthetic leaflet rupture. The clinical tolerance for prosthetic malfunction]. / Factores clínicos y ecocardiográficos predictivos de rotura de velos bioprotésicos. Tolerancia clínica a la disfunción protésica.

OBJECTIVE: The objective of this research was to determine the existence of predictors of bioprosthetic valve disruption depending on the echocardiographic characteristic of the biologic prosthesis. It also determines the factors that provoke a need of emergency surgery and a bad clinical tolerance to the prosthetic dysfunction. METHODS: Clinical and echocardiographic features of two groups of 28 and 21 patients, all of them carrying bioprosthesis, were compared. The groups were homogeneous in sex, age, location and durability of the prosthesis. The first group showed leaflet disruption in a period of 6 months to 1 year after the study, not in the second group. Calcification, thickness and mobility of leaflets, prosthetic function were studied. An echocardiographic score was given between 4 and 10 points. Left ventricular function and pulmonary pressure were also studied. RESULTS: Valve thickness was statistically different in both groups (95% of the first group vs 71.3% of the second, p = 0.0281). There was no significant difference in calcification (52% vs 38.7%), nor in leaflet mobility (71.5% normal in the first group vs the 80% of the second group), nor in the prosthetic function (52.3% vs 76.6%, respectively). It was not found in the echocardiographic score either. Left ventricular function and pulmonary pressure were 91.6% and 55% normal respectively in the first group. They were 80% and 45.83% normal in the second group. Clinical onset of disruption was: 5 asymptomatic patients, 2 patients noticed a change in prosthetic click, 14 cases with progressive dyspnea, 6 patients with acute pulmonary edema and 1 patient with cardiopulmonary arrest and effective resuscitation. Symptoms were kept under control with medical treatment in 22 patients (78.55%) and 6 patients were referred to surgery. These latter suffered from pulmonary hypertension and two of them had left ventricular dysfunction. Surgical mortality was 3% (1 patient). CONCLUSIONS: No echocardiographic features were found as being predictors of imminent bioprosthetic disruption. However, leaflet thickness is the most common finding. Symptoms of disruption in patients without high surgical risk factors (left ventricular dysfunction or pulmonary hypertension) are kept under control with medical treatment. Therefore, "prophylactic" surgery is not needed in bioprosthesis with signs of degeneration and normal hemodynamic performance.

[Acute pericarditis as the initial presentation of a primary cardiac angiosarcoma. The anatomicoclinical correlations]. / Pericarditis aguda como presentación inicial de un angiosarcoma primario cardíaco. Correlaciones anatomoclínicas.

We report the clinic and postmortem pathologic examination of a 38-years-old man with a primary angiosarcoma of right atrium and many widespread metastatic. Both his presentation, a clinical course of acute pericarditis self-limited, as the negatives complementary examination, give at case unusual characteristics, for his high malignancy.