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-β1) in an in vivo model. Six-week-old male wild-type (WT) and TGF-β1-overexpressing transgenic (TGF-β1-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-β1-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%,
< 0.005). Ald increased the phosphorylation of p44/42 and p38 in the WT but not the TGF-β1-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-β1, while in the case of fibrosis, the downstream signaling pathways of these two factors probably converge.
Cardiac dysfunction is frequently observed in patients with cirrhosis, and has long been linked to the direct toxic effect of alcohol. Cirrhotic cardiomyopathy(CCM) has recently been identified as an ...entity regardless of the cirrhosis etiology. Increased cardiac output due to hyperdynamic circulation is a pathophysiological hallmark of the disease. The underlying mechanisms involved in pathogenesis of CCM are complex and involve various neurohumoral and cellular pathways, including the impaired β-receptor and calcium signaling, altered cardiomyocyte membrane physiology, elevated sympathetic nervous tone and increased activity of vasodilatory pathways predominantly through the actions of nitric oxide, carbon monoxide and endocannabinoids. The main clinical features of CCM include attenuated systolic contractility in response to physiologic or pharmacologic strain, diastolic dysfunction, electrical conductance abnormalities and chronotropic incompetence. Particularly the diastolic dysfunction with impaired ventricularrelaxation and ventricular filling is a prominent feature of CCM.The underlying mechanism of diastolic dysfunction in cirrhosis is likely due to the increased myocardial wall stiffness caused by myocardial hypertrophy,fibrosis and subendothelial edema,subsequently resulting in high filling pressures of the left ventricle and atrium.Currently,no specific treatment exists for CCM.The liver transplantation is the only established effective therapy for patients with end-stage liver disease and associated cardiac failure.Liver transplantation has been shown to reverse systolic and diastolic dysfunction and the prolonged QT interval after transplantation.Here,we review the pathophysiological basis and clinical features of cirrhotic cardiomyopathy,and discuss currently available limited therapeutic options.
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.
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.
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 ± 7.9 % vs. 32.6 ± 8.3 %; p = 0,24). Patients with arrhythmia exhibited significantly longer QRS duration (109.5 ± 23.1 ms vs. 100.6 ± 22.3 ms, p = 0,04), Tpeak-Tend (Tp-e) (103.1 ± 15.6 ms vs. 93.2 ± 19.2 ms, p = 0,01) and QTc (475.0 ± 60.0 ms vs. 429.6 ± 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.
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.
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•The wearable cardioverter defibrillator is safe and effective in patients with elevated risk for fatal arrhythmias.•Tp-e and QTc are independent electrocardiographic (ECG) predictors of adverse events in these patients.•ECG can serve as an additional risk stratification tool in this high-risk subgroup.
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.
Patients with PAH exhibit enhanced expression and phosphorylation of β PDGF receptor (βPDGFR) 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 βPDGFR-mediated proliferation and migration of pulmonary arterial smooth muscle cells. We, therefore, investigated mice expressing a mutated βPDGFR that is unable to recruit phophatidyl-inositol-3-kinase and PLCγ (βPDGFR(F3/F3)). PDGF-dependent Erk1/2 and Akt phosphorylation, cyclin D1 induction, and proliferation, migration, and protection against apoptosis were abolished in βPDGFR(F3/F3) pulmonary arterial smooth muscle cells. On exposure to chronic hypoxia, vascular remodeling of pulmonary arteries was blunted in βPDGFR(F3/F3) mice compared with wild-type littermates. These alterations led to protection from hypoxia-induced PAH and right ventricular hypertrophy.
By means of a genetic approach, our data provide definite evidence that the activated βPDGFR 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.
Abstract
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.
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.
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.
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.
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.
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).
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.
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.
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.
Despite recent advances, pulmonary arterial hypertension (PAH) remains a devastating disease which harbors a poor prognosis. Novel therapeutic approaches directly targeting pulmonary vascular ...remodeling are warranted.
This review delineates the current limitations in the management of PAH and focuses on a novel, anti-proliferative therapeutic concept. It will help readers understand the mechanisms of receptor tyrosine kinase signaling, with a special focus on platelet-derived growth factor (PDGF) receptors and their role in the pathobiology of PAH. Furthermore, it provides a comprehensive summary regarding the rationale, efficacy and safety of the tyrosine kinase inhibitor imatinib mesylate , which potently inhibits the PDGF receptor, as an additional treatment option in PAH.
PDGF is a potent mitogen for pulmonary vascular smooth muscle cells and represents an important mediator of pulmonary vascular remodeling. Imatinib mesylate, a compound that inhibits the Bcr-Abl kinase and was developed for the treatment of chronic myeloid leukemia, also targets PDGF receptors. Both experimental and clinical data indicate that it reverses the vascular remodeling process even when it is fully established. Results from Phase II and III clinical trials suggest potent and prolonged efficacy in patients with severe PAH (i.e., pulmonary vascular resistance > 800 dynes*s*cm(-5)). Future studies should evaluate the long-term clinical efficacy and safety of imatinib, including patients with less impaired hemodynamics. Based on the current knowledge, this compound is likely to become an additional treatment option for patients with PAH and has the potential to at least partially correct the pathology of the disease.
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.
To investigate whether hypoxia alters PDGF β receptor (βPDGFR) signaling in the pulmonary vasculature.
The impact of chronic hypoxia on signal transduction by the βPDGFR was measured in human pulmonary arterial smooth muscle cells (hPASMC) in vitro, and in mice with hypoxia-induced PH in vivo.
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 βPDGFR expression, it increased the ligand-induced tyrosine phosphorylation of the receptor, particularly at binding sites for PI3K (Y751) and PLCγ (Y1021). The activated βPDGFR 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 βPDGFR hyperphosphorylation and PTP down-regulation were abolished by HIF-1α siRNA and by the HIF-1α inhibitor 2-methoxyestradiol. βPDGFR hyperphosphorylation and PTP down-regulation were also present in vivo in mice with chronic hypoxia-induced PH.
Hypoxia reduces expression and activity of βPDGFR-antagonizing PTPs in a HIF-1α-dependent manner, thereby enhancing receptor activation and proliferation and chemotaxis of hPASMC. Because hyperphosphorylation of the βPDGFR 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.
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. Keywords: Atrial fibrillation, Cryptogenic shock, Transient ischemic attack, Insertable cardiac monitoring
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