Differential Role of Aldosterone and Transforming Growth Factor Beta-1 in Cardiac Remodeling.

Angiotensin II, a major culprit in cardiovascular disease, activates mediators that are also involved in pathological cardiac remodeling. In this context, we aimed at investigating the effects of two of them: aldosterone (Ald) and transforming growth factor beta-1 (TGF-ß1) in an in vivo model. Six-week-old male wild-type (WT) and TGF-ß1-overexpressing transgenic (TGF-ß1-TG) mice were infused with subhypertensive doses of Ald for 2 weeks and/or treated orally with eplerenone from postnatal day 21. Thehearts' ventricles were examined by morphometry, immunoblotting to assess the intracellular signaling pathways and RT qPCR to determine hypertrophy and fibrosis marker genes. The TGF-ß1-TG mice spontaneously developed cardiac hypertrophy and interstitial fibrosis and exhibited a higher baseline phosphorylation of p44/42 and p38 kinases, fibronectin and ANP mRNA expression. Ald induced a comparable increase in the ventricular-heart-weight-to-body-weight ratio and cardiomyocyte diameter in both strains, but a less pronounced increase in interstitial fibrosis in the transgenic compared to the WT mice (23.6% vs. 80.9%, p < 0.005). Ald increased the phosphorylation of p44/42 and p38 in the WT but not the TGF-ß1-TG mice. While the eplerenone-enriched chow partially prevented Ald-induced cardiac hypertrophy in both genotypes and interstitial fibrosis in the WT controls, it completely protected against additional fibrosis in transgenic mice. Ald appears to induce cardiac hypertrophy independently of TGF-ß1, while in the case of fibrosis, the downstream signaling pathways of these two factors probably converge.

Surgical revision after percutaneous mitral valve repair by edge-to-edge device in high-risk patients.

BACKGROUND: Patients scheduled for surgery after unsuccessful MitraClip® intervention present increasingly with multiple comorbidities, and they are often referred to the heart team to suggest the most appropriate intervention. The publication of successful results of initial patient cohorts treated with the MitraClip device has resulted in recruitment of more seriously ill patients, who otherwise would have been denied catheter-based/surgical treatment. There has been increasingly reports on conventional surgery after failed mitral valve repair with the MitraClip device. However, data on such procedures remain scarce and mostly focused on individual case studies. The inevitable increase in use of MitraClip, however, will raise the number of patients in need of surgery post MitraClip, making it imperative for surgeons to understand challenges and outcome data related with surgery in this patient cohort. We present our long-term institutional experience with surgery after MitraClip intervention in highest risk patients. METHODS: Eighteen patients underwent surgery of the mitral valve at our Institution between January 2015 and June 2020. These patients developed recurrent mitral regurgitation grade more than 2° at various intervals after MitraClip. Mitral valve repair was performed where possible and gross examination Valve/MitraClip were intra-operatively documented. Implanted MitraClip devices were analyzed histopathologically to evaluate the healing process and rule out inflammation. Regular patient follow-up was performed. RESULTS: Mean patient age was 74 (±9 years) and MitraClip implantation was performed at various tertiary institutions. Sixteen out of eighteen (16/18) patients received mitral valve replacement, whereas the remaining two patients received mitral valve repair and extracorporal membrane oxygenation, respectively. Four patients died of sepsis and intractable multi organ failure in-hospital. The remaining patients were discharged alive out of hospital to different rehabilitation centers. Follow-up was complete in all patients. CONCLUSIONS: Surgery is demanding when patients require surgery for persistent or recurrent mitral regurgitation after MitraClip therapy and can be successfully implemented as a possible therapy option for selective cases as an interdisciplinary approach despite calculated high perioperative mortality risk. These patients should not be denied surgery outright.

Pulmonary arterial remodelling by deficiency of peroxisome proliferator-activated receptor-γ in murine vascular smooth muscle cells occurs independently of obesity-related pulmonary hypertension.

BACKGROUND: Obesity is associated with cardiovascular complications, including pulmonary hypertension (PH). Reports suggest that peroxisome proliferator-activated receptor-γ (PPARγ) has direct action in preventing vascular remodelling in PH. Here we dissected the specific role of high-fat-diet (HFD)-induced obesity and vascular smooth muscle cell (VSMC)-PPARγ for remodelling of small pulmonary arteries. METHODS: Wild-type (WT) and VSMC-specific PPARγ-knockout (SmPparγ-/-) mice were fed a low-fat-diet (LFD, 10% kcal from fat) or HFD (60% kcal from fat) for 24 weeks. Mice were metabolically phenotyped (e.g. weight development, insulin/glucose tolerance) at the beginning, and after 12 and 24 weeks, respectively. At 24 weeks additionally pulmonary pressure, heart structure, pulmonary vascular muscularization together with gene and protein expression in heart and lung tissues were determined. RESULTS: HFD increased right ventricular systolic pressure (RVSP) to a similar extent in WT and SmPparγ-/- mice. HFD decreased glucose tolerance and insulin sensitivity in both WT and SmPparγ-/- mice. Importantly, the increase in RVSP correlated with the degree of insulin resistance. However, VSMC-PPARγ deficiency increased pulmonary vascular muscularization independently of the diet-induced rise in RVSP. This increase was associated with elevated expression of early growth response protein 1 in heart and osteopontin in lung tissue. CONCLUSIONS: Here we demonstrate a correlation of insulin resistance and pulmonary pressure. Further, deficiency of PPARγ in VSMCs diet-independently leads to increased pulmonary vascular muscularization.

Transaortic Transcatheter Aortic Valve Implantation: Learning Curve, Perioperative, and Midterm Follow-Up Results of a Single Center.

BACKGROUND: We present our initial institutional experience with transaortic (TAo) transcatheter aortic valve implantation (TAVI) using a self-expanding aortic bioprosthesis. METHODS: A total of 106 patients underwent TAo TAVI with Medtronic CoreValve through a small partial upper sternotomy. We focus our analysis on the overall perioperative results, procedural learning curve (first 30 patients), and midterm follow-up outcomes. RESULTS: VARC-2 device success was achieved in 95 patients (89%), and there were no intraoperative deaths. Nine patients (8.4%) required a second valve and conversion to standard surgery was required in 2 patients (1.8%). The final aortic insufficiency was grade 0 in 65 patients (62%) and grade 1 in 39 (37%). Although patients treated in the TAo TAVI learning phase required a significantly longer radiation time and contrast agent use, device success (93.4% versus 88.2%, P = .7) and prostheses hemodynamics were similar. All-cause mortality at 30 days was 12% (13/106). At a median follow-up of 392 days (IQR: 216-494 days) estimated overall 1-year survival was 72%. No significant differences were reported in terms of 30-day and 1-year observed mortality, and estimated 1-year survival in the learning and later phase of TAo TAVI. CONCLUSION: TAo TAVI can be performed safely even in the very early phase of the learning curve. Although satisfactory results can be achieved from the beginning, a significant reduction in contrast agent use and radiological exposure are expected as the technique is mastered. Good hemodynamics have been documented and should be further improved with modifications achieved in the TAVI self-expandable valves technology.

New generation cardioverter-defibrillator lead with a floating atrial sensing dipole: Long-term performance.

OBJECTIVES: The study aim is to present the long-term performance of a new generation implantable cardioverter defibrillator (ICD) electrode with floating atrial dipole (Linox S DX, Biotronik, Berlin, Germany). BACKGROUND: The single ICD electrode with a floating dipole in the atrial chamber was introduced about 15 years ago to overcome risk of inappropriate shock. METHODS: After implantation, internal electrocardiogram data were prospectively collected via telemonitoring (Home Monitoring, Biotronik). RESULTS: A total of 93 patients (81.5% male, 18.5% female; 58.9 ± 12.3 years) were implanted with a single-chamber ICD using the Linox S DX. Patients were followed up for a median of 693 days (33-2,460 days). At time of implantation average p-wave value was 3.5 ± 1.7 mV and remained stable throughout follow-up with an average value of 3.7 ± 1 mV (P = 0.2). A total of 460 arrhythmic episodes were recorded and 185 (40.2%) were incorrectly stratified by the device software. Seven patients (7.5%) experienced inappropriate ICD therapy. In three patients, VT episodes were not detected and remained untreated. CONCLUSIONS: Although the Linox S DX lead presents a satisfactory long-term stability of the atrial sensing, many of the messages sent to the device during follow-up were incorrectly classified by the ICD software. As a result, inappropriate therapy occurred with a rate similar to that observed with dual-chamber ICDs, but some malignant arrhythmias remained undiagnosed and untreated while occurring. Results in larger prospective cohorts should be analyzed and software improvements of the device should be suggested to overcome these potential drawbacks.

Genetic Ablation of PDGF-Dependent Signaling Pathways Abolishes Vascular Remodeling and Experimental Pulmonary Hypertension.

OBJECTIVE: Despite modern therapies, pulmonary arterial hypertension (PAH) harbors a high mortality. Vascular remodeling is a hallmark of the disease. Recent clinical studies revealed that antiremodeling approaches with tyrosine-kinase inhibitors such as imatinib are effective, but its applicability is limited by significant side effects. Although imatinib has multiple targets, expression analyses support a role for platelet-derived growth factor (PDGF) in the pathobiology of the disease. However, its precise role and downstream signaling events have not been established. APPROACH AND RESULTS: Patients with PAH exhibit enhanced expression and phosphorylation of ß PDGF receptor (ßPDGFR) in remodeled pulmonary arterioles, particularly at the binding sites for phophatidyl-inositol-3-kinase and PLCγ at tyrosine residues 751 and 1021, respectively. These signaling molecules were identified as critical downstream mediators of ßPDGFR-mediated proliferation and migration of pulmonary arterial smooth muscle cells. We, therefore, investigated mice expressing a mutated ßPDGFR that is unable to recruit phophatidyl-inositol-3-kinase and PLCγ (ßPDGFR(F3/F3)). PDGF-dependent Erk1/2 and Akt phosphorylation, cyclin D1 induction, and proliferation, migration, and protection against apoptosis were abolished in ßPDGFR(F3/F3) pulmonary arterial smooth muscle cells. On exposure to chronic hypoxia, vascular remodeling of pulmonary arteries was blunted in ßPDGFR(F3/F3) mice compared with wild-type littermates. These alterations led to protection from hypoxia-induced PAH and right ventricular hypertrophy. CONCLUSIONS: By means of a genetic approach, our data provide definite evidence that the activated ßPDGFR is a key contributor to pulmonary vascular remodeling and PAH. Selective disruption of PDGF-dependent phophatidyl-inositol-3-kinase and PLCγ activity is sufficient to abolish these pathogenic responses in vivo, identifying these signaling events as valuable targets for antiremodeling strategies in PAH.

Remote ischemic preconditioning and renoprotection: from myth to a novel therapeutic option?

There is currently no effective prophylactic regimen available to prevent contrast-induced AKI (CI-AKI), a frequent and life-threatening complication after cardiac catheterization. Therefore, novel treatment strategies are required to decrease CI-AKI incidence and to improve clinical outcomes in these patients. Remote ischemic preconditioning (rIPC), defined as transient brief episodes of ischemia at a remote site before a subsequent prolonged ischemia/reperfusion injury of the target organ, is an adaptational response that protects against ischemic and reperfusion insult. Indeed, several studies demonstrated the tissue-protective effects of rIPC in various target organs, including the kidneys. In this regard, rIPC may offer a novel noninvasive and virtually cost-free treatment strategy for decreasing CI-AKI incidence. This review evaluates the current experimental and clinical evidence for rIPC as a potential renoprotective strategy, and discusses the underlying mechanisms and key areas for future research.

Ischemic preconditioning for prevention of contrast medium-induced nephropathy: randomized pilot RenPro Trial (Renal Protection Trial).

BACKGROUND: Contrast medium-induced acute kidney injury is associated with substantial morbidity and mortality. The underlying mechanism has been attributed in part to ischemic kidney injury. The aim of this randomized, double-blind, sham-controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium-induced acute kidney injury. METHODS AND RESULTS: Patients with impaired renal function (serum creatinine >1.4 mg/dL or estimated glomerular filtration rate <60 mL · min(-1) · 1.73 m(-2)) undergoing elective coronary angiography were randomized in a 1:1 ratio to standard care with (n=50) or without ischemic preconditioning (n=50; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff). Overall, both study groups were at high risk of developing contrast medium-induced acute kidney injury according to the Mehran risk score. The primary end point was the incidence of contrast medium-induced kidney injury, defined as an increase in serum creatinine ≥25% or ≥0.5 mg/dL above baseline at 48 hours after contrast medium exposure. Contrast medium-induced acute kidney injury occurred in 26 patients (26%), 20 (40%) in the control group and 6 (12%) in the remote ischemic preconditioning group (odds ratio, 0.21; 95% confidence interval, 0.07-0.57; P=0.002). No major adverse events were related to remote ischemic preconditioning. CONCLUSIONS: Remote ischemic preconditioning before contrast medium use prevents contrast medium-induced acute kidney injury in high-risk patients. Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes. CLINICAL TRIAL REGISTRATION: URL: http://www.germanctr.de. Unique identifier: U1111-1118-8098.

Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud's phenomenon: systematic review and meta-analysis of randomised trials.

INTRODUCTION: Recent controlled trials have assessed the efficacy of phosphodiesterase-5 (PDE-5) inhibitors in secondary Raynaud's phenomenon (RP). However, the conclusions are conflicting, and whether these drugs are effective remains unclear. The objective of this meta-analysis was to determine the efficacy of PDE-5 inhibitors on Raynaud's Condition Score (RCS) and frequency and duration of attacks. METHODS: A systematic review of articles was performed (sources included Medline, Embase, Web of Science, the Cochrane Central Register of Controlled Trials). Only double-blind, randomised controlled trials (RCTs) were included. Studies were selected independently by two authors using predefined data fields, including study quality indicators. RESULTS: Six RCTs were included (one with sildenafil, one with modified-release sildenafil, three with tadalafil and one with vardenafil). PDE-5 inhibitors significantly decreased mean RCS by -0.46 (-0.74 to -0.17) (p=0.002), the daily frequency of ischaemic attacks by -0.49 (-0.71 to -0.28) (p<0.0001), and daily duration of RP attacks by -14.62 (-20.25 to -9.00) min (p<0.0001). CONCLUSIONS: PDE-5 inhibitors appear to have significant but moderate efficacy in secondary RP. A further large RCT is needed.

Natriuretic peptides in therapy for decompensated heart failure.

Congestive heart failure (CHF) is the most frequent cause of hospitalization for patients >65 years of age and continues to be a major public health burden among the ageing population. Unlike therapy for chronic CHF, there has been only modest progress in medical treatment for acutely decompensated CHF over the past several decades. Moreover, current treatment-consisting generally of diuretic, inotropic, and vasodilatory agents-is associated with many limitations in clinical practice. Natriuretic peptides provide a promising mechanism of action in the pathophysiologic background for CHF treatment based on their vasodilatory and diuretic properties and effective inhibition of the renin-angiotensin-aldosterone system, which is activated early in the course of CHF. Nesiritide (Natrecor® or Noratak®) is a recombinant natriuretic peptide that has the same 32 amino-acid sequence as human B-type natriuretic peptide. Nesiritide has been shown to improve dyspnea and hemodynamic parameters in patients with decompensated heart failure. Ularitide is a synthetic form of urodilatin, a natriuretic peptide hormone secreted by the kidney. Recent clinical studies suggest that ularitide may play a role in managing decompensated heart failure. This review provides an update on natriuretic peptides and their therapeutic potential in advanced CHF.

Hypoxia enhances platelet-derived growth factor signaling in the pulmonary vasculature by down-regulation of protein tyrosine phosphatases.

RATIONALE: Platelet-derived growth factor (PDGF) plays a pivotal role in the pathobiology of pulmonary hypertension (PH) because it promotes pulmonary vascular remodeling. PH is frequently associated with pulmonary hypoxia. OBJECTIVES: To investigate whether hypoxia alters PDGF ß receptor (ßPDGFR) signaling in the pulmonary vasculature. METHODS: The impact of chronic hypoxia on signal transduction by the ßPDGFR was measured in human pulmonary arterial smooth muscle cells (hPASMC) in vitro, and in mice with hypoxia-induced PH in vivo. MEASUREMENTS AND MAIN RESULTS: Chronic hypoxia significantly enhanced PDGF-BB-dependent proliferation and chemotaxis of hPASMC. Pharmacologic inhibition of PI3 kinase (PI3K) and PLCγ abrogated these events under both normoxia and hypoxia. Although hypoxia did not affect ßPDGFR expression, it increased the ligand-induced tyrosine phosphorylation of the receptor, particularly at binding sites for PI3K (Y751) and PLCγ (Y1021). The activated ßPDGFR is dephosphorylated by protein tyrosine phosphatases (PTPs). Interestingly, hypoxia decreased expression of numerous PTPs (T cell PTP, density-enhanced phosphatase-1, PTP1B, and SH2 domain-containing phosphatase-2), resulting in reduced PTP activity. Hypoxia-inducible factor (HIF)-1α is involved in this regulation of gene expression, because hypoxia-induced ßPDGFR hyperphosphorylation and PTP down-regulation were abolished by HIF-1α siRNA and by the HIF-1α inhibitor 2-methoxyestradiol. ßPDGFR hyperphosphorylation and PTP down-regulation were also present in vivo in mice with chronic hypoxia-induced PH. CONCLUSIONS: Hypoxia reduces expression and activity of ßPDGFR-antagonizing PTPs in a HIF-1α-dependent manner, thereby enhancing receptor activation and proliferation and chemotaxis of hPASMC. Because hyperphosphorylation of the ßPDGFR and down-regulation of PTPs occur in vivo, this mechanism likely has significant impact on the development and progression of PH and other hypoxia-associated diseases.

ECG as a risk stratification tool in patients with wearable cardioverter-defibrillator.

BACKGROUND: The wearable cardioverter defibrillator (WCD) is increasingly used in patients at elevated risk for ventricular arrhythmias but not fulfilling the indications for an implantable cardioverter defibrillator (ICD). Currently, there is an insufficient risk prediction of fatal arrhythmias in patients at risk. In this study, we assessed the prognostic role of baseline electrocardiogram (ECG) in WCD patients. METHODS: WCD patients from diverse clinical institutions in Germany (n = 227) were retrospectively enrolled and investigated for the incidences of death or ventricular arrhythmias during WCD wearing. In addition, the widely accepted ECG predictors of adverse outcome were analyzed in patients with arrhythmic events. RESULTS: Life-threatening arrhythmias occurred in 22 (9.7 %) patients, mostly in subjects with ischemic heart disease (15 of 22). There was no difference in baseline left ventricular ejection fraction (LVEF) in subjects with and without arrhythmic events (31.3 ±â€¯7.9 % vs. 32.6 ±â€¯8.3 %; p = 0,24). Patients with arrhythmia exhibited significantly longer QRS duration (109.5 ±â€¯23.1 ms vs. 100.6 ±â€¯22.3 ms, p = 0,04), Tpeak-Tend (Tp-e) (103.1 ±â€¯15.6 ms vs. 93.2 ±â€¯19.2 ms, p = 0,01) and QTc (475.0 ±â€¯60.0 ms vs. 429.6 ±â€¯59.4 ms, p < 0,001) intervals. In contrast, no significant differences were found for incidences of fragmented QRS (27.3 % vs. 24 %, p = 0.79) and inverted/biphasic T-waves (16.6 % vs. 22.7 %, p = 0,55). In multivariate regression analysis both Tp-e (HR 1.03; 95 % CI 1.001-1.057; p = 0.02) and QTc (HR 1.02; 95 % CI 1.006-1.026; p < 0.001) were identified as independent predictors of ventricular arrhythmias. After WCD use, the prophylactic ICD was indicated in 76 patients (33 %) with uneventful clinical course but persistent LVEF ≤35 %. The ECG analysis in these subjects did not reveal any relevant changes in arrhythmogenesis markers. CONCLUSIONS: ECG repolarization markers Tp-e and QTc are associated with malignant arrhythmias in WCD patients and may be used - in addition to other established risk markers - to identify appropriate patients for ICD implantation.

Local thrombolysis for successful treatment of acute stroke in an adolescent with cardiac myxoma.

Intracardiac myxomas are the most common benign cardiac tumors in adults. They are a rare source of cardiogenic embolisms and sudden death, especially in young patients. This report describes the case of a male adolescent who presented with right-sided paresis and aphasia. Magnetic resonance imaging of the brain revealed an ischemic stroke without evidence of acute bleeding. Intra-arterial local thrombolysis was immediately started. An echocardiographic screening after successful thrombolysis with a remarkable recovery of symptoms detected a thrombotic-like mass in the left atrium. The mass was excised surgically, confirmed as a benign atrial myxoma, and the patient was discharged with restitution ad integrum. Thus, contrary to some critical reports, thrombolytic therapy for acute ischemic strokes due to atrial myxomas may be safe and highly effective.

Heart rate at discharge in patients with acute decompensated heart failure is a predictor of mortality.

AIMS: Heart failure is a syndrome with increasing prevalence in concordance with the aging population and better survival rates from myocardial infarction. Morbidity and mortality are high in chronic heart failure patients, particularly in those with hospital admission for acute decompensation. Several risk stratification tools and score systems have been established to predict mortality in chronic heart failure patients. However, identification of patients at risk with easy obtainable clinical factors that can predict mortality in acute decompensated heart failure (ADHF) are needed to optimize the care-path. METHODS AND RESULTS: We retrospectively analyzed electronic medical records of 78 patients with HFrEF and HFmrEF who were hospitalized with ADHF in the Heart Center of the University Hospital Cologne in the year 2011 and discharged from the ward after successful treatment. 37.6 ± 16.4 months after index hospitalization 30 (38.5%) patients had died. This mortality rate correlated well with the calculated predicted survival with the Seattle Heart Failure Model (SHFM) for each individual patient. In our cohort, we identified elevated heart rate at discharge as an independent predictor for mortality (p = 0.016). The mean heart rate at discharge was lower in survived patients compared to patients who died (72.5 ± 11.9 vs. 79.1 ± 11.2 bpm. Heart rate of 77 bpm or higher was associated with an almost doubled mortality risk (p = 0.015). Heart rate elevation of 5 bpm was associated with an increase of mortality of 25% (p = 0.022). CONCLUSIONS: Patients hospitalized for ADHF seem to have a better prognosis, when heart rate at discharge is < 77 bpm. Heart rate at discharge is an easily obtainable biomarker for risk prediction of mortality in HFrEF and HFmrEF patients treated for acute cardiac decompensation. Taking into account this parameter could be useful for guiding treatment strategies in these high-risk patients. Prospective data for validation of this biomarker and specific intervention are needed.

Detection of arrhythmia using an implantable cardiac monitor following a cryptogenic stroke: a single-center observational study.

BACKGROUND: Detection of atrial fibrillation (AF) after cryptogenic stroke (CS) has therapeutic implications, but the most effective type and optimal duration of monitoring have still to be defined. This study that involved patients with CS or transient ischemic attack (TIA), all of whom carried an implantable cardiac monitor (ICM), sought to assess the incidence of AF and other arrhythmia detected using tele-monitoring or interval-based follow-up by an internal cardiologist at the university medical center of Rostock (UMR) or an external cardiologist. METHODS: The ICM implantation was performed during the inpatient stay in the neurology department, with inclusion and exclusion criteria jointly determined by the neurology and cardiology departments. Cardiologists programmed individual threshold values during ICM implantation, which were designed to instantly trigger an episode being recording and an alarm message being sent out. Outpatient care consisted of tele-monitoring of implants or interval-based follow-up care. RESULTS: The indication for ICM implantation was made for 102 patients, 88 of whom underwent ICM implantation, with full documentation available for these 88 study patients. Within a median observation period of 21.5 months, AF occurred in 19 patients, with a median observation time to the event of 7 months. In all cases, AF detection was followed by immediate medical intervention. Comparing patients with and without AF revealed that the median age of the AF group exceeded by 10 years that of the other patients. Stroke recurrence was recorded in five patients, with a median observation time to the event of 9 months. Comparing patients with and without stroke recurrence revealed that the median age in the stroke recurrence group tended to be higher by 14 years. No statistically significant between-group differences were found with regard to integration into tele-monitoring, nor were there any differences identified between outpatient care at the UMR or in the outpatient sector. CONCLUSIONS: This study confirmed the feasibility of using an interdisciplinary and intersectoral therapeutic approach for monitoring CS patients with implanted ICMs. Further randomized studies are warranted to confirm these encouraging data. An open discussion concerning optimal care forms and opportunities for introducing digitizing care pathways appears warranted.

Novel ECG-based scoring tool for prediction of takotsubo syndrome.

BACKGROUND: Takotsubo syndrome (TS) usually involves ECG changes mimicking acute myocardial infarction (AMI). The differentiation of both disorders is crucial for selection of appropriate treatment. The aim of this study was to assess ECG parameters in patients with TS and AMI, and try to establish a scoring tool for TS prediction. METHODS: The study consisted of two study parts: evaluation and validation cohorts. Overall, the study included 82 patients with TS and 141 subjects with AMI. In addition to the major demographic characteristics and comorbidities, the following ECG parameters were analyzed: heart rate, QRS duration, QTc, QRS amplitudes in frontal and precordial leads, frequencies for ST-segment elevation, combined sign of positive ST-segment elevation in -aVR and absent in V1, negative T-wave in lead I and positive in III, inverted or biphasic T-waves in V2-V5, T-wave inversions in frontal and precordial leads. All significant variables were identified in univariate regression analysis and further included for multivariate logistic regression analysis predicting TS. RESULTS: TS was frequently diagnosed in women and in elderly patients. Presence of ST-segment elevation, inverted/biphasic T-waves in V2-V5, QRS amplitudes in frontal and precordial leads were significantly different in evaluation group. By multivariate regression analysis sex, QRS amplitudes in frontal, inverted or biphasic T-waves in septal leads and QTc were identified as powerful variables to calculate TS probability. The diagnostic accuracy of the developed 6-points-TS-score was then evaluated in the validation group. Thus, no subject with a TS-score of ≥ 5 had AMI (specificity 99%, sensitivity > 92%). CONCLUSION: The developed ECG-based TS-score model may be a useful complimentary tool for TS prediction in acute clinical setting.

Pacing-induced cardiomyopathy in chronic right ventricular apical pacing: a midterm follow-up study.

BACKGROUND: Data concerning the effect of chronic right ventricular pacing in patients with normal left ventricular ejection fraction (LVEF%) are contradictory. The aim of this study is to evaluate the prevalence of pacing-induced cardiomyopathy (PICM) at midterm follow-up after permanent pacemaker implantation (PPM). METHODS: A series of 170 patients were submitted to PPM within our facility. Inclusion criteria were the absence of structural heart disease and a preserved LVEF% (> 45%) at the time of PPM. A midterm clinical and echocardiographic follow-up was performed, and data were collected and analyzed retrospectively. PICM was defined as follow-up LVEF ≤ 45%, dyskinesia during RV pacing, and the absence of other known causes of cardiomyopathy. RESULTS: At a median echocardiographic follow-up of 24.5 months (IQR 10.0-43.0 months), the overall mean LVEF% decreased from a preimplantation value of 66.7% (± 8.6%) to 63.2% (± 10.6%) (p < 0.0001). PICM occurred in 11 patients (6.5%). Patients developing PICM had a significantly lower preimplantation LVEF% (58.4 ± 8.0% vs. 67.3 ± 8.4%; p = 0.005), a trend for higher right ventricular pacing time rate (0.7 ± 0.3 vs. 0.5 ± 0.4; p = 0.1), a significantly lower rate of PPM indication for sick sinus syndrome (SSS) (18.2% vs. 61.0%; p = 0.009), and significantly higher rate of second-grade cardiac conduction block (36.4% vs. 11.3%; p = 0.03). At multivariate logistic regression, only preimplantation LVEF% (OR = 0.88; CI 0.80-0.96; p = 0.006) and the presence of SSS (OR = 0.1; CI 0.03-0.9; p = 0.04) were independently related (inverse relationship) to follow-up PICM. CONCLUSIONS: In this selected PPM patient cohort with preserved LVEF%, the rate of PICM at midterm follow-up is relatively low, but its occurrence seems to be related to baseline LVEF% and PPM indication category.

Prevalence and Progression of Cognitive Impairment in Atrial Fibrillation Patients after Treatment with Catheter Ablation or Drug Therapy.

PURPOSE: In atrial fibrillation (AF) patients, the effect of catheter ablation or drug therapy on cognition is currently not well investigated. Therefore, we prospectively evaluated AF patients who were either treated 'with drug therapy or underwent catheter ablation for the prevalence and progression of cognitive impairment (CI). METHODS: Randomized participants of the CABANA trial (catheter ablation versus antiarrhythmic drug therapy for atrial fibrillation) and the CASTLE-AF (catheter ablation versus standard conventional treatment in patients with left ventricular dysfunction and atrial fibrillation) study were assessed twice within 6 months by Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) in our institution. RESULTS: Forty-five patients from both trials were investigated, and twenty-eight patients received catheter ablation, whereas seventeen patients received drug therapy for rhythm or rate control. The mean age of the twenty-one CABANA trial patients (AF group) was 68.8 ± 7.0 years and of the twenty-four CASTLE-AF study patients (AF/HF group) was 66.8 ± 8.1 years, respectively. Mean time from ablation/randomization to the first interview was 16.8 ± 11 months in the AF group and 28.3 ± 18.4 months in the AF/HF group, respectively. All patients investigated were classified as cognitively impaired with mean cutoff scores <24 by MoCA. Overall, we could not detect significant differences in medically treated versus catheter ablation patients within both groups in mean MMSE or MoCA scores between the first and the second interview (p > 0.09). Moreover, patients who received catheter ablation did not show statistically significant differences in the prevalence or progression of cognitive impairment compared to patients who were treated medically, neither within the two groups nor between AF and AF/HF patients (p > 0.05). CONCLUSIONS: Prevalence of cognitive impairment in AF patients with comorbidities is substantial. However, in this preliminary prospective study, no apparent impact of AF pretreatment on the prevalence and course of cognitive impairment could be observed.

A nuclear receptor corepressor-dependent pathway mediates suppression of cytokine-induced C-reactive protein gene expression by liver X receptor.

C-reactive protein (CRP), the prototypical human acute phase protein, is an independent risk predictor of future cardiovascular events, both in healthy individuals and in patients with known cardiovascular disease. In addition, previous studies indicate that CRP might have direct proatherogenic properties. Ligand activation of the liver X receptor (LXR), a member of the nuclear hormone receptor superfamily, inhibits inflammatory gene expression in macrophages and attenuates the development of atherosclerosis in various animal models. We demonstrate herein that 2 synthetic LXR ligands, T0901317 and GW3965, inhibit interleukin-1beta/interleukin-6-induced CRP mRNA and protein expression in human hepatocytes. Knockdown of LXRalpha/beta by short interfering RNAs completely abolished the inhibitory effect of the LXR agonist T0901317 on cytokine-induced CRP gene transcription. Transient transfection experiments with 5'-deletion CRP promoter constructs identified a region from -125 to -256 relative to the initiation site that mediated the inhibitory effect of LXR ligands on CRP gene transcription. Depletion of the nuclear receptor corepressor by specific short interfering RNA increased cytokine-inducible CRP mRNA expression and promoter activity and reversed LXR ligand-mediated repression of CRP gene transcription. Chromatin immunoprecipitation assays indicated that nuclear receptor corepressor is present on the endogenous CRP promoter under basal conditions. Cytokine-induced clearance of nuclear receptor corepressor complexes was inhibited by LXR ligand treatment, maintaining the CRP gene in a repressed state. Finally, treatment of C57Bl6/J mice with LXR ligands attenuated lipopolysaccharide-induced mouse CRP and serum amyloid P component gene expression in the liver, whereas no effect was observed in LXRalphabeta knockout mice. Our observations identify a novel mechanism of inflammatory gene regulation by LXR ligands. Thus, inhibition of CRP expression by LXR agonists may provide a promising approach to impact initiation and progression of atherosclerosis.