Florian Blaschke

Myocardial systolic and diastolic consequences of left ventricular mechanical dyssynchrony in heart failure with normal left ventricular ejection fraction

AIMS The purpose of this study was to test the hypothesis that left ventricular (LV) mechanical dyssynchrony deteriorates the longitudinal systolic and diastolic function of the left ventricle (LV) in patients with heart failure with a normal LV ejection fraction (HFNEF). METHODS AND RESULTS In patients with HFNEF and in a control group consisting of asymptomatic patients with LV diastolic dysfunction [LVDD], matched by age, gender, and LV ejection fraction, we assessed the global longitudinal systolic (global strain), diastolic [global early-diastolic strain rate (SRe)], and synchronous (standard deviation of time-to-peak systolic strain) function of the LV by two-dimensional speckle-tracking echocardiography using a 18-segment LV model. A total of 325 patients were included (85 with HFNEF and 240 with asymptomatic LVDD). Patients with HFNEF had a significant impairment of the longitudinal systolic and diastolic function of the LV as compared with the control group. Concerning the pathophysiological mechanisms linked to these findings, we found that HFNEF patients with asynchronous LV contractions had significantly more impaired longitudinal systolic and diastolic LV function (global strain -14.76 ± 3.44%, global SRe 0.79 ± 0.24 s(-1)) than patients without asynchronous LV contractions (global strain -18.57 ± 3.10%, global SRe 1.06 ± 0.32 s(-1); all P < 0.0001). Accordingly, in HFNEF patients with LV mechanical dyssynchrony the rates of LV longitudinal systolic and diastolic dysfunction were 64 and 70%, respectively, whereas these rates were significantly lower (19.5 and 41.3%), respectively, in patients without asynchronous LV contractions. In addition, HFNEF patients with LV mechanical dyssynchrony presented higher LV filling pressures and worse NYHA functional class than those with normal LV contractions. CONCLUSION In patients with HFNEF, LV mechanical dyssynchrony is associated with an important impairment of the longitudinal systolic and diastolic function of the LV. Therefore, the restoration of asynchronous LV contractions could help to improve and/or correct both the systolic and the diastolic longitudinal dysfunction of the LV in HFNEF and thereby improve the symptomatology of these patients.

Normal range and usefulness of right ventricular systolic strain to detect subtle right ventricular systolic abnormalities in patients with heart failure: a multicentre study

Aims The aim of the present multicentre study was to analyse a large cohort of healthy subjects and patients with a common condition such as heart failure (HF) with the purpose of determining the normal range and the usefulness of right ventricular (RV) systolic strain to detect subtle RV systolic abnormalities using 2D speckle-tracking echocardiography. Methods and results We analysed 238 healthy subjects and a cohort of 642 patients characterized by asymptomatic patients (n = 216) and patients with HF with preserved (HFpEF) and reduced (HFrEF) ejection fraction (n = 218 and n = 208, respectively) prospectively included in 10 centres. The normal range of RV systolic strain analysing the healthy subjects was as follows: RV global strain −24.5 ± 3.8 and RV free wall strain −28.5 ± 4.8 (lowest expected value −17 and −19%, respectively). Concerning the ability of these myocardial parameters to detect subtle RV systolic abnormalities, RV global and free wall systolic strain were able to detect subtle RV longitudinal systolic abnormalities in a significant proportion of patients with HFrEF and to a lesser extent in HFpEF despite preserved tricuspid annular plane systolic excursion, tricuspid lateral annular peak systolic velocity by pulsed tissue Doppler imaging, and RV fractional area change. In addition, RV global and free wall systolic strain were significantly linked to the symptomatic status of the patients. Conclusions The findings from this study provide important data regarding the normal range of RV global and free wall systolic strain and highlight the clinical relevance of these RV myocardial parameters to detect subtle RV systolic abnormalities in patients with HF.

Ventricular tachycardia or ventricular fibrillation occurs less often in patients with left bundle branch block and combined resynchronization and defibrillators than in patients with narrow QRS and conventional defibrillators

AIMS 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. METHODS AND RESULTS 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). CONCLUSIONS 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.

Impaired myocardial development resulting in neonatal cardiac hypoplasia alters postnatal growth and stress response in the heart

AIMS Foetal growth has been proposed to influence cardiovascular health in adulthood, a process referred to as foetal programming. Indeed, intrauterine growth restriction in animal models alters heart size and cardiomyocyte number in the perinatal period, yet the consequences for the adult or challenged heart are largely unknown. The aim of this study was to elucidate postnatal myocardial growth pattern, left ventricular function, and stress response in the adult heart after neonatal cardiac hypoplasia in mice. METHODS AND RESULTS Utilizing a new mouse model of impaired cardiac development leading to fully functional but hypoplastic hearts at birth, we show that myocardial mass is normalized until early adulthood by accelerated physiological cardiomyocyte hypertrophy. Compensatory hypertrophy, however, cannot be maintained upon ageing, resulting in reduced organ size without maladaptive myocardial remodelling. Angiotensin II stress revealed aberrant cardiomyocyte growth kinetics in adult hearts after neonatal hypoplasia compared with normally developed controls, characterized by reversible overshooting hypertrophy. This exaggerated growth mainly depends on STAT3, whose inhibition during angiotensin II treatment reduces left ventricular mass in both groups but causes contractile dysfunction in developmentally impaired hearts only. Whereas JAK/STAT3 inhibition reduces cardiomyocyte cross-sectional area in the latter, it prevents fibrosis in control hearts, indicating fundamentally different mechanisms of action. CONCLUSION Impaired prenatal development leading to neonatal cardiac hypoplasia alters postnatal cardiac growth and stress response in vivo, thereby linking foetal programming to organ size control in the heart.

Safety and efficacy of applying a low-dose radiation fluoroscopy protocol in device implantations

Aims For cardiac implantable electronic device (CIED) implantations, visualization of lead placement is necessary and fluoroscopy remains by far the most commonly used technique. With simple changes in the X-ray system settings, total radiation dose can be reduced significantly. The purpose of this study was to assess the safety and efficacy of various CIED implantations performed after implementation of a new dose reduction protocol (DRP). Methods and results We conducted a retrospective chart review of 584 patients undergoing CIED implantation or revision in our hospital. Of these patients, 280 (48%) underwent the implantation prior to and 304 (52%) after the DRP introduction. The DRP included various changes for optimized image processing and exposure system settings to enable dose reduction, as well as a reduced frame rates (4 FPS for fluoroscopy and 7.5 FPS for cinematographic images). Of the 584 patients, 53 (9.1%) had a one-chamber pacemaker, 232 (39.7%) a two-chamber pacemaker, 133 (22.8%) a one-chamber ICD, 35 (6.0%) a two-chamber ICD, 82 (14.0%) a CRT (de novo) implantation, and 49 (8.3%) had an upgrade to a CRT device. DRP was associated with a 64% reduction of the dose-area product (1372 ± 2659 vs. 3792 ± 5025 cGcm2, P < 0.001), while fluoroscopy duration (13 ± 15 vs. 13 ± 15 min) and procedural duration (93 ± 52 vs. 92 ± 52 min.) did not significantly increase. Complication rates did not differ significantly between the two groups. Conclusion The DRP proved to effectively reduce radiation dose for all types of CIED implantations. Fluoroscopy time, total procedure time, and the number of complications did not increase after introducing the DRP.

Minimal and deep sedation during ablation of ventricular tachycardia

BACKGROUND Catheter ablation is a curative treatment option for ventricular premature contractions (VPC) and ventricular tachycardia (VT). Procedures require different sedation levels, depending on duration, ablation approach and patient characteristics. The aim of our study was to evaluate feasibility of minimal and deep sedation for ablation of VPC/VT. METHODS Patients underwent catheter ablation of VPC/VT under minimal or deep sedation. Events of hypotension, hypoxia, bradycardia, procedural complications and VT inducibility were compared between the groups. RESULTS 120 patients were included. In 42 patients (53.6 ± 17.1 years, 47.6% male) ablation was performed under minimal sedation with midazolam, and in 78 patients (54.2 ± 17.5 years, 67.9% male) ablation was performed under deep sedation with propofol/midazolam. There were significantly fewer patients with idiopathic VT (62.8 vs. 88.1%, p=0.011) in the deep sedation group, LVEF was significantly lower (47 ± 14.4 vs. 53.1 ± 11.7) and the procedure duration was significantly longer (201.9 ± 85.9 vs. 137.9 ± 98.7). No significant differences in procedural complications or sedation related events (hypotension: 0 vs. 3.8%, p=0.2, no hypoxia, no bradycardia) were detected. CONCLUSIONS Minimal sedation and deep sedation are both feasible during VPC/VT ablation procedures. Propofol does not increase complications even in a collective with pre-existing impairment of LVEF. Adequate monitoring and trained personnel should be present.

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.

Zinc Inhibits Phosphate-Induced Vascular Calcification through TNFAIP3-Mediated Suppression of NF-κB

Background The high cardiovascular morbidity and mortality of patients with CKD may result in large part from medial vascular calcification, a process promoted by hyperphosphatemia and involving osteo-/chondrogenic transdifferentiation of vascular smooth muscle cells (VSMCs). Reduced serum zinc levels have frequently been observed in patients with CKD, but the functional relevance of this remains unclear.Methods We performed experiments in primary human aortic VSMCs; klotho-hypomorphic (kl/kl), subtotal nephrectomy, and cholecalciferol-overload mouse calcification models; and serum samples from patients with CKD.Results In cultured VSMCs, treatment with zinc sulfate (ZnSO4) blunted phosphate-induced calcification, osteo-/chondrogenic signaling, and NF-κB activation. ZnSO4 increased the abundance of zinc-finger protein TNF-α-induced protein 3 (TNFAIP3, also known as A20), a suppressor of the NF-κB pathway, by zinc-sensing receptor ZnR/GPR39-dependent upregulation of TNFAIP3 gene expression. Silencing of TNFAIP3 in VSMCs blunted the anticalcific effects of ZnSO4 under high phosphate conditions. kl/kl mice showed reduced plasma zinc levels, and ZnSO4 supplementation strongly blunted vascular calcification and aortic osteoinduction and upregulated aortic Tnfaip3 expression. ZnSO4 ameliorated vascular calcification in mice with chronic renal failure and mice with cholecalciferol overload. In patients with CKD, serum zinc concentrations inversely correlated with serum calcification propensity. Finally, ZnSO4 ameliorated the osteoinductive effects of uremic serum in VSMCs.Conclusions Zinc supplementation ameliorates phosphate-induced osteo-/chondrogenic transdifferentiation of VSMCs and vascular calcification through an active cellular mechanism resulting from GPR39-dependent induction of TNFAIP3 and subsequent suppression of the NF-κB pathway. Zinc supplementation may be a simple treatment to reduce the burden of vascular calcification in CKD.

Atrial remodelling in heart failure: recent developments and relevance for heart failure with preserved ejection fraction: Guest Editorial

As specialized compartments of the heart, the atria feature unique mechanical and structural properties that differ considerably from those of the ventricular myocardium. Beyond their contribution to cardiac output as a reservoir, conduit, and booster pump at different phases of the cardiac cycle, the atria determine heart rhythm, regularity, and rate (chronotropy). They also function as mechanical sensors and exert relevant endocrine activity (e.g. natriuretic peptides). Atrial remodelling is often observed in association with ventricular remodelling in heart failure (HF) but by itself adds to the complexity of the disease.

Near-Fatal ICD Lead Dysfunction with Implications for ICD Testing.

A 31‐year‐old male patient with an implantable cardioverter defibrillator (ICD) experienced ventricular fibrillation. After resuscitation, no communication between the device and an ICD programmer was possible. The ICD was explanted, no signs of destruction were visible, and the ICD leads revealed normal values. A new ICD was implanted, interrogation values were stable. However, immediately after defibrillation testing the connection between programmer and ICD was interrupted and could not be established again. The device showed burn marks and a hole in the can. Analysis revealed an isolation defect of the ICD lead, which was not detectable with standard interrogation.