Increased expression of the auxiliary beta2-subunit of ventricular L-type Ca2+ channels leads to single-channel activity characteristic of heart failure

BACKGROUND: Increased activity of single ventricular L-type Ca(2+)-channels (L-VDCC) is a hallmark in human heart failure. Recent findings suggest differential modulation by several auxiliary beta-subunits as a possible explanation. METHODS AND RESULTS: By molecular and functional analyses of human and murine ventricles, we find that enhanced L-VDCC activity is accompanied by altered expression pattern of auxiliary L-VDCC beta-subunit gene products. In HEK293-cells we show differential modulation of single L-VDCC activity by coexpression of several human cardiac beta-subunits: Unlike beta(1) or beta(3) isoforms, beta(2a) and beta(2b) induce a high-activity channel behavior typical of failing myocytes. In accordance, beta(2)-subunit mRNA and protein are up-regulated in failing human myocardium. In a model of heart failure we find that mice overexpressing the human cardiac Ca(V)1.2 also reveal increased single-channel activity and sarcolemmal beta(2) expression when entering into the maladaptive stage of heart failure. Interestingly, these animals, when still young and non-failing ("Adaptive Phase"), reveal the opposite phenotype, viz: reduced single-channel activity accompanied by lowered beta(2) expression. Additional evidence for the cause-effect relationship between beta(2)-subunit expression and single L-VDCC activity is provided by newly engineered, double-transgenic mice bearing both constitutive Ca(V)1.2 and inducible beta(2) cardiac overexpression. Here in non-failing hearts induction of beta(2)-subunit overexpression mimicked the increase of single L-VDCC activity observed in murine and human chronic heart failure. CONCLUSIONS: Our study presents evidence of the pathobiochemical relevance of beta(2)-subunits for the electrophysiological phenotype of cardiac L-VDCC and thus provides an explanation for the single L-VDCC gating observed in human and murine heart failure.

Dysphagia due to triple A syndrome: successful treatment of achalasia by balloon dilatation

Triple A syndrome is a rare autosomal recessive inherited disorder which is characterized by alacrima, adrenal insufficiency, and achalasia. We report on a 14-year old girl with dysphagia, regurgitation, and vomiting since 5 years. At the age of five years an Addison crisis was diagnosed and cortisone substitution was initiated. In addition, the patient had episodes of conjunctivitis. Severe esophagitis and candida infection were diagnosed by esophago-gastro-duodenoscopy and treated with omeprazole and fluconazole. The esophageal barium swallow was typical for achalasia. Medical treatment of achalasia with oral nifedipine resulted only in a partial and temporal improvement. But after seven balloon dilatations dysphagia and nocturnal coughing improved clearly and a remarkable gain of weight could be seen. Direct sequencing showed a homozygous nonsense mutation in exon 11 of the AAAS gene leading to truncation at position 342 of the 546 amino acid protein. CONCLUSION: Triple A syndrome has to be considered in patients with dysphagia. In our patient, the absence of tears since birth followed by adrenal insufficiency were early signs of the triple A syndrome. Balloon dilatation of the esophago-gastric junction is an effective treatment, which can avoid surgical interventions.

Contractile performance of adult ventricular rat cardiomyocytes is not directly jeopardized by NO/cGMP-dependent induction of pro-apoptotic pathways

The activation of NO/cGMP pathways can induce pro-apoptotic pathways in cardiomyocytes although only a small number of cardiomyocytes fulfill the criteria of apoptosis. The same pathways reduce the contractile performance of cardiomyocytes. In the present study, we tested the hypothesis that exposure of cells to NO/cGMP for 24 h decrease their contractile performance due to an activation of pro-apoptotic pathways. Experiments were performed on freshly isolated and cultured adult ventricular rat cardiomyocytes. Cells were incubated with 8-bromo-cyclo-GMP (100 nmol/L-1 micromol/L), the NO donor SNAP (1 nmol/L-100 micromol/L), or the guanylyl cyclase activator YC-1 (3 micromol/L). Cell shortening, contraction and relaxation velocities, and diastolic cell lengths were determined at beating frequencies of 0.5, 1, and 2 Hz 24 h later. The activation of pro-apoptotic pathways was determined by staining of cardiomyocytes with an antibody directed against active caspase-3 and quantification of the number of apoptotic cells (annexin staining). Caspase-3 activation and an increase in the number of apoptotic cells was observed, but only at the highest concentrations tested (8-bromo-cyclo-GMP: 1-10 mmol/L; SNAP: 1-100 micromol/L). At these concentrations, none of the drugs decreased the mean cell shortening of cardiomyocytes. However, at concentrations lower than those required for induction of apoptotic cell death, the diastolic cell lengths and sarcomere lengths increased but cell shortening decreased. In conclusion, low concentrations of either NO or cGMP cause a desensitization of myofibrils, as indicated by elongated cell shapes, increased sarcomere lengths and reduced load-free cell shortening. High concentrations of NO/cGMP induce caspase-3 activation and increase the number of cells fulfilling the criteria of apoptotic cell death but did not impair cell function. Therefore, induction of apoptotic cell death per se seems not to contribute to the loss of contractile efficiency on the cellular level.

Influence of pulmonary status and diabetes mellitus on aortic neck dilatation following endovascular repair of abdominal aortic aneurysms: a EUROSTAR report

PURPOSE: To elucidate the association of impaired pulmonary status (IPS) and diabetes mellitus (DM) with clinical outcome and the incidences of aortic neck dilatation and type I endoleak after elective endovascular infrarenal aortic aneurysm repair (EVAR). METHODS: In 164 European institutions participating in the EUROSTAR registry, 6383 patients (5985 men; mean age 72.4+/-7.6 years) underwent EVAR. Patients were divided into patients without versus with IPS or with/without DM. Clinical assessment and contrast-enhanced computed tomography (CT) were performed at 1, 3, 6, 12, 18, and 24 months and annually thereafter. Cumulative endpoint analysis comprised death, aortic rupture, type I endoleak, endovascular reintervention, and surgical conversion. RESULTS: Prevalence of IPS was 2733/6383 (43%) and prevalence of DM was 810/6383 (13%). Mean follow-up was 21.1+/-18.4 months. Thirty-day mortality, AAA rupture, and conversion rates did not differ between patients with versus without IPS and between patients with versus without DM. All-cause and AAA-related mortality, respectively, were significantly higher in patients with IPS compared to patients with normal pulmonary status (31.0% versus 19.0%, p<0.0001 and 6.8% versus 3.3%, p = 0.0057) throughout follow-up. In multivariate analysis adjusted for smoking, age, gender, comorbidities, fitness for open repair, co-existing common iliac aneurysm, neck and aneurysm size, arterial angulations, aneurysm classification, endograft oversizing >or=15%, and type of stent-graft, the presence of IPS was not associated with significantly higher rates of aortic neck dilatation (30.6% versus 38.0%, p>0.05) and did not influence cumulative rates of type I endoleak, endovascular reintervention, or conversion to open surgery (p>0.05). Similarly, the presence of DM did not influence the above-mentioned study endpoints. CONCLUSION: In contrast to observations regarding the natural course of AAAs, impaired pulmonary status does not negatively influence aortic neck dilatation, while the presence of diabetes does not protect from these dismal events after EVAR.

Traumatic free wall and ventricular septal rupture - 'hybrid' management in a child

A 8-year-old boy showed a traumatic ventricular septal rupture following a blunt chest trauma, and was scheduled for elective catheter closure. Two weeks later, a follow-up echocardiogram revealed a pseudoaneurysm of the anterior wall of the left ventricle. Because of the apical location of the VSD, it was decided to proceed with transcatheter occlusion. After successful VSD closure, the patient was taken to the operation room for surgical repair of the left ventricular pseudoaneurysm. Symptoms and signs seen in patients with ventricular pseudoaneurysms appear to be discrete and variable, and a high clinical index of suspicion with a very close echocardiographic follow-up is strongly recommended after occurrence of a blunt cardiac trauma. The combined 'hybrid' approach of transcatheter closure of the intraventricular rupture followed by surgical closure of the pseudoaneurysm allows for a less invasive and efficient management of this rare combination of post-traumatic ventricular free wall and septal rupture in a child.

Takotsubo cardiomyopathy or transient left ventricular apical ballooning syndrome: A systematic review

BACKGROUND: Transient left ventricular apical ballooning syndrome (TLVABS) is an acute cardiac syndrome mimicking ST-segment elevation myocardial infarction characterized by transient wall-motion abnormalities involving apical and mid-portions of the left ventricle in the absence of significant obstructive coronary disease. METHODS: Searching the MEDLINE database 28 case series met the eligibility criteria and were summarized in a narrative synthesis of the demographic characteristics, clinical features and pathophysiological mechanisms. RESULTS: TLVABS is observed in 0.7-2.5% of patients with suspected ACS, affects women in 90.7% (95% CI: 88.2-93.2%) with a mean age ranging from 62 to 76 years and most commonly presents with chest pain (83.4%, 95% CI: 80.0-86.7%) and dyspnea (20.4%, 95% CI: 16.3-24.5%) following an emotionally or physically stressful event. ECG on admission shows ST-segment elevations in 71.1% (95% CI: 67.2-75.1%) and is accompanied by usually mild elevations of Troponins in 85.0% (95% CI: 80.8-89.1%). Despite dramatic clinical presentation and substantial risk of heart failure, cardiogenic shock and arrhythmias, LVEF improved from 20-49.9% to 59-76% within a mean time of 7-37 days with an in-hospital mortality rate of 1.7% (95% CI: 0.5-2.8%), complete recovery in 95.9% (95% CI: 93.8-98.1%) and rare recurrence. The underlying etiology is thought to be based on an exaggerated sympathetic stimulation. CONCLUSION: TLVABS is a considerable differential diagnosis in ACS, especially in postmenopausal women with a preceding stressful event. Data on longterm follow-up is pending and further studies will be necessary to clarify the etiology and reach consensus in acute and longterm management of TLVABS.

Inhibition of ErbB2/neuregulin signaling augments paclitaxel-induced cardiotoxicity in adult ventricular myocytes

Paclitaxel (Taxol) has been successfully combined with the monoclonal antibody trastuzumab (Herceptin) in the treatment of ErbB2 overexpressing cancers. However, this combination therapy showed an unexpected synergistic increase in cardiac dysfunction. We have studied the mechanisms of paclitaxel/anti-ErbB2 cardiotoxicity in adult rat ventricular myocytes (ARVM). Myofibrillar organization was assessed by immunofluorescence microscopy and cell viability was tested by the TUNEL-, LDH- and MTT-assay. Oxidative stress was measured by DCF-fluorescence and myocyte contractile function by video edge-detection and fura-2 fluorescence. Treatment of ARVM with paclitaxel or antibodies to ErbB2 caused a significant increase in myofilament degradation, similarly as observed with an inhibitor of MAPK-signaling, but not apoptosis, necrosis or changes in mitochondrial activity. Paclitaxel-treatment and anti-ErbB2 reduced Erk1/2 phosphorylation. Paclitaxel increased diastolic calcium, shortened relaxation time and reduced fractional shortening in combination with anti-ErbB2. A minor increase in oxidative stress by paclitaxel or anti-ErbB2 was found. We conclude, that concomitant inhibition of ErbB2 receptors and paclitaxel treatment has an additive worsening effect on adult cardiomyocytes, mainly discernible in changes of myofibrillar structure and function, but in the absence of cell death. A potential mechanism is the modulation of the MAPK/Erk1/2 signaling by both drugs.

Percutaneous left ventricular assist devices for treatment of patients with cardiogenic shock

PURPOSE OF REVIEW: This review will discuss the rationale and clinical utility of percutaneous left ventricular assist devices in the management of patients with cardiogenic shock. RECENT FINDINGS: Left ventricular assist devices maintain partial or total circulatory support in case of severe left ventricular failure. Currently, two percutaneous left ventricular assist devices are available for clinical use: the TandemHeart and the Impella Recover LP system. Compared with the intraaortic balloon pump, the TandemHeart has been shown to significantly reduce preload and to augment cardiac output. In a randomized comparison between the TandemHeart and intraaortic balloon pump support in patients with cardiogenic shock, the improved cardiac index afforded by the left ventricular assist device resulted in a more rapid decrease in serum lactate and improved renal function. There were, however, no significant differences with respect to 30-day mortality, and complications including limb ischemia and severe bleeding were more frequent with left ventricular assist devices than intraaortic balloon pump support. SUMMARY: The advent of percutaneous left ventricular assist devices constitutes an important advance in the management of patients with severe cardiogenic shock and may serve as bridge to recovery or heart transplantation in carefully selected patients. While improvement of hemodynamic parameters appears promising, it remains to be determined whether this benefit translates into improved clinical outcome.

Aquatic therapies in patients with compromised left ventricular function and heart failure

With water immersion, gravity is partly eliminated, and the water exerts a pressure on the body surface. Consequently there is a blood volume shift from the periphery to the central circulation, resulting in marked volume loading of the thorax and heart. This paper presents a selection of published literature on water immersion, balneotherapy, aqua exercises, and swimming, in patients with left ventricular dysfunction (LVD) and/or stable chronic heart failure (CHF). Based on exploratory studies, central hemodynamic and neurohumoral responses of aquatic therapies will be illustrated. Major findings are: 1. In LVD and CHF, a positive effect of therapeutic warm-water tub bathing has been observed, which is assumed to be from afterload reduction due to peripheral vasodilatation caused by the warm water. 2. In coronary patients with LVD, at low-level water cycling the heart is working more efficiently than at lowlevel cycling outside of water. 3. In patients with previous extensive myocardial infarction, upright immersion to the neck resulted in temporary pathological increases in mean pulmonary artery pressure (mPAP) and mean pulmonary capillary pressures (mPCP). 4. Additionally, during slow swimming (20-25m/min) the mPAP and/or PCP were higher than during supine cycling outside water at a 100W load. 5. In CHF patients, neck- deep immersion resulted in a decrease or no change in stroke volume. 6. Although patients are hemodynamically compromised, they usually maintain a feeling of well-being during aquatic therapy. Based on these findings, clinical indications for aquatic therapies are proposed and ideas are presented to provoke further research.

Aortic neck dilatation after endovascular abdominal aortic aneurysm repair: a word of caution

Continuing aortic neck dilatation, most probably an expression of ongoing aneurysmal wall degeneration of the infrarenal aortic segment, has been shown to seriously impair clinical results after endovascular abdominal aortic aneurysm repair. However, conflicting data on the extent and clinical relevance on this observation have recently been published. This article reviews the recent literature, summarizing our current understanding of the role of aortic neck dilatation after open surgical and endovascular abdominal aortic aneurysm repair. In addition, differences in methodology of studies on aortic neck dilatation are highlighted.

Percutaneous ventricular assist devices for cardiogenic shock

Cardiogenic shock complicates up to 7% of ST-segment elevation myocardial infarctions and 2.5% of non-ST-segment elevation myocardial infarctions, with an associated mortality of 50% to 70%. Primary cardiac pump failure is followed by secondary vital organ hypoperfusion and subsequent activation of various cascade pathways, resulting in a downward spiral leading to multiple organ failure and, ultimately, death. Immediate restoration of cardiac output by means of percutaneous ventricular assist devices restores hemodynamic -stability and is an important advance in the management of patients with severe left ventricular dysfunction and cardiogenic shock. This article reviews available evidence supporting the use of percutaneous ventricular assist devices in patients suffering from cardiogenic shock.

His-Purkinje system re-entry in patients with clustering ventricular tachycardia episodes

AIMS: Multiple arrhythmia re-inductions were recently shown in His-Purkinje system (HPS) ventricular tachycardia (VT). We hypothesized that HPS VT was a frequent mechanism of repetitive or incessant VT and assessed diagnostic criteria to select patients likely to have HPS VT. METHODS AND RESULTS: Consecutive patients with clustering VT episodes (>3 sustained monomorphic VT within 2 weeks) were included in the analysis. HPS VT was considered plausible in patients with (i) impaired left ventricular function associated with dilated cardiomyopathy or valvular heart disease; or (ii) ECG during VT similar to sinus rhythm QRS or to bundle-branch block QRS. HPS VT was plausible in 12 of 48 patients and HPS VT was demonstrated in 6 of 12 patients (50%, or 13% of the whole study group). Median VT cycle length was 318 ms (250-550). Catheter ablation was successful in all six patients. CONCLUSION: His-Purkinje system VT is found in a significant number of patients with repetitive or incessant VT episodes, and in a large proportion of patients with predefined clinical or electrocardiographic characteristics. Since it is easily amenable to catheter ablation, our data support the screening of all patients with repetitive VT in this regard and an invasive approach in a selected group of patients.

Preliminary results following reinforcement of the pulmonary autograft to prevent dilatation after the Ross procedure

OBJECTIVE: The Ross operation remains a controversially discussed procedure, because concern exists regarding late dilatation of the neoaortic root and progressive regurgitation of the autograft valve. We present our early experience with an external reinforcement of the autograft, which is inserted into a prosthetic Dacron graft with an artificial aortic root configuration. This detail should help to prevent neoaortic root dilatation. PATIENTS AND METHODS: Between 2006 and 2007, 12 patients (mean age 16 +/- 38 years; range 15-38 years) underwent a Ross procedure by this technique. Indications were aortic regurgitation (n = 2), aortic stenosis (n = 5), and combined aortic stenosis and insufficiency (n = 5). A bicuspid aortic valve was present in 9 patients. Balloon valvuloplasty had been performed in 7 patients. Follow-up was performed by clinical and echocardiographic examinations. RESULTS: No early or late deaths occurred in this small series, and freedom from reoperation is 100%. Echocardiographic follow-up confirmed absence of aortic insufficiency in 11 patients after a mean of 11 months (range 2-30 months). In 1 patient, a small asymmetric regurgitation jet was already observed at discharge echocardiography. As expected, no neoaortic root dilatation was observed during follow-up. All patients are in New York Heart Association class I. CONCLUSIONS: The present technique is a simple and reproducible technical step that does not require significant additional time. Inclusion of the autograft within a root prosthesis may be especially indicated in situations known for late autograft dilatation, namely, bicuspid aortic valve, predominant aortic insufficiency, and ascending aortic enlargement.