Efficacy of multi-electrode linear irreversible electroporation.

AIMS: We investigated the efficacy of linear multi-electrode irreversible electroporation (IRE) ablation in a porcine model. METHODS AND RESULTS: The study was performed in six pigs (weight 60-75 kg). After median sternotomy and opening of the pericardium, a pericardial cradle was formed and filled with blood. A linear seven polar 7-Fr electrode catheter with 2.5 mm electrodes and 2.5 mm inter-electrode spacing was placed in good contact with epicardial tissue. A single IRE application was delivered using 50 J at one site and 100 J at two other sites, in random sequence, using a standard monophasic defibrillator connected to all seven electrodes connected in parallel. The pericardium and thorax were closed and after 3 weeks survival animals were euthanized. A total of 82 histological sections from all 18 electroporation lesions were analysed. A total of seven 50 J and fourteen 100 J epicardial IRE applications were performed. Mean peak voltages at 50 and 100 J were 1079.2 V ± 81.1 and 1609.5 V ± 56.8, with a mean peak current of 15.4 A ± 2.3 and 20.2 A ± 1.7, respectively. Median depth of the 50 and 100 J lesions were 3.2 mm [interquartile range (IQR) 3.1-3.6] and 5.5 mm (IQR 4.6-6.6) (P < 0.001), respectively. Median lesion width of the 50 and 100 J lesions was 3.9 mm (IQR 3.7-4.8) and 5.4 mm (IQR 5.0-6.3), respectively (P < 0.001). Longitudinal sections showed continuous lesions for 100 J applications. CONCLUSION: Epicardial multi-electrode linear application of IRE pulses is effective in creating continuous deep lesions.

Inhibition of miR-25 improves cardiac contractility in the failing heart.

Heart failure is characterized by a debilitating decline in cardiac function, and recent clinical trial results indicate that improving the contractility of heart muscle cells by boosting intracellular calcium handling might be an effective therapy. MicroRNAs (miRNAs) are dysregulated in heart failure but whether they control contractility or constitute therapeutic targets remains speculative. Using high-throughput functional screening of the human microRNAome, here we identify miRNAs that suppress intracellular calcium handling in heart muscle by interacting with messenger RNA encoding the sarcoplasmic reticulum calcium uptake pump SERCA2a (also known as ATP2A2). Of 875 miRNAs tested, miR-25 potently delayed calcium uptake kinetics in cardiomyocytes in vitro and was upregulated in heart failure, both in mice and humans. Whereas adeno-associated virus 9 (AAV9)-mediated overexpression of miR-25 in vivo resulted in a significant loss of contractile function, injection of an antisense oligonucleotide (antagomiR) against miR-25 markedly halted established heart failure in a mouse model, improving cardiac function and survival relative to a control antagomiR oligonucleotide. These data reveal that increased expression of endogenous miR-25 contributes to declining cardiac function during heart failure and suggest that it might be targeted therapeutically to restore function.

Impact of baseline cigarette smoking status on clinical outcome after transcatheter aortic valve replacement.

OBJECTIVES: To explore the prevalence of smoking, and its association with clinical and mortality outcome among patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Less data exist regarding the effect of baseline smoking status on clinical and mortality outcome among patients undergoing TAVR. METHODS: Consecutive patients who underwent TAVR at two high volume Dutch centers were included. Smoking status was prospectively questioned by a structured interview at admission. Primary endpoint was 1-year all-cause mortality after TAVR. RESULTS: A total of 913 consecutive patients (80.1 ± 7.6 years; logistic EuroSCORE: 16.5 ± 9.9%) who underwent TAVR for severe aortic valve stenosis were included. There were 47% (n = 432) males, and 57% (n = 522) never-smokers, and 35% (n = 317) prior-smokers, and 8% (n = 74) current-smokers. Smokers (i.e., prior-smokers or current-smokers) were younger compared to never-smokers (78.9 ± 7.9 and 76.4 ± 8.0 vs. 81.3 ± 7.1, P < 0.000, respectively). Median follow-up time was 365 (interquartile range [IQR]: 280-365) days. Overall, prior-smoking was not associated with all-cause mortality at 1-year following TAVR (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.55-1.23). After stratification according to sex, male prior-smokers showed better 1-year survival after TAVR than male never-smokers (12% vs. 20%; P = 0.018, respectively, HR 0.52, 95% CI 0.29-0.89), while this reversed effect was not observed among female prior-smokers versus female never-smokers after TAVR (HR 1.70, 95% CI 0.95-3.05). CONCLUSIONS: Overall, baseline prior-smokers had similar 1-year mortality outcome after TAVR compared with baseline never-smokers. However, there was a reversed association between baseline prior-smoking status and 1-year mortality after TAVR among males, which could partially be explained due to the favorable baseline characteristics.

High-frequency irreversible electroporation for cardiac ablation using an asymmetrical waveform.

BACKGROUND: Irreversible electroporation (IRE) using direct current (DC) is an effective method for the ablation of cardiac tissue. A major drawback of the use of DC-IRE, however, are two problems: requirement of general anesthesia due to severe muscle contractions and the formation of bubbles containing gaseous products from electrolysis. The use of high-frequency alternating current (HF-IRE) is expected to solve both problems, because HF-IRE produces little to no muscle spasms and does not cause electrolysis. METHODS: In the present study, we introduce a novel asymmetric, high-frequency (aHF) waveform for HF-IRE and present the results of a first, small, animal study to test its efficacy. RESULTS: The data of the experiments suggest that the aHF waveform creates significantly deeper lesions than a symmetric HF waveform of the same energy and frequency (p = 0.003). CONCLUSION: We therefore conclude that the use of the aHF enhances the feasibility of the HF-IRE method.

Anomalous coronary artery originating from the opposite sinus of Valsalva (ACAOS), fractional flow reserve- and intravascular ultrasound-guided management in adult patients.

OBJECTIVES: To describe the use of fractional flow reserve (FFR) and intravascular ultrasound (IVUS) in the evaluation of patients with anomalous coronary arteries originating from the opposite sinus of Valsalva (ACAOS). BACKGROUND: ACAOS of the right and left coronary are rare, but may lead to symptoms and impose a risk for sudden cardiac death, depending on several anatomical features. Assessment and risk estimation is challenging in (nonathlete) adults, especially if they present without symptoms or with atypical complaints. METHODS: The team retrospectively studied 30 consecutive patients with ACAOS with interarterial course, who received IVUS- and FFR-guided treatment at our institution between October 2010 and September 2017. RESULTS: FFR was abnormal in only seven patients. IVUS showed the typical slit-like anatomy of the orifice in 23 patients. Based on FFR and/or IVUS results, in conjunction with the clinical presentation, clinical decision was made. A decision for intervention was made if at least two out of three entities were abnormal. Intervention implied unroofing of the coronary artery (n = 10) or coronary artery bypass grafting (n = 1). In all other patients a conservative strategy was followed. No adverse events occurred in the total population after a median of 37 (0-62) months of follow-up. CONCLUSIONS: Conservative treatment may be justifiable in adult patients with ACAOS in the presence of normal FFR and nonsuspicious symptoms, despite the presence of an interarterial course and/or slitlike orifice on IVUS. We recommend the use of FFR and IVUS in the standard work-up for adult patients with ACAOS and propose the use of a flowchart to aid in decision-making.

Evaluation of Cognitive Function Following Transcatheter Aortic Valve Replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is associated with procedural-related neurological events and acute cognitive decline. However, data on the effect of TAVR on mid-term cognitive outcome are scarce. Therefore, we aimed to assess the impact of TAVR on mid-term cognitive outcome using different neurocognitive test batteries. METHODS: Patients with severe aortic valve stenosis scheduled for TAVR were enrolled. Cognitive assessment was performed at baseline and 4 months post-TAVR using an eight-word verbal-learning test ("Immediate Recall Memory Test" [IRMT], "Delayed Recall Memory Test" [DRMT], "Recognition of Verbal Information Test" [RVIT]), global cognitive function ("Mini Mental State Examination" [MMSE]), and executive function ("Trail Making Test" [TMT], "Clock-Drawing Test" [CDT]). RESULTS: A total of 30 patients (age: 81±6years, logistic EuroSCORE: 19±10%) completed the follow-up cognitive assessments. Postoperatively, 17% (n=5) developed delirium, 13% (n=4) received permanent pacemaker, and there were no cerebrovascular events. Mean hospital duration time was 5±2 days. Patients (n=22) who did not complete the follow-up cognitive assessments had comparable baseline, procedural and hospital outcome. At follow-up there was a significant improvement in IRMT (27±5 vs. 30±4, p=0.016), with a trend toward improved DRMT (4±2 vs. 5±2, p=0.079). Moreover, patients with lower baseline MMSE and IRMT improved significantly during the follow-up. CONCLUSIONS: Transcatheter aortic valve replacement was associated with an improved IRMT during follow-up. Both MMSE and IRMT were significantly improved among those with lower baseline scores.

The concept of triple wavefront fusion during biventricular pacing: Using the EGM to produce the best acute hemodynamic improvement in CRT.

BACKGROUND: Previous reports suggest that biventricular pacing (BiVp) fused with intrinsic conduction (BiVp-fusion, triple wavefront fusion) is associated with improved resynchronization compared to pure-BiVp in cardiac resynchronization therapy (CRT). This study aimed to assess the association between acute hemodynamic benefit of CRT and signs of BiVp-fusion by using a novel electrogram (EGM)-based method. METHODS: In 17 patients undergoing CRT implantation, 28 combinations of atrioventricular (AV) and interventricular (VV) delays were applied while invasively measuring acute hemodynamic response based on maximum rate of left ventricular (LV) pressure rise (LV dP/dtmax ) to assess optimal BiVp settings. BiVp-fusion was noted if farfield signal (caused by first intrinsic ventricular depolarization) was seen prior to right ventricular (RV) pacing (RVp) artifact on integrated bipolar RV EGM, or QRS morphology changed compared to pure-BiVp (short AV-delay) as seen on electrocardiogram (ECG). RESULTS: Mean optimal RVp timing was at 98 ± 17% of intrinsic right atrial (RA)-RVfarfield (interval from right atrial pace or sense to RV farfield signal) interval, while preactivating the LV at 50 ± 11% of RA-RVsense (interval from right atrial pace or sense to RV sense interval) interval. BiVp-fusion was noted in 16 of 17 (94%) patients on ECG during optimal BiVp. Eight of these patients showed intrinsic farfield signal prior to RVp artifact on RV EGM. In the remaining eight, the RVp was paced just within the RA-RVfarfield interval with a mean of 25 ± 14 ms prior to the onset; therefore, the intrinsic farfield was masked. CONCLUSION: Optimal hemodynamic BiVp facilitates triple wavefront fusion, by pacing the RV around the onset of intrinsic farfield signal on RV EGM, while preactivating the LV. Aiming at BiVp-fusion could be a target for noninvasive EGM-based CRT device setting optimization.

Characterization of exercise limitations by evaluating individual cardiac output patterns: a prospective cohort study in patients with chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) suffer from exercise intolerance due to impaired central hemodynamics and subsequent alterations in peripheral skeletal muscle function and structure. The relative contribution of central versus peripheral factors in the reduced exercise capacity is still subject of debate. The main purpose was to investigate heterogeneity in the nature of exercise intolerance by evaluating individual cardiac output (Q) patterns. The secondary purpose was to evaluate whether patient and disease characteristics were associated with a central hemodynamic exercise limitation. METHODS: Sixty-four stable CHF patients performed a symptom limited incremental exercise test with respiratory gas analysis and simultaneous assessment of Q, using a radial artery pulse contour analysis method. A central hemodynamic exercise limitation was defined as a plateau or decline in Q from 90 to 100 % of exercise duration. RESULTS: Data from 61 patients were analyzed. A central hemodynamic exercise limitation was observed in 21 patients (34 %). In these patients, a higher occurrence of a plateau/decrease in oxygen uptake (VO2) (52 % vs 23 %, p = 0.02), stroke volume (SV) (100 % vs. 75 %, p = 0.01) and chronotropic incompetence (31 % vs. 2.5 %, p = 0.01) was observed, while presence of a left bundle branch block (LBBB) occurred significantly less (19 % vs 48 %, p = 0.03) There was no difference in disease characteristics such as etiology, duration, NYHA class, mitral regurgitation or ischemia. CONCLUSIONS: The study revealed considerable heterogeneity in the nature of exercise limitations between moderately impaired CHF patients. In one third of the study population a plateau or decrease in Q towards peak exercise was demonstrated, which is indicative of a central hemodynamic exercise limitation. A central hemodynamic exercise limitation was associated with an impairment to augment stroke volume and heart rate.

The impact of susceptibility loci for coronary artery disease on other vascular domains and recurrence risk.

AIMS: Genome-wide association studies (GWAS) have identified many genetic loci related to coronary artery disease (CAD) and myocardial infarction (MI). However, the extent to which these loci are related to other vascular diseases is not clear. The aim of this study is to investigate the cumulative effects of risk alleles associated with CAD/MI on ischaemic stroke (IS), abdominal aortic aneurysm (AAA), and peripheral artery disease (PAD). METHODS AND RESULTS: We calculated a multi-locus genetic risk score (GRS) in 8446 participants of the SMART (Second Manifestations of ARTerial disease) study based on the lead single-nucleotide polymorphisms (SNPs) at 30 CAD/MI loci, and tested this GRS for cross-sectional association with CAD/MI, IS, AAA and PAD, adjusting for age and sex. We also investigated whether this GRS was associated with recurrent vascular events using Cox regression, adjusting for age, sex, body mass index, type 2 diabetes, low-density lipoprotein-cholesterol, smoking, and hypertension. We found that the GRS was significantly associated with CAD (P = 1.31 × 10(-9)), IS (P = 0.030), and PAD (P = 6.93 × 10(-04)), but not with AAA (P = 0.057). The lead SNP at the 9p21 locus (rs4977574) was associated with all four vascular diseases (P < 4 × 10(-3)), illustrating the functional pleiotropy of this locus. The GRS was associated with recurrent risk of MI (P = 0.026), with a hazard ratio of 1.13 (95% CI 1.00-1.28) for individuals in the top quartile of the GRS distribution (n = 30 recurrent events) compared with those in the bottom quartile (n = 8 recurrent events). Finally, we found a significant positive relationship between the GRS and the number of vascular events (P = 3.26 × 10(-05)). CONCLUSIONS: These findings suggest that CAD/MI-associated risk alleles play an aetiological role in different types of atherosclerotic disease.

A genome-wide association study identifies a region at chromosome 12 as a potential susceptibility locus for restenosis after percutaneous coronary intervention.

Percutaneous coronary intervention (PCI) has become an effective therapy to treat obstructive coronary artery diseases (CAD). However, one of the major drawbacks of PCI is the occurrence of restenosis in 5-25% of all initially treated patients. Restenosis is defined as the re-narrowing of the lumen of the blood vessel, resulting in renewed symptoms and the need for repeated intervention. To identify genetic variants that are associated with restenosis, a genome-wide association study (GWAS) was conducted in 295 patients who developed restenosis (cases) and 571 who did not (controls) from the GENetic Determinants of Restenosis (GENDER) study. Analysis of ~550 000 single nucleotide polymorphisms (SNPs) in GENDER was followed by a replication phase in three independent case-control populations (533 cases and 3067 controls). A potential susceptibility locus for restenosis at chromosome 12, including rs10861032 (P(combined) = 1.11 × 10(-7)) and rs9804922 (P(combined) = 1.45 × 10(-6)), was identified in the GWAS and replication phase. In addition, both SNPs were also associated with coronary events (rs10861032, P(additive) = 0.005; rs9804922, P(additive) = 0.023) in a trial based cohort set of elderly patients with (enhanced risk of) CAD (PROSPER) and all-cause mortality in PROSPER (rs10861032, P(additive) = 0.007; rs9804922, P(additive) = 0.013) and GENDER (rs10861032, P(additive) = 0.005; rs9804922, P(additive) = 0.023). Further analysis suggests that this locus could be involved in regulatory functions.

Feasibility of Linear Irreversible Electroporation Ablation in the Coronary Sinus.

INTRODUCTION: Previous studies demonstrated that the coronary sinus (CS) is an important target for ablation in persistent atrial fibrillation. However, radiofrequency ablation in the CS is associated with coronary vessel damage and tamponade. Animal data suggest irreversible electroporation (IRE) ablation can be a safe ablation modality in vicinity of coronary arteries. We investigated the feasibility of IRE in the CS in a porcine model. METHODS: Ablation and pacing was performed in the CS in six pigs (weight 60-75 kg) using a modified 9-French steerable linear hexapolar Tip-Versatile Ablation Catheter. Pacing maneuvers were performed from distal to proximal segments of the CS to assess atrial capture thresholds before and after IRE application. IRE ablations were performed with 100 J IRE pulses. After 3-week survival animals were euthanized and histological sections from the CS were analyzed. RESULTS: A total of 27 IRE applications in six animals were performed. Mean peak voltage was 1509 ± 36 V, with a mean peak current of 22.9 ± 1.0 A. No complications occurred during procedure and 3-week survival. At 30 min post ablation 100% isolation was achieved in all animals. At 3 weeks follow-up pacing thresholds were significant higher as compared to baseline. Histological analysis showed transmural ablation lesions in muscular sleeves surrounding the CS. CONCLUSION: IRE ablation of the musculature along the CS using a multi-electrode catheter is feasible in a porcine model.

Prognostic implications of invasive hemodynamics during cardiac resynchronization therapy: Stroke work outperforms dP/dtmax.

Background: Invasive measurements of left ventricular (LV) hemodynamic performance can evaluate acute response to cardiac resynchronization therapy (CRT). Objective: The study sought to determine which metric, maximum rate of LV pressure rise (LV dP/dtmax) or LV stroke work (LVSW), is more strongly associated with long-term prognosis. Methods: CRT patients were prospectively included from 3 academic centers. Invasive pressure-volume loop measurements during implantation were performed, and LV dP/dtmax and LVSW were determined at baseline and during biventricular pacing (BVP) as well as their relative increase (%Δ). Hazard ratios (HRs) for the primary outcome of 8-year all-cause mortality were derived using Cox proportional hazards. The secondary endpoint was echocardiographic response, defined as 6-month LV end-systolic volume reduction ≥15%. Results: Paired data from 82 patients were analyzed (67% male; age 66 ± 9 years; QRS duration 158 ± 22 ms, median survival time 72 months). Survival was better when LVSW during BVP was ≥4400 mL∙mm Hg (HR 0.21, 95% CI 0.08-0.58, P < .003) or when ΔLVSW% was ≥10% (HR 0.22, 95% CI 0.08-0.65, P = .006). In multivariate analysis, following direct comparison of continuous measures of acute ΔLV dP/dtmax% and ΔLVSW%, only ΔLVSW% remained associated with the primary endpoint (HR 0.982 per percentage point, P = .028). In contrast to LV dP/dtmax (all P > .05), significant associations with echocardiographic response were found for stroke work during BVP (area under the receiver-operating characteristic curve 0.745, P = .001) and ΔLVSW% (area under the receiver-operating characteristic curve 0.803, P < .001). Conclusion: Stroke work, but not LV dP/dtmax, is consistently associated with long-term prognosis and response after CRT. Our results therefore favor the use of stroke work as the hemodynamic parameter to predict long-term outcome after CRT.

Importance of Systematic Diagnostic Testing in Idiopathic Ventricular Fibrillation: Results From the Dutch iVF Registry.

BACKGROUND: Idiopathic ventricular fibrillation (iVF) is a diagnosis of exclusion. Systematic diagnostic testing is important to exclude alternative causes for VF. The early use of "high yield" testing, including cardiac magnetic resonance (CMR), exercise testing, and sodium channel blocker provocation, has been increasingly recognized. OBJECTIVES: The purpose of this study was to investigate the importance and consistency of systematic diagnostic testing in iVF. METHODS: This study included 423 iVF patients from 11 large secondary and tertiary hospitals in the Netherlands. Clinical characteristics and diagnostic testing data were ascertained. RESULTS: IVF patients experienced the index event at a median age of 40 years (IQR: 28-52 years), and 61% were men. The median follow-up time was 6 years (IQR: 2-12 years). Over the years, "high yield" diagnostic tests were increasingly performed (mean 68% in 2000-2010 vs 75% in 2011-2021; P < 0.001). During follow-up, 38 patients (9%) originally labeled as iVF received an alternative diagnosis. Patients in whom "high-yield" diagnostic tests were consistently performed during the initial work-up received an alternative diagnosis less frequently during follow-up (HR: 0.439; 95% CI: 0.219-0.878; P = 0.020). Patients who received an alternative diagnosis during follow-up had a worse prognosis in terms of cardiac death (P = 0.012) with a trend toward more implantable cardioverter-defibrillator therapy (P = 0.055). CONCLUSIONS: Although adherence to (near) complete diagnostic testing in this population of iVF patients increased over the years, patients with iVF still undergo varying levels of diagnostic evaluation. The latter leads to initial underdiagnosis of alternative conditions and is associated with a worse prognosis. Our results underscore the importance of early systematic diagnostic assessment in patients with apparent iVF.

The circadian clock remains intact, but with dampened hormonal output in heart failure.

BACKGROUND: Circadian (24-h) rhythms are important regulators in physiology and disease, but systemic disease may disrupt circadian rhythmicity. Heart failure (HF) is a systemic disease affecting hormonal regulation. We investigate whether HF affects the rhythmic expression of melatonin and cortisol, main endocrine products of the central clock, and cardiac-specific troponin in patients. We corroborate the functionality of the peripheral clock directly in the organs of translational models, inaccessible in human participants. METHODS: We included 46 HF patients (71.7% male, median age of 60 years, NYHA class II (32.6%) or III (67.4%), ischemic cardiomyopathy (43.5%), comorbidities: diabetes 21.7%, atrial fibrillation 30.4%), and 24 matched controls. Blood was collected at seven time-points during a 24-h period (totalling 320 HF and 167 control samples) for melatonin, cortisol, and cardiac troponin T (cTnT) measurements after which circadian rhythms were assessed through cosinor analyses, both on the individual and the group level. Next, we analysed peripheral circadian clock functionality using cosinor analysis in male animal HF models: nocturnal mice and diurnal zebrafish, based on expression of core clock genes in heart, kidneys, and liver, every 4 h during a 24-h period in a light/darkness synchronised environment. FINDINGS: Melatonin and cortisol concentrations followed a physiological 24-h pattern in both patients and controls. For melatonin, acrophase occurred during the night for both groups, with significantly decreased amplitude (median 5.2 vs 8.8, P = 0.0001) and circadian variation ([maximum]/[minimum]) in heart failure patients. For cortisol, mesor showed a significant increase for HF patients (mean 331.9 vs 275.1, P = 0.017) with a difference of 56.8 (95% CI 10.3-103.3) again resulting in a relatively lower variation: median 3.9 vs 6.3 (P = 0.0058). A nocturnal blood pressure dip was absent in 77.8% of HF patients. Clock gene expression profiles (Bmal, Clock, Per, Cry) were similar and with expected phase relations in animal HF models and controls, demonstrating preserved peripheral clock functionality in HF. Furthermore, oscillations in diurnal zebrafish were expectedly in opposite phases to those of nocturnal mice. Concordantly, cTnT concentrations in HF patients revealed significant circadian oscillations. INTERPRETATION: Central clock output is dampened in HF patients while the molecular peripheral clock, as confirmed in animal models, remains intact. This emphasises the importance of taking timing into account in research and therapy for HF, setting the stage for another dimension of diagnostic, prognostic and therapeutic approaches. FUNDING: Hartstichting.

Long-term outcome of cardiac pacing in octogenarians and nonagenarians.

AIMS: The number of patients >80 years receiving pacemakers (PMs) is increasing. Little is known about survival and complications in this specific subgroup. We aim to determine predictors of long-term survival. METHODS AND RESULTS: Pacemaker-related complications and death occurring in patients receiving a first PM for conventional bradycardia indications were systematically documented (the FollowPace registry). This report describes 481 patients ≥80 years during a mean follow-up of 5.8 (SD 1.2) years. Within 2 months 54 PM complications occurred in 47 patients (9.8%). During follow-up, 35 adverse PM events were reported in 33 patients (6.9%). Complication rates in patients ≥80 years were comparable with those for patients <80 years. Survival rates were 86, 75, and 49% after 1, 2, and 5 years, respectively, and were comparable with survival for age- and sex-matched controls from the general Dutch population. Most patients died of non-cardiac causes. Age at the time of implantation, male gender, the presence of congestive heart failure, coronary pathology, and diabetes mellitus were independent predictors of all-cause mortality. CONCLUSION: This large study of long-term cardiac pacing for bradycardia in octogenarians and nonagenarians showed a cumulative 5-year survival of ~50%, which compares with that of age- and sex-matched controls. These data suggest a beneficial impact of bradycardia pacing, restoring life expectancy to previous levels. The occurrence of PM complications during long-term follow-up is not infrequent with 18.1% of patients experiencing a PM-related complication during a mean of 5.8 years follow-up. The complication rate was not higher than in younger PM patients.

Atherosclerotic renal artery stenosis is prevalent in cardiorenal patients but not associated with left ventricular function and myocardial fibrosis as assessed by cardiac magnetic resonance imaging.

BACKGROUND: Atherosclerotic renal artery stenosis (ARAS) is common in cardiovascular diseases and associated with hypertension, renal dysfunction and/or heart failure. There is a paucity of data about the prevalence and the role of ARAS in the pathophysiology of combined chronic heart failure (CHF) and chronic kidney disease (CKD). We investigated the prevalence in patients with combined CHF/CKD and its association with renal function, cardiac dysfunction and the presence and extent of myocardial fibrosis. METHODS: The EPOCARES study (ClinTrialsNCT00356733) investigates the role of erythropoietin in anaemic patients with combined CHF/CKD. Eligible subjects underwent combined cardiac magnetic resonance imaging (cMRI), including late gadolinium enhancement, with magnetic resonance angiography of the renal arteries (MRA). RESULTS: MR study was performed in 37 patients (median age 74 years, eGFR 37.4 ± 15.6 ml/min, left ventricular ejection fraction (LVEF) 43.3 ± 11.2%), of which 21 (56.8%) had ARAS (defined as stenosis >50%). Of these 21 subjects, 8 (21.6%) had more severe ARAS >70% and 8 (21.6%) had a bilateral ARAS >50% (or previous bilateral PTA). There were no differences in age, NT-proBNP levels and medication profile between patients with ARAS versus those without. Renal function declined with the severity of ARAS (p = 0.03), although this was not significantly different between patients with ARAS versus those without. Diabetes mellitus was more prevalent in patients without ARAS (56.3%) against those with ARAS (23.8%) (p = 0.04). The presence and extent of late gadolinium enhancement, depicting myocardial fibrosis, did not differ (p = 0.80), nor did end diastolic volume (p = 0.60), left ventricular mass index (p = 0.11) or LVEF (p = 0.15). Neither was there a difference in the presence of an ischemic pattern of late enhancement in patients with ARAS versus those without. CONCLUSIONS: ARAS is prevalent in combined CHF/CKD and its severity is associated with a decline in renal function. However, its presence does not correlate with a worse LVEF, a higher left ventricular mass or with the presence and extent of myocardial fibrosis. Further research is required for the role of ARAS in the pathophysiology of combined chronic heart and renal failure.

Safety and feasibility study of non-invasive robot-assisted high-intensity focused ultrasound therapy for the treatment of atherosclerotic plaques in the femoral artery: protocol for a pilot study.

INTRODUCTION: Peripheral arterial disease (PAD) is an atherosclerotic disease leading to stenosis and/or occlusion of the arterial circulation of the lower extremities. The currently available revascularisation methods have an acceptable initial success rate, but the long-term patency is limited, while surgical revascularisation is associated with a relatively high perioperative risk. This urges the need for development of less invasive and more effective treatment modalities. This protocol article describes a study investigating a new non-invasive technique that uses robot assisted high-intensity focused ultrasound (HIFU) to treat atherosclerosis in the femoral artery. METHODS AND ANALYSIS: A pilot study is currently performed in 15 symptomatic patients with PAD with a significant stenosis in the common femoral and/or proximal superficial femoral artery. All patients will be treated with the dual-mode ultrasound array system to deliver imaging-guided HIFU to the atherosclerotic plaque. Safety and feasibility are the primary objectives assessed by the technical feasibility of this therapy and the 30-day major complication rate as primary endpoints. Secondary endpoints are angiographic and clinical success and quality of life. ETHICS AND DISSEMINATION: Ethical approval for this study was obtained in 2019 from the Medical Ethics Committee of the University Medical Center Utrecht, the Netherlands. Data will be presented at national and international conferences and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NL7564.

Multielectrode Contact Measurement Can Improve Long-Term Outcome of Pulmonary Vein Isolation Using Circular Single-Pulse Electroporation Ablation.

BACKGROUND: Irreversible electroporation (IRE) ablation is generally performed with multielectrode catheters. Electrode-tissue contact is an important predictor for the success of pulmonary vein (PV) isolation; however, contact force is difficult to measure with multielectrode ablation catheters. In a preclinical study, we assessed the feasibility of a multielectrode impedance system (MEIS) as a predictor of long-term success of PV isolation. In addition, we present the first-in-human clinical experience with MEIS. METHODS: In 10 pigs, one PV was ablated based on impedance (MEIS group), and the other PV was solely based on local electrogram information (EP group). IRE ablations were performed at 200 J. After 3 months, recurrence of conduction was assessed. Subsequently, in 30 patients undergoing PV isolation with IRE, MEIS was evaluated and MEIS contact values were compared to local electrograms. RESULTS: In the porcine study, 43 IRE applications were delivered in 19 PVs. Acutely, no reconnections were observed in either group. After 3 months, 0 versus 3 (P=0.21) PVs showed conduction recurrence in the MEIS and EP groups, respectively. Results from the clinical study showed a significant linear relation was found between mean MEIS value and bipolar dV/dt (r2=0.49, P<0.001), with a slope of 20.6 mV/s per Ohm. CONCLUSIONS: Data from the animal study suggest that MEIS values predict effective IRE applications. For the long-term success of electrical PV isolation with circular IRE applications, no significant difference in efficacy was found between ablation based on the measurement of electrode interface impedance and ablation using the classical EP approach for determining electrode-tissue contact. Experiences of the first clinical use of MEIS were promising and serve as an important basis for future research.

Determinants of red cell distribution width (RDW) in cardiorenal patients: RDW is not related to erythropoietin resistance.

BACKGROUND: Studies have shown that red cell distribution width (RDW) is related to outcome in chronic heart failure (CHF). The pathophysiological process is unknown. We studied the relationship between RDW and erythropoietin (EPO) resistance, and related factors such as erythropoietic activity, functional iron availability and hepcidin. METHODS AND RESULTS: In the Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome (EPOCARES) study, which investigates the role of EPO in 54 iron-supplemented anemic patients with CHF and chronic kidney disease (CKD) (n = 35 treated with 50 IU/kg/wk Epopoetin beta, n = 19 control), RDW was not associated with EPO resistance. We defined EPO resistance by EPO levels (r = 0.12, P = .42), the observed/predicted log EPO ratio (r = 0.12, P = .42), the increase in reticulocytes after 2 weeks of EPO treatment (r = -0.18, P = .31), and the increase of hemoglobin after 6 months of EPO treatment (r = 0.26, P = .35). However, RDW was negatively correlated with functional iron availability (reticulocyte hemoglobin content, r = -0.48, P < .001, and transferrin saturation, r = -0.39, P = .005) and positively with erythropoietic activity (soluble transferrin receptor, r = 0.48, P < .001, immature reticulocyte fraction, r = 0.36, P = .01) and positively with interleukin-6 (r = 0.48, P < .001). No correlation existed between hepcidin-25 and RDW. CONCLUSIONS: EPO resistance was not associated with RDW. RDW was associated with functional iron availability, erythropoietic activity, and interleukin-6 in anemic patients with CHF and CKD.

Toll-like receptor 2 and 4 stimulation elicits an enhanced inflammatory response in human obese patients with atherosclerosis.

The innate immune response elicited by activation of TLRs (Toll-like receptors) plays an important role in the pathogenesis of atherosclerosis. We hypothesized that cardiovascular risk factors are associated with the activation status of the innate immune system. We therefore assessed the responsiveness of TLRs on circulating cells in two groups of patients with established atherosclerosis and related this to the presence of cardiovascular risk factors. TNF (tumour necrosis factor)-α release induced by TLR2 and TLR4 activation was measured in patients with established coronary [PCI (percutaneous coronary intervention) study, n=78] or carotid artery disease [CEA (carotid endarterectomy) study, n=104], by stimulating whole blood samples with lipopolysaccharide (TLR4 ligand) and Pam3CSK4 [tripalmitoylcysteinylseryl-(lysyl)4; TLR2 ligand]. As an early activation marker, CD11b expression was measured by flow cytometry on CD14+ cells. Obesity was the 'only' risk factor that correlated with the TLR response. In both studies, obese patients had significantly higher TNF-α levels after stimulation of TLR2 compared with non-obese patients [16.9 (7.7-49.4) compared with 7.5 (1.5-19.2) pg/ml (P=0.008) in coronary artery disease and 14.6 (8.1-28.4) compared with 9.5 (6.1-15.7) pg/ml (P=0.015) in carotid artery disease; values are medians (interquartile range)]. Similar results were obtained following TLR4 stimulation. The enhanced inflammatory state in obese patients was also confirmed by a significant increased expression of the activation marker CD11b on circulating monocytes. In conclusion, obesity is associated with an enhanced TLR response in patients suffering from established atherosclerotic disease.