[Show abstract][Hide abstract]ABSTRACT: Wnt/β-catenin signalling controls adult heart remodelling in part via regulation of cardiac progenitor cell (CPC) differentiation. An enhanced understanding of mechanisms controlling CPC biology might facilitate the development of new therapeutic strategies in heart failure. We identified and characterized a novel cardiac interaction between Krueppel-like factor 15 and components of the Wnt/β-catenin pathway leading to inhibition of transcription. In vitro mutation, reporter assays and co-localization analyses revealed that KLF15 requires both the C-terminus, necessary for nuclear localization, and a minimal N-terminal regulatory region to inhibit transcription. In line with this, functional Klf15 knock-out mice exhibited cardiac β-catenin transcriptional activation along with functional cardiac deterioration in normal homeostasis and upon hypertrophy. We further provide in vivo and in vitro evidences for preferential endothelial lineage differentiation of CPCs upon KLF15 deletion. Via inhibition of β-catenin transcription, KLF15 controls CPC homeostasis in the adult heart similar to embryonic cardiogenesis. This knowledge may provide a tool for reactivation of this apparently dormant CPC population in the adult heart and thus be an attractive approach to enhance endogenous cardiac repair.
Full-text · Article · Sep 2012 · EMBO Molecular Medicine
[Show abstract][Hide abstract]ABSTRACT: To explore the relationship between coronary artery disease and renal vascular disease, we performed renal arterial angiography in 609 patients undergoing coronary angiography for suspected coronary artery disease. We defined renal artery stenosis as nonsignificant (<40%), borderline (40–60%) and significant (>60%). One-hundred fifty-two patients had renal artery stenosis, while 457 did not. Two-hundred and ten patients had no coronary disease; of these, only 9 had renal artery stenosis. On the other hand, the 143 patients with renal artery stenosis, when subdivided, had similar degrees of coronary disease; three vessel disease was significantly more common than one or two vessel disease in all groups. Renal artery stenosis of all severity degrees was associated with common atherosclerotic risk factors. However, hypertension was not a clue to the presence of renal artery stenosis. To evaluate the effect of percutaneous revascularization on hypertension and renal function all 51 patients with significant renal artery stenosis were treated by primary stent implantation and were follwed up for 6 months. Stent implantation showed a marked decrease in systolic and diastolic blood pressure (163±30 to 145±17 and 93±18 to 83±10 mmHg; p=0.008) with a decrease in the amount of antihypertensive medication but without beneficial effect on serum creatinine during follow-up (1.46±0.70 mg/dl to 1.39±0.58 mg/dl, p=ns). We conclude that renal artery stenosis of any severity is strongly suggestive of three vessel coronary artery disease. The fact that renal stenting lowers blood pressure decreases antihypertensive drugs and increases medication flexibility in patients with coronary artery disease would support the notion of revascularization in patients with significant stenoses.
No preview · Article · Apr 2012 · Zeitschrift für Kardiologie
[Show abstract][Hide abstract]ABSTRACT: Basierend auf pathophysiologischen Forschungsergebnissen, z.B. hinsichtlich der Bedeutung des sympathischen Nervensystems und des Renin-Angiotensin- Aldosteron-Systems, hat auch die Therapie der chronischen Herzinsuffizienz einen wichtigen Wandel erfahren. Wurde im Oktober 1993, als im INTERNIST letztmalig ein Heft mit dem Schwerpunktthema Herzinsuffizienz erschien (Einzelarbeiten zu diesem Thema wurden natürlich seither veröffentlicht), die Rolle von Betarezeptorblockern noch sehr zurückhaltend beurteilt und standen damals Herzglykoside noch ganz im Vordergrund der Therapie, so hat sich dieser Trend gegenläufig entwickelt, zumindestens was diese beiden Medikamente betrifft. Darüber wird an dieser Stelle referiert.
Derzeit bestimmen im wesentlichen 6 Medikamentengruppen, genannt nach ihrer Wichtigkeit, die Behandlung der chronischen Herzinsuffizienz: ACE-Hemmer, Betarezeptorenblocker, Diuretika, Aldosteron-Antagonisten, Digitalisglykoside und eventuell Antikoagulantien. Sie kommen, auch kombiniert, je nach NYHA-Schweregrad zum Einsatz.
An die unter pragmatischen Gesichtspunkten bewährte Klassifizierung der New York Heart Association sei kurz erinnert: in 4 NYHA-Stadien wird die Einschränkung der kardialen Funktionen definiert: (1.) Herzerkrankung ohne, (2.) mit leichter, (3.) mit höhergradiger und (4.) mit dauernder schwerer Funktionseinschränkung.
[Show abstract][Hide abstract]ABSTRACT: Thrombin potently activates platelets through the protease-activated receptor PAR-1. Vorapaxar is a novel antiplatelet agent that selectively inhibits the cellular actions of thrombin through antagonism of PAR-1.
We randomly assigned 26,449 patients who had a history of myocardial infarction, ischemic stroke, or peripheral arterial disease to receive vorapaxar (2.5 mg daily) or matching placebo and followed them for a median of 30 months. The primary efficacy end point was the composite of death from cardiovascular causes, myocardial infarction, or stroke. After 2 years, the data and safety monitoring board recommended discontinuation of the study treatment in patients with a history of stroke owing to the risk of intracranial hemorrhage.
At 3 years, the primary end point had occurred in 1028 patients (9.3%) in the vorapaxar group and in 1176 patients (10.5%) in the placebo group (hazard ratio for the vorapaxar group, 0.87; 95% confidence interval [CI], 0.80 to 0.94; P<0.001). Cardiovascular death, myocardial infarction, stroke, or recurrent ischemia leading to revascularization occurred in 1259 patients (11.2%) in the vorapaxar group and 1417 patients (12.4%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.82 to 0.95; P=0.001). Moderate or severe bleeding occurred in 4.2% of patients who received vorapaxar and 2.5% of those who received placebo (hazard ratio, 1.66; 95% CI, 1.43 to 1.93; P<0.001). There was an increase in the rate of intracranial hemorrhage in the vorapaxar group (1.0%, vs. 0.5% in the placebo group; P<0.001).
Inhibition of PAR-1 with vorapaxar reduced the risk of cardiovascular death or ischemic events in patients with stable atherosclerosis who were receiving standard therapy. However, it increased the risk of moderate or severe bleeding, including intracranial hemorrhage. (Funded by Merck; TRA 2P-TIMI 50 ClinicalTrials.gov number, NCT00526474.).
Full-text · Article · Mar 2012 · New England Journal of Medicine
[Show abstract][Hide abstract]ABSTRACT: Guideline-recommended beta-blocker (BB) target doses for patients with chronic heart failure can often not be reached. This secondary analysis of the CIBIS-ELD trial was carried out to better understand reasons for not achieving target doses.
Changes in heart rate (HR) and other parameters during a 12-week up-titration period in 302 BB naïve patients were evaluated in the subgroups achieving 12.5, 25, 50, and 100% of the target dose (groups 1, 2, 3, and 4, respectively).
Achieved doses predominantly depended on baseline HR (means 68, 74, 76, and 84 bpm in groups 1-4, respectively, P<0.001). HR was consistently reduced with each dose level to 65, 63, and 62 bpm in groups 1-3 and to 71 bpm in group 4 (P<0.001). When adjusted for baseline, HR reduction achieved in group 3 was better than in group 4 (difference -5.4 bpm, P<0.05). More patients in groups 3/4 than in groups 1/2 improved in NYHA class (P = 0.01). NTproBNP increased by 38% in group 4 (P<0.01) but not in the others (P<0.05 between groups). Changes in blood pressure, six-minute walk distance and self-rated health were comparable in all groups.
The desired effect of HR reduction appears to be a predominant limitation for BB up-titration. Vice versa, achieving the target dose may be a sign of insufficient response rather than successful treatment. In view of these results and the well-known importance of HR for survival, not target doses, but HR control should be given priority in BB treatment for heart failure.
No preview · Article · Nov 2011 · International journal of cardiology
[Show abstract][Hide abstract]ABSTRACT: The combination of intravenous propofol and midazolam is frequently used to provide unconscious sedation during catheter ablation of atrial fibrillation (AF), but only a very few reports are available on the influence of prolonged propofol infusion on arterial blood gas, blood pressure, and anesthesia-associated complications during ablation of AF. The purpose of this study was to assess tolerance and safety of unconscious sedation with intravenous propofol and midazolam during catheter ablation of AF.
A total of 316 consecutive patients (age 59 ± 10 years, 68% men) presenting to our center for catheter ablation of symptomatic AF were enrolled prospectively. A total number of 424 procedures were performed under unconscious sedation with propofol and midazolam. SaO(2), electrocardiogram, arterial blood pressure, and arterial blood gases were monitored throughout the procedure.
Mean procedure duration was 235 ± 48 minutes. Patients received 1.125 ± 684 mg propofol, 9.5 ± 3 midazolam, and 1.963 ± 813 mL NaCl infusion. Complications during the procedure were identified in eight patients (2.5%, one × coronary air embolization, one × myocardial infarction, four × pericardial effusion, two × pericardial tamponade). All eight patients were symptomatic (distress, report of pain); none of the complications was attributable to unconscious sedation itself.
Unconscious sedation with propofol and midazolam in AF ablation procedures lasting 3-5 hours did not result in severe changes of vital parameters or serum electrolytes. Anesthesia-associated problems were not observed. Propofol and midazolam can be safely used during catheter ablation of AF.
No preview · Article · Nov 2011 · Pacing and Clinical Electrophysiology
[Show abstract][Hide abstract]ABSTRACT: Mortality in chronic heart failure (CHF) patients with left bundle branch block (LBBB) is high. Cardiac resynchronization therapy (CRT) reduces symptoms and mortality in CHF patients with LBBB. Whether CRT promotes or prevents ventricular tachycardia (VT)/ventricular fibrillation (VF) remains controversial, however. Therefore, we aimed to analyse arrhythmia-related CRT effects and characterized the VT/VF incidence in CRT-defibrillator patients and matched controls with conventional implantable cardioverter-defibrillators (ICDs) for primary prevention of sudden cardiac death.
We enrolled 134 patients [110 men, left ventricular ejection fraction (LVEF) 24 ± 8%, 71 coronary artery disease, CRT-ICD 67, conventional ICD matched controls 67, follow-up 31 ± 17 months] and monitored overall survival and the time to a first VT/VF episode. Controls did not have LBBB. They were otherwise matched for age, LVEF, and follow-up duration. Gender and underlying disease did not differ between the groups. Kaplan-Meier analysis revealed more favourable arrhythmia-free survival in CRT-ICD vs. conventional ICD patients [hazard ratio (HR) 2.26, confidence interval (CI) 1.09-4.67, log rank P = 0.023]. The difference persisted in the multivariate Cox regression analysis (HR 3.25, CI 1.18-8.93, P= 0.022). Overall survival was similar in both groups (HR 1.45, CI 0.55-3.82, P = 0.45).
Chronic heart failure patients with LBBB treated with CRT-ICD, experience less and delayed VT/VF episodes compared with matched controls without LBBB receiving conventional ICD. In the long-term, CRT appears to exert antiarrhythmic effects and to attenuate the particularly high arrhythmia-related risk of CHF patients with LBBB. The incremental benefit of adding the ICD option to CRT pacing in LBBB patients appears questionable.
[Show abstract][Hide abstract]ABSTRACT: The aim of this study was to evaluate a comprehensive cardiac magnetic resonance (MR) imaging approach in patients with peripartum cardiomyopathy (PPCM). The focus was on inflammatory myocardial changes.
Retrospective analysis of 12 cardiac MR examinations was performed in 6 patients with PPCM. The protocol comprised cine sequences for the determination of chamber sizes and function. T 2-weighted sequences for determination of edema (T 2 ratio), T 1-weighted images for measurement of early gadolinium enhancement ratio (EGER), and late gadolinium enhancement (LGE) sequences were used for tissue characterization. 5 examinations were performed during the acute stage, and 7 examinations were performed during the course of the disease.
Initially, 3 of 5 patients presented with an elevated left ventricular end-diastolic volume (LVEDV); in one patient, the LVEDV was in the upper range. In 4 of 5 subjects, the left ventricular ejection fraction (LVEF) was decreased. The T 2 ratio and EGER values were initially elevated in all women. No LGE was detected in initial scans. In follow-up examinations, the LVEDV decreased and the LVEF increased in all patients. Tissue-characterizing parameters decreased to normal in all but 1 patient. 2 patients showing LGE did not present a favorable clinical course.
Myocardial inflammation was detected in the acute stage of PPCM, which was mostly transient. In our small group, patients showing LGE had a non-favorable clinical course. Future studies should include tissue-characterizing parameters, such as T 2 ratio and EGER. Thus, further insights into pathophysiology can be gained and therapeutic effects can be measured in a more extensive manner.
No preview · Article · Aug 2011 · RöFo - Fortschritte auf dem Gebiet der R
[Show abstract][Hide abstract]ABSTRACT: We hypothesized that infarct transmurality assessed with late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) predicts arrhythmic events in patients with chronic myocardial infarction.
Patients with decreased left ventricular function due to chronic myocardial infarction are at increased risk for life-threatening arrhythmias related to infarcted tissue. LGE-CMR accurately detects infarct morphology.
We prospectively enrolled 52 patients with chronic myocardial infarction referred for primary preventive implantable cardioverter-defibrillator (ICD) implantation following MADIT (Multicenter Automatic Defibrillator Implantation Trial) study criteria. Using LGE-CMR, left ventricular volumes, function, and infarct morphology were assessed including calculation of total and relative infarct mass, infarct border, infarct border zone, and infarct transmurality.
Patients were followed for 1,235 ± 341 days. The primary combined endpoint including appropriate device therapy (ICD discharge or antitachycardia pacing) or death from cardiac cause occurred in 16 individuals resulting in an annual event rate of 4.7%. Six patients received an appropriate shock, 7 patients received recurrent appropriate antitachycardia pacing for sustained ventricular tachycardia, and 3 patients died of cardiac cause. There was a significant association to relative infarct mass (38 ± 8% vs. 28 ± 14%, p = 0.02), infarct transmurality (24 ± 8 g vs. 16 ± 12 g, p = 0.02), and relative infarct transmurality (RIT) (63 ± 12% vs. 48 ± 23%, p = 0.01). In separate logistic regression models, no variable emerged as significant when combined with RIT. As a single effect, RIT emerged as a predictor of the primary endpoint (p = 0.02). A RIT cutoff at 43% resulted in a sensitivity of 88%, a specificity of 50%, a positive predictive value of 44%, and a negative predictive value of 90%.
In patients with chronic myocardial infarction scheduled for primary preventive ICD implantation, infarct transmurality as defined by LGE-CMR identifies a subgroup with increased risk for life-threatening arrhythmias and cardiac death.
Preview · Article · Aug 2011 · JACC. Cardiovascular imaging
[Show abstract][Hide abstract]ABSTRACT: We hypothesized that in patients with heart failure with normal left ventricular (LV) ejection fraction (HFNEF), the same fibrotic processes that affect the subendocardial layer of the LV could also alter the subendocardial fibers of the right ventricle (RV). Consequently, these alterations and to a lesser extent chronically elevated pulmonary arterial pressures would lead to both systolic and diastolic subendocardial dysfunction of the RV (i.e., impaired RV longitudinal systolic and diastolic function) in patients with HFNEF.
Patients with HFNEF and a control group consisting of asymptomatic patients with LV diastolic dysfunction (asymptomatic LVDD) matched by age, gender, and LV ejection fraction were studied by two-dimensional speckle-tracking echocardiography.
A total of 565 patients were included (201 with HFNEF and 364 with asymptomatic LVDD). RV longitudinal diastolic (RV global longitudinal early-diastolic strain rate [RV-SRe]) and systolic (RV global longitudinal systolic strain [RV-Strain]) function were significantly more impaired in patients with HFNEF than in patients with asymptomatic LVDD (HFNEF: RV-Strain -14.41% ± 3.80% and RV-SRe 0.86 ± 0.33 s(-1); asymptomatic LVDD: RV-Strain -16.90% ± 4.28% and RV-SRe 1.02 ± 0.34 s(-1); all P < .0001). On multiple regression analysis, LV global longitudinal systolic strain was the most important independent predictor of RV longitudinal systolic and diastolic function, in contrast with pulmonary arterial systolic pressure, which was weakly related to these functions. Furthermore, in patients with HFNEF the subendocardial function of both the LV and RV were significantly impaired in similar proportions. In that regard, in patients with HFNEF the prevalences of RV longitudinal systolic and diastolic dysfunction were 75% and 48%, whereas the rates of LV longitudinal systolic and diastolic dysfunction were 80% and 60%, respectively. In addition, patients with both systolic and diastolic longitudinal dysfunction of the RV presented worse New York Heart Association functional class.
In patients with HFNEF, RV subendocardial systolic and diastolic dysfunction are common and possibly associated with the same fibrotic processes that affect the subendocardial layer of the LV and to a lesser extent with RV pressure overload. Furthermore, our findings suggest that RV longitudinal systolic and diastolic dysfunction could contribute to the symptomatology of patients with HFNEF.
No preview · Article · May 2011 · Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography
[Show abstract][Hide abstract]ABSTRACT: Low-dose epoetin-β improved neo-angiogenesis and cardiac regeneration in experimental models of ischaemic cardiomyopathy without raising haemoglobin. No clinical study has tested this approach to date.
We performed a randomized, placebo-controlled, double-blind, single-centre study of 35 IU/kg body weight epoetin-β given subcutaneously once weekly for 6 months started within 3 weeks after successful percutaneous coronary intervention (PCI). Patients were included if they presented with a lesion within the proximal segment of the left anterior descending artery, the right coronary artery, or circumflex and had symptomatic heart failure. Patients with ST-segment elevation due to an acute myocardial infarct were excluded. The outcome variables were measured at baseline and at 6 months. Primary outcome measure was individual change in ejection fraction; secondary outcome was safety, change in N-terminal pro-brain natriuretic peptide, and peak VO(2). Twenty-four patients completed the 6-month treatment course. No adverse event related to the treatment occurred. Low-dose epoetin-β following PCI significantly improved global ejection fraction as measured by echocardiography (EPO: ΔEF 5.2 ± 2.0%, P= 0.013; placebo: ΔEF 0.3 ± 1.6%, P= 0.851; P= 0.019 for the inter-group difference) and cardiac magnetic resonance (EPO: ΔEF 3.1 ± 1.6%, P= 0.124; placebo: -1.9 ± 1.2%, P= 0.167; P= 0.042 for the inter-group difference). N-terminal pro-brain natriuretic peptide levels decreased in both groups without significant inter-group differences. Peak VO(2) levels increased significantly by 3.9 ± 1.1% (P< 0.05) in the EPO group, whereas in the placebo group the increase did not reach statistical significance (Δpeak VO(2) 3.0 ± 1.6, P = ns). No significant difference regarding peak VO(2) was observed between the EPO and placebo groups.
Low-dose epoetin-β treatment following PCI is safe and feasible, and has possible beneficial effects on global ejection fraction and measures of exercise capacity. Extended low-dose epoetin-β treatment warrants further mechanistic studies as well as larger clinical trials. Clinical Trial Registration Information: NCT00568542.
Full-text · Article · May 2011 · European Journal of Heart Failure
[Show abstract][Hide abstract]ABSTRACT: Various beta-blockers with distinct pharmacological profiles are approved in heart failure, yet they remain underused and underdosed. Although potentially of major public health importance, whether one agent is superior in terms of tolerability and optimal dosing has not been investigated. The aim of this study was therefore to compare the tolerability and clinical effects of two proven beta-blockers in elderly patients with heart failure.
We performed a double-blind superiority trial of bisoprolol vs. carvedilol in 883 elderly heart failure patients with reduced or preserved left ventricular ejection fraction in 41 European centres. The primary endpoint was tolerability, defined as reaching and maintaining guideline-recommended target doses after 12 weeks treatment. Adverse events and clinical parameters of patient status were secondary endpoints. None of the beta-blockers was superior with regards to tolerability: 24% [95% confidence interval (CI) 20-28] of patients in the bisoprolol arm and 25% (95% CI 21-29) of patients in the carvedilol arm achieved the primary endpoint (P= 0.64). The use of bisoprolol resulted in greater reduction of heart rate (adjusted mean difference 2.1 b.p.m., 95% CI 0.5-3.6, P= 0.008) and more, dose-limiting, bradycardic adverse events (16 vs. 11%; P= 0.02). The use of carvedilol led to a reduction of forced expiratory volume (adjusted mean difference 50 mL, 95% CI 4-95, P= 0.03) and more, non-dose-limiting, pulmonary adverse events (10 vs. 4%; P < 0.001).
Overall tolerability to target doses was comparable. The pattern of intolerance, however, was different: bradycardia occurred more often in the bisoprolol group, whereas pulmonary adverse events occurred more often in the carvedilol group. This study is registered with controlled-trials.com, number ISRCTN34827306.
Full-text · Article · Mar 2011 · European Journal of Heart Failure
[Show abstract][Hide abstract]ABSTRACT: The authors hypothesized that in patients with heart failure with normal left ventricular (LV) ejection fraction (HFNEF), the same fibrotic processes that affect the subendocardial layer of the left ventricle could also alter the subendocardial fibers of the left atrium. Consequently, these fibrotic alterations, together with chronically elevated LV filling pressures, would lead to both systolic and diastolic subendocardial dysfunction of the left atrium (i.e., impaired left atrial [LA] longitudinal systolic and diastolic function) in patients with HFNEF.
Patients with HFNEF and a control group consisting of asymptomatic patients with LV diastolic dysfunction (LVDD) matched by age, gender, and LV ejection fraction were studied using two-dimensional speckle-tracking echocardiography.
A total of 420 patients were included (119 with HFNEF and 301 with asymptomatic LVDD). LA longitudinal systolic (LA late diastolic strain rate) and diastolic (LA systolic strain and strain rate) function was significantly more impaired in patients with HFNEF (LA late diastolic strain rate, -1.17 ± 0.63 s(-1); LA systolic strain, 19.9 ± 7.3%; LA systolic strain rate, 1.17 ± 0.46 s(-1)) compared with those with asymptomatic LVDD (-1.80 ± 0.70 s(-1), 30.8 ± 11.4%, and 1.67 ± 0.59 s(-1), respectively) (all P values < .0001). On multiple regression analysis, LV global longitudinal systolic strain and diastolic strain rate were the most important independent predictors of LA longitudinal systolic and diastolic function, in contrast to noninvasive LV filling pressures (i.e., mitral E/e' average septal-lateral ratio), which were modestly related to LA longitudinal systolic and diastolic function. Furthermore, in patients with HFNEF, the subendocardial function of both the left atrium and the left ventricle was significantly impaired in high proportions. In that regard, in patients with HFNEF, the rate of LA longitudinal systolic and diastolic dysfunction was 65.5% and 28.5%, whereas the prevalence of LV longitudinal systolic and diastolic dysfunction was 81.5% and 58%, respectively. In addition, patients with both systolic and diastolic longitudinal dysfunction of the left atrium presented worse NYHA functional class as compared with those with normal LA longitudinal function.
In patients with HFNEF, LA subendocardial systolic and diastolic dysfunction is common and possibly associated with the same fibrotic processes that affect the subendocardial fibers of the left ventricle and to a lesser extent with elevated LV filling pressures. Furthermore, these findings suggest that LA longitudinal systolic and diastolic dysfunction could be related to reduced functional capacity during effort in patients with HFNEF.
No preview · Article · Mar 2011 · Journal of the American Society of Echocardiography: official publication of the American Society of Echocardiography