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Background and AimsGhrelin is an endogenous appetite-stimulating peptide hormone with potential cardiovascular benefits. Effects of acylated (activated) ghrelin were assessed in patients with heart failure and reduced ejection fraction (HFrEF) and in ex vivo mouse cardiomyocytes.Methods and resultsIn a randomized placebo-controlled double-blind trial, 31 patients with chronic HFrEF were randomized to synthetic human acyl ghrelin (0.1 µg/kg/min) or placebo intravenously over 120 min. The primary outcome was change in cardiac output (CO). Isolated mouse cardiomyocytes were treated with acyl ghrelin and fractional shortening and calcium transients were assessed. Acyl ghrelin but not placebo increased cardiac output (acyl ghrelin: 4.08 ± 1.15 to 5.23 ± 1.98 L/min; placebo: 4.26 ± 1.23 to 4.11 ± 1.99 L/min, P < 0.001). Acyl ghrelin caused a significant increase in stroke volume and nominal increases in left ventricular ejection fraction and segmental longitudinal strain and tricuspid annular plane systolic excursion. There were no effects on blood pressure, arrhythmias, or ischaemia. Heart rate decreased nominally (acyl ghrelin: 71 ± 11 to 67 ± 11 b.p.m.; placebo 69 ± 8 to 68 ± 10 b.p.m.). In cardiomyocytes, acyl ghrelin increased fractional shortening, did not affect cellular Ca2+ transients, and reduced troponin I phosphorylation. The increase in fractional shortening and reduction in troponin I phosphorylation was blocked by the acyl ghrelin antagonist D-Lys 3.ConclusionIn patients with HFrEF, acyl ghrelin increased cardiac output without causing hypotension, tachycardia, arrhythmia, or ischaemia. In isolated cardiomyocytes, acyl ghrelin increased contractility independently of preload and afterload and without Ca2+ mobilization, which may explain the lack of clinical side effects. Ghrelin treatment should be explored in additional randomized trials.Clinical Trial RegistrationClinicalTrials.gov Identifier: NCT05277415

Background Congenitally corrected transposition of the great arteries (ccTGA) is a rare congenital heart anomaly with atrioventricular and ventriculoarterial discordance that is often associated with other cardiac and coronary artery anomalies. Here, we report a case of a patient with ccTGA and non-ST elevation myocardial infarction (NSTEMI) with challenging coronary anatomy that was treated with stress-perfusion cardiac magnetic resonance imaging (spCMR) guided percutaneous coronary intervention (PCI). Case summary A 46-year-old male smoker with ccTGA, dyslipidaemia, diabetes Type 2 managed with dietary restrictions and a family history of premature myocardial infarction, presented with typical chest pain, elevated cardiac troponin levels and ECG-changes indicative of ischaemia. The patient was diagnosed with NSTEMI and underwent initial urgent coronary angiography (CA) without apparent significant stenosis, although the right coronary artery (RCA) could not be selectively investigated. The patient had coronary anatomy 1R-2LCX according to the Leiden convention, which is the usual anatomy in patients with ccTGA. Despite this, CA was challenging due to the different anatomy compared with individuals with normally positioned great vessels. The patient remained highly symptomatic with chest pain at moderate exertion. To improve identification of the anatomic location and extent of ischaemia, we performed spCMR with adenosine. This revealed a limited septal infarction (likely embolic) in the right ventricle and reversible ischaemia in two inferior right ventricular segments. A second angiography, selectively investigating RCA demonstrated a significant stenosis in the distal RCA that was successfully treated with a drug-eluting stent. Fractional flow reserve (FFR) measurements of the left coronary arteries demonstrated hemodynamically non-significant stenosis. The patient’s symptoms resolved, and he remained asymptomatic at one month follow-up. Discussion This ccTGA patient had multiple risk factors for coronary artery disease and presented with NSTEMI. Diagnosis and treatment were challenging due to complex cardiac anatomy and associated different origins of the coronary arteries. We highlight the importance of careful evaluation of the coronary anatomy and functional testing using for example spCMR and FFR to target the culprit coronary vessel(s) in ccTGA complicated by NSTEMI.

Aims: To test the hypothesis that spinal cord stimulation (SCS) acutely improves heart rate variability (HRV) and baroreceptor sensitivity (BRS) in patients with heart failure (HF). Methods: SCS (15 minutes) was delivered in four different settings: 90% of maximal tolerated stimulation amplitude (MTA) targeting the T1-T4 spinal cord segments (SCS90T1-4), 60% of MTA (SCS60T1-4), 90% of MTA with cranial (SCS90CR) and caudal (SCS90CA) electrode configuration. HRV and BRS were recorded continuously and stimulation was compared to device off. Results: Fifteen HF patients were included. SCS90T1-4 did not change the standard deviation of intervals between normal beats (SDNN, p = 0.90), BRS (p = 0.55) or other HRV parameters. In patients with baseline SDNN

Background With ~ 50 million individuals suffering from post-COVID condition (PCC), low health related quality of life (HRQoL) is a vast problem. Common symptoms of PCC, that persists 3 months from the onset of COVID-19 are fatigue, shortness of breath and cognitive dysfunction. No effective treatment options have been widely adopted in clinical practice. Hyperbaric oxygen (HBO2) is a candidate drug. Methods The objective of this interim analysis is to describe our cohort and evaluate the safety of HBO2 for post covid condition. In an ongoing randomised, placebo-controlled, double blind, clinical trial, 20 previously healthy subjects with PCC were assigned to HBO2 or placebo. Primary endpoints are physical domains in RAND-36; Physical functioning (PF) and Role Physical (RP) at 13 weeks. Secondary endpoints include objective physical tests. Safety endpoints are occurrence, frequency, and seriousness of Adverse Events (AEs). An independent data safety monitoring board (DSMB) reviewed unblinded data. The trial complies with Good Clinical Practice. Safety endpoints are evaluated descriptively. Comparisons against norm data was done using t-test. Results Twenty subjects were randomised, they had very low HRQoL compared to norm data. Mean (SD) PF 31.75 (19.55) (95% Confidence interval; 22.60–40.90) vs 83.5 (23.9) p Conclusions An (unexpectedly) high frequency of AEs was observed but the DSMB assessed HBO2 to have a favourable safety profile. Our data may help other researchers in designing trials. Trial Registration ClinicalTrials.gov: NCT04842448. Registered 13 April 2021, https://clinicaltrials.gov/ct2/show/NCT04842448. EudraCT: 2021-000764-30. Registered 21 May 2021, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-000764-30/SE

IntroductionLong COVID, where symptoms persist 12 weeks after the initial SARS-CoV-2-infection, is a substantial problem for individuals and society in the surge of the pandemic. Common symptoms are fatigue, post-exertional malaise, and cognitive dysfunction. There is currently no effective treatment, and the underlying mechanisms are unknown although several hypotheses exist, with chronic inflammation as a common denominator. In prospective studies, hyperbaric oxygen therapy (HBOT) has been suggested to be effective for the treatment of similar syndromes such as chronic fatigue syndrome and fibromyalgia. A case series has suggested positive effects of HBOT in Long COVID. This randomised placebo-controlled clinical trial will explore HBOT as a potential treatment for Long COVID. The primary objective is to evaluate if HBOT improves health related quality of life (HRQoL) for patients with Long COVID compared to placebo/sham. The main secondary objectives are to evaluate whether HBOT improves endothelial function, objective physical performance, and short term HRQoL.Methods and AnalysisA randomised, placebo-controlled, double-blind, phase II clinical trial in 80 previously healthy subjects debilitated due to Long COVID, with low HRQoL. Clinical data, HRQoL- questionnaires, blood samples, objective tests and activity meter data will be collected at baseline. Subjects will be randomised to a maximum of 10 treatments with hyperbaric oxygen or sham treatment over six weeks. Assessments for safety and efficacy will be performed at six, 13, 26 and 52 weeks, with the primary endpoint (physical domains in RAND-36) and main secondary endpoints defined at 13 weeks after baseline. Data will be reviewed by an independent Data Safety Monitoring Board.Ethics and DisseminationThe trial is approved by The Swedish National Institutional Review Board (2021-02634) and the Swedish Medical Product Agency (5.1-2020-36673). Positive, negative, and inconclusive results will be published in peer-reviewed scientific journals with open access.Trial RegistrationNCT04842448. EudraCT: 2021-000764-30Strengths and limitations of this trialStrengthsRandomised placebo-controlled, double-blind, parallel groups, clinical trial in compliance with ICH-GCPEvaluation of safety and efficacy, including objective and explanatory endpointsIndependent Data Safety Monitoring Board (DSMB)LimitationsNew syndrome with unknown mechanismsPower calculation is based on similar syndromesSelection bias as patients are enrolled from the same post-COVID clinic

Aims The biological mechanisms conveying the salutary effects of cardiac resynchronization therapy in heart failure remain elusive. We have recently developed a mouse model of heart failure with dyssynchrony/resynchronization. The aim of this study was to characterize regional left ventricular heterogeneity in protein expression comparing early (septum) and late (lateral) activated left ventricular wall segments in synchronous (SHF), dyssynchronous (DHF), and resynchronized heart failure (RHF). Methods and results Mice subjected to ischaemia/reperfusion were divided into three groups: sinus rhythm for 4 weeks (SHF), right ventricular pacing for 4 weeks (DHF), and right ventricular pacing for 2 weeks and 2 weeks of sinus rhythm (RHF). Relative concentrations of 92 proteins from septal and lateral left ventricular wall segments (n = 10 per group) were compared within each group. We also analysed the effect of DHF vs. SHF and RHF vs. DHF on protein expression pattern comparing the same left ventricular segments between the groups. Proteins with significantly differential expression between left ventricular segments were analysed for protein–protein correlations, protein–protein interactions, and biological and signalling pathways. Eight proteins were significantly down‐regulated in the late activated (compared with early activated) lateral wall uniquely in RHF (P

Post-acute sequelae of SARS-CoV-2 (PASC), or long COVID syndrome, is emerging as a major health issue in patients with previous SARS-CoV-2 infection. Symptoms commonly experienced by patients include fatigue, palpitations, chest pain, dyspnea, reduced exercise tolerance, and “brain fog”. Additionally, symptoms of orthostatic intolerance and syncope suggest the involvement of the autonomic nervous system. Signs of cardiovascular autonomic dysfunction appear to be common in PASC and are similar to those observed in postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. In this review, we report on the epidemiology of PASC, discuss current evidence and possible mechanisms underpinning the dysregulation of the autonomic nervous system, and suggest nonpharmacological and pharmacological interventions to treat and relieve symptoms of PASC-associated dysautonomia.

In this paper we highlight the presence of tachycardia in post-acute COVID-19 syndrome by introducing a new label for this phenomenon-post-COVID-19 tachycardia syndrome-and argue that this constitutes a phenotype or sub-syndrome in post-acute COVID-19 syndrome. We also discuss epidemiology, putative mechanisms, treatment options, and future research directions in this novel clinical syndrome.

Aims: To assess the prevalence of indication for cardiac resynchronization therapy (CRT) in patients with heart failure (HF) and reduced ejection fraction (EF) when recommendations from evolving Eu ...

The objective of this pilot study was to describe the impact of paced heart rate on left ventricular (LV) mechanical dyssynchrony in synchronous compared to dyssynchronous pacing modes in patients with heart failure.Echocardiography was performed in 14 cardiac resynchronization therapy (CRT) patients at paced heart rates of 70 and 90 bpm in synchronous- (CRT), and dyssynchronous (atrial pacing + wide QRS activation) pacing modes. LV dyssynchrony was quantified using the 12-segment standard deviation model (Ts-SD) derived from Tissue Doppler Imaging. In addition, cardiac cycle intervals were assessed using cardiac state diagrams and stroke volume (SV) and filling pressure were estimated.Ts-SD decreased significantly with CRT at 90 bpm (25 ± 12 ms) compared to 70 bpm (35 ± 15 ms, p = .01), but remained unchanged with atrial pacing at different paced heart rates (p = .96). The paced heart rate dependent reduction in Ts-SD was consistent when Ts-SD was indexed to average Ts and systolic time interval. Cardiac state diagram derived analysis of cardiac cycle intervals demonstrated a significant reduction of the pre-ejection interval and an increase in diastole with CRT compared to atrial pacing. SV was maintained at the higher paced heart rate with CRT pacing but decreased with atrial pacing.Due to the small sample size in this pilot study general and firm conclusions are difficult to render. However, the data suggest that pacing at higher heart rates acutely reduces remaining LV dyssynchrony during CRT, but not during atrial pacing with dyssynchronous ventricular activation. These results need confirmation in a larger patient cohort.

Background Spinal cord stimulation (SCS) reduces sympathetic activity in animal models of heart failure with reduced ejection fraction (HF) but limited data exist of SCS in patients with HF. The aim of the present study was to test the primary hypothesis that SCS reduces cardiac sympathetic nerve activity in HF patients. Secondary hypotheses were that SCS improves left ventricular function and dimension, exercise capacity, and clinical variables relevant to HF. Methods HF patients with a SCS device previously participating in the DEFEAT-HF trial were included in this crossover study with 6-week intervention periods (SCS-ON and SCS-OFF). SCS (50 Hz, 210-μs pulse duration, aiming at T2–T4 segments) was delivered for 12 hours daily. Indices of myocardial sympathetic neuronal function (heart-to-mediastinum ratio, HMR) and activity (washout rate, WR) were assessed using 123I-metaiodobenzylguanidine (MIBG) scintigraphy. Echocardiography, exercise testing, and clinical data collection were also performed. Results We included 13 patients (65.3 ± 8.0 years, nine males) and MIBG scintigraphy data were available in 10. HMR was not different comparing SCS-ON (1.37 ± 0.16) and SCS-OFF (1.41 ± 0.21, P = 0.46). WR was also unchanged comparing SCS-ON (41.5 ± 5.3) and SCS-OFF (39.1 ± 5.8, P = 0.30). Similarly, average New York Heart Association class (2.4 ± 0.5 vs 2.3 ± 0.6, P = 0.34), quality of life score (24 ± 16 vs 24 ± 16, P = 0.94), and left ventricular dimension and function as well as exercise capacity were all unchanged comparing SCS-ON and SCS-OFF. Conclusion In patients with HF, SCS (12 hours daily, targeting the T2–T4 segments of the spinal cord) does not appear to influence cardiac sympathetic neuronal activity or function as assessed by MIBG scintigraphy.

Background: Most randomized trials on implantable cardioverter-defibrillator (ICD) use for primary prevention of sudden cardiac death in heart failure with reduced ejection fraction enrolled patients >20 years ago. We investigated the association between ICD use and all-cause mortality in a contemporary heart failure with reduced ejection fraction cohort and examined relevant subgroups. Methods: Patients from the Swedish Heart Failure Registry fulfilling the European Society of Cardiology criteria for primary-prevention ICD were included. The association between ICD use and 1-year and 5-year all-cause and cardiovascular (CV) mortality was assessed by Cox regression models in a 1:1 propensity score–matched cohort and in prespecified subgroups. Results: Of 16 702 eligible patients, only 1599 (10%) had an ICD. After matching, 1305 ICD recipients were compared with 1305 nonrecipients. ICD use was associated with a reduction in all-cause mortality risk within 1 year (hazard ratio, 0.73 [95% CI, 0.60–0.90]) and 5 years (hazard ratio, 0.88 [95% CI, 0.78–0.99]). Results were consistent in all subgroups including patients with versus without ischemic heart disease, men versus women, those aged Conclusions: In a contemporary heart failure with reduced ejection fraction population, ICD for primary prevention was underused, although it was associated with reduced short- and long-term all-cause mortality. This association was consistent across all the investigated subgroups. These results call for better implementation of ICD therapy.

Background: The mouse is the most widely used mammal in experimental biology. Although many clinically relevant in vivo cardiac stressors are used, one that has eluded translation is long-term cardiac pacing. Here, we present the first method to chronically simulate and simultaneously record cardiac electrical activity in conscious mobile mice. We then apply it to study right ventricular pacing induced electromechanical dyssynchrony and its reversal (resynchronization). Methods and Results: The method includes a custom implantable bipolar stimulation and recording lead and flexible external conduit and electrical micro-commutator linked to a pulse generator/recorder. This achieved continuous pacing for at least 1 month in 77% of implants. Mice were then subjected to cardiac ischemia/reperfusion injury to depress heart function, followed by 4 weeks pacing at the right ventricle (dyssynchrony), right atrium (synchrony), or for 2 weeks right ventricle and then 2 weeks normal sinus (resynchronization). Right ventricular pacing–induced dyssynchrony substantially reduced heart and myocyte function compared with the other groups, increased gene expression heterogeneity (>10 fold) comparing septum to lateral walls, and enhanced growth and metabolic kinase activity in the late-contracting lateral wall. This was ameliorated by restoring contractile synchronization. Conclusions: The new method to chronically pace conscious mice yields stable atrial and ventricular capture and a means to dissect basic mechanisms of electromechanical physiology and therapy. The data on dyssynchrony and resynchronization in ischemia/reperfusion hearts is the most comprehensive to date in ischemic heart disease, and its similarities to nonischemic canine results support the translational utility of the mouse.

Aims Symptom severity assessed by NYHA functional class and QRS duration are essential criteria for selection of heart failure (HF) patients for CRT. This study assessed the relationship between NYHA class, QRS duration, and survival in a nationwide HF registry. Methods and results We studied 13 423 patients with HF in NYHA class II–IV and LVEF

Current optimization of atrioventricular (AV) and interventricular (VV) intervals in cardiac resynchronization therapy (CRT) is time consuming and subject to noise. We aimed to prove the principle that the best hemodynamic effect of CRT is achieved by cancelation of opposing electrical forces, detectable from the QRS morphology in the 3D vectorcardiogram (VCG). Different degrees of left (LV) and right ventricular (RV) pre-excitation were induced, using variation in AV intervals during LV pacing in 20 patients with left bundle branch block (LBBB) and variation in VV intervals during biventricular pacing in 18 patients with complete AV block or atrial fibrillation. The smallest QRS vector area identified stimulation intervals with minimal systolic stretch (median difference [IQR] 20 ms [-20, 20 ms] and maximal hemodynamic response (10 ms [-20, 40 ms]). Reliability of VCG measurements was superior to hemodynamic measurements. This study proves the principle that VCG analysis may allow easy and reliable optimization of stimulation intervals in CRT patients.

Aims To test the hypothesis that acute increased biventricularly (BiV) paced heart rate (pHR) results in decreased muscle sympathetic nerve activity (MSNA), and that dyssynchronous pacing (AAI) attenuates this effect, in heart failure patients receiving cardiac resynchronization therapy (CRT). Methods and results Fourteen CRT patients (NYHA II–III, 12 males, mean EF 28 ± 14%) were recruited. Three different pHRs (50–90 b.p.m.) were randomly programmed in BiV- and AAI-pacing modes. Muscle sympathetic nerve activity (total sympathetic nerve activity/min (units) and number of bursts/100 RR) were recorded from the peroneal nerve using a microelectrode. In addition, cardiac output (CO) and mean blood pressure (mBP) were measured. With BiV pacing, the total MSNA/min was lower at 70 b.p.m. (−7 ± 21%, P = 0.18) and 90 b.p.m. (−29 ± 18%, P = 0.01) compared with at 50 b.p.m. (280 ± 180 U). Similarly, bursts/100RR decreased with increased BiV pHR. Cardiac output (3.7 L/min at 50 b.p.m., +12 ± 12% at 70 b.p.m., and +18 ± 19% at 90 b.p.m.) and mBP (78 ± 11 mmHg at 50 b.p.m., +6 ± 6% at 70 b.p.m. and +11 ± 8% at 90 b.p.m.) increased significantly at elevated pHRs in BiV-pacing mode. The effect on MSNA, CO, and mBP was less pronounced in AAImode but we found no significant differences between the pacing modes. Conclusion Increased pHR acutely reduces MSNA and improves haemodynamics in HF patients treated with CRT with no evident differences between BiV- and AAI-pacing modes. Further studies are warranted to guide the programming of basic pHR in CRT patients.

Objectives The purpose of this study was to evaluate simple criteria for referral of patients from the general practitioner to a heart failure (HF) center. Background In advanced HF, the criteria for heart transplantation, left ventricular assist device, and palliative care are well known among HF specialists, but criteria for referral to an advanced HF center have not been developed for generalists. Methods We assessed observed and expected all-cause mortality in 10,062 patients with New York Heart Association (NYHA) functional class III to IV HF and ejection fraction Results In NYHA functional class III to IV and age groups ≤65 years, 66 to 80 years, and >80 years, there were 2,247, 4,632, and 3,183 patients, with 1-year observed versus expected survivals of 90% versus 99%, 79% versus 97%, and 61% versus 89%, respectively. In the age ≤80 years group, the presence of 1, 2, or 3 to 5 of these risk factors conferred an independent hazard ratio for all-cause mortality of 1.40, 2.30, and 4.07, and a 1-year survival of 79%, 60%, and 39%, respectively (p Conclusions In patients ≤80 years of age with NYHA functional class III to IV HF and ejection fraction

Aims Cardiac resynchronization therapy (CRT) and primary prophylactic implantable cardioverter-defibrillators (ICDs) are underutilized in heart failure (HF). This may originate from an unawareness of device benefits and indications among physicians responsible for HF care and referral. We aimed to describe the awareness of indications for device therapy in a generalized sample of Swedish physicians. Methods and results A randomly selected sample of Swedish physicians specializing in cardiology, internal medicine, and family medicine and interns (5% of eligible physicians, n = 519) was invited to fill in a 23-item survey, testing their awareness of indications for device therapy and, as comparison, pharmacological therapy. Acceptable awareness (AA) of CRT indication was predefined as recognizing that a left bundle branch block on ECG warrants further evaluation for CRT. Acceptable awareness of ICD indication was predefined as recognizing that ejection fraction ≤35% alone, without a history of ventricular tachycardia, is sufficient to warrant a primary prophylactic ICD. The response rate was 37% ( n = 168). Overall, 32% met AA of CRT indication, and significantly less (15%) met AA of ICD indication. Specialist certification in cardiology was the only significant predictor for AA [odds ratio (95% confidence interval): 37 (10–138)]. However, even among cardiologists, awareness of ICD indications was low (61% with AA). Guideline-recommended indications for pharmacological therapy were conceived significantly better ( P = 0.02) than device therapy [median (interquartile range) of correct answers: 50% (33–50) compared with 36% (14–57)]. Conclusions The study identified an important and substantial awareness gap in the medical community that may explain some of the previously reported low referral rates and utilization of device therapy in HF.

Spinal cord stimulation (SCS) reduces sympathetic activity in animal models of heart failure with reduced ejection fraction (HF) but limited data exist of SCS in patients with HF. The aim of the present study was to test the primary hypothesis that SCS reduces cardiac sympathetic nerve activity in HF patients. Secondary hypotheses were that SCS improves left ventricular function and dimension, exercise capacity, and clinical variables relevant to HF.HF patients with a SCS device previously participating in the DEFEAT-HF trial were included in this crossover study with 6-week intervention periods (SCS-ON and SCS-OFF). SCS (50 Hz, 210-μs pulse duration, aiming at T2-T4 segments) was delivered for 12 hours daily. Indices of myocardial sympathetic neuronal function (heart-to-mediastinum ratio, HMR) and activity (washout rate, WR) were assessed usingWe included 13 patients (65.3 ± 8.0 years, nine males) and MIBG scintigraphy data were available in 10. HMR was not different comparing SCS-ON (1.37 ± 0.16) and SCS-OFF (1.41 ± 0.21, P = 0.46). WR was also unchanged comparing SCS-ON (41.5 ± 5.3) and SCS-OFF (39.1 ± 5.8, P = 0.30). Similarly, average New York Heart Association class (2.4 ± 0.5 vs 2.3 ± 0.6, P = 0.34), quality of life score (24 ± 16 vs 24 ± 16, P = 0.94), and left ventricular dimension and function as well as exercise capacity were all unchanged comparing SCS-ON and SCS-OFF.In patients with HF, SCS (12 hours daily, targeting the T2-T4 segments of the spinal cord) does not appear to influence cardiac sympathetic neuronal activity or function as assessed by MIBG scintigraphy.

To assess the prevalence of indication for cardiac resynchronization therapy (CRT) in patients with heart failure (HF) and reduced ejection fraction (EF) when recommendations from evolving European Society of Cardiology (ESC) guidelines are considered.Unique patients (n=17 193) with EF ≤39% and key data available for evaluation of CRT indication from the Swedish HF Registry were included. Indication for CRT was defined as either CRT implanted or CRT device absent but fulfilling criteria for class I-IIa recommendations in ESC guidelines published between 2005/2007 and 2016. Prevalence was calculated as the ratio of patients with CRT indication to the study population. The prevalence of CRT indication increased from 24.5% when the 2005/2007 ESC guidelines were considered to a peak of 30.0% when the 2013 ESC guidelines were considered (P0.001, 22.4% relative increase). Compared to the 2013 ESC guidelines, the prevalence declined significantly when the 2016 ESC guidelines were used as determinant for CRT indication (26.8%, 10.7% relative reduction, P0.001). Actual CRT utilization was 6.8%.Among patients with HF and reduced EF, the prevalence of CRT indication increased significantly comparing recommendations from ESC guidelines published between 2005/2007 and 2013, but then declined when the 2016 ESC guidelines were considered. The 2005-2013 increase may reflect the expansion of documented CRT efficacy to New York Heart Association class II, whereas the subsequent drop likely results from the more stringent criteria for QRS duration in the 2016 ESC guidelines. Actual CRT utilization is lower than indicated, regardless of which guidelines are considered.

Aims The impact of different basic paced heart rates (pHRs) in patients receiving cardiac resynchronization therapy (CRT) remains largely unknown. The aim of the present study was to investigate the haemodynamic effects of different pHRs (60 or 80 b.p.m.), using an implanted haemodynamic monitor (IHM), during a 2-week period in ambulatory CRT patients. Methods and results Ten CRT patients received an IHM (Chronicle®, Medtronic Inc.) to continuously record right ventricular systolic (RVSP) and diastolic (RVDP) pressure, as well as estimated pulmonary artery diastolic pressure (ePAD) during a 2-week period at two basic pHR programming (60 and 80 b.p.m.). Cardiac output (CO) was calculated using a validated IHM algorithm. At the end of each period, 6 min walk test (6MWT), quality of life (QoL), and plasma levels of brain natriuretic peptide (BNP) were also assessed. Pacing at 80 b.p.m. significantly reduced the 2-week average of ePAD compared with 60 b.p.m. (23.4 ± 6.2 vs. 25.1 ± 6.5 mmHg, P = 0.03), whereas CO was increased (4.5 ± 1.3 vs. 4.2 ± 1.4 L/min; P = 0.01). Similarly ePAD, RVSP, and RVDP were significantly lower with a pHR of 80 b.p.m. ( P < 0.05). The 6MWT, QoL score, and BNP were not affected by the pHR. Conclusion In CRT patients, a basic pHR of 80 b.p.m. compared with 60 b.p.m. reduces filling pressures and increases CO during a 2-week period of ambulatory living. This suggests that increasing the basic pHR may be considered to achieve short-term haemodynamic improvement. The long-term effects of differential pHR programming remain to be established.

Cardiac resynchronization therapy (CRT) improves outcomes in heart failure (HF) but may be underutilized. The reasons are unknown.We linked the Swedish Heart Failure Registry to national registries with ICD-10 (International Classification of Diseases-10th Revision) co-morbidity diagnoses and demographic and socio-economic data. In patients with EF ≤39% and NYHA II-IV, we assessed prevalence of CRT indication and CRT use. In those with CRT indication, we assessed the association between 37 potential baseline covariates and CRT non-use using multivariable generalized estimating equation (GEE) models. Of 12 807 patients (mean age 71 ± 12 years, 28% female), 841 (7%) had CRT, 3094 (24%) had an indication for but non-use of CRT, and 8872 (69%) had no indication. Important variables independently associated with CRT non-use were: HF duration6 months [risk ratio (RR) 1.21, 95% confidence interval (CI) 1.17-1.24]; non-cardiology planned follow-up (RR 1.14, 95% CI 1.09-1.18); age75 years (RR 1.13, 95% CI 1.09-1.18); non-cardiology care at baseline (RR 1.10, 95% CI 1.07-1.14); small-town non-university centre (RR 1.08, 95% CI 1.05-1.12); female sex (RR 1.07 95% CI 1.03-1.10) (all P0.05); as was absence of AF, living alone; psychiatric diagnosis; smoking; and non-use of HF drugs. Education, income, cancer, or HF characteristics were not independently associated with CRT non-use.In this population-wide HF registry, CRT was underutilized. Non-use was associated mostly with demographic and organizational, but not clinical or socio-economic factors. This calls for programmes to raise awareness of CRT indications and improve access and referrals to cardiology specialists.

The aim of this study was to evaluate an algorithm that estimates changes in cardiac output (CO) from right ventricular (RV) pressure waveforms derived from an implantable hemodynamic monitor (IHM) in heart failure patients.Twelve heart failure patients (NYHA II-III, EF 32%) with an implantable hemodynamic monitor (Chronicle) were included in this study. Changes in cardiac output were provoked by body position change at rest (left lateral supine, horizontal supine, sitting, and standing) and a steady state bicycle exercise at 20 watts. Estimated CO derived from the IHM (CO(IHM)) was compared to CO measured with inert gas rebreathing (CO(RB)), echocardiography (CO(ECHO)) and impedance cardiography (CO(ICG)). CO(RB) was considered the reference method.The median intra-patient correlation coefficient comparing CO(RB) and CO(IHM) was 0.83 (range: 0.63-0.98). Comparing CO(RB) with CO(ECHO) and CO(ICG) resulted in mean intra-patient correlation coefficients of 0.73 (-0.29-0.94) and 0.63 (-0.29-0.96). In a statistical model where slope and intercept was considered random between patients the coefficient of determination (R2) comparing CO(RB) and CO(IHM) was 0.91. Mean bias was -0.39 L/min (11%). Limits of agreement were +/-1.56 L/min and relative error was 21%.A simple algorithm based on RV pressure wave form characteristics derived from an IHM can be used to estimate changes in CO in heart failure patients. These findings encourage further research aiming to improve and validate the algorithm.

Background— Hemodynamic monitoring using implantable devices may provide early warning of volume overload in patients with heart failure (HF). This study was designed to prospectively compare information from intrathoracic impedance monitoring and continuous right ventricular pressure measurements in patients with HF. Methods and Results— Sixteen patients with HF (age, 63.5±13.8 years; left ventricular ejection fraction, 23.2±11.3%; New York Heart Association, II and III) and a previous HF decompensation received both a cardiac resynchronization therapy defibrillator providing a daily average of intrathoracic impedance and an implantable hemodynamic monitor providing an estimate of the pulmonary artery diastolic pressure. At the end of a 6-month investigator-blinded period, baseline reference hemodynamic values were determined over 4 weeks during which the patient was clinically stable. A major HF event was defined as HF decompensation requiring hospitalization, IV diuretic treatment, or leading to death. Sixteen major HF events occurred in 10 patients. Within 30 days and 14 days before a major HF event, impedance decreased by 0.12±0.21 Ω/d and 0.20±0.20 Ω/d, respectively, whereas estimated pulmonary arterial diastolic pressure increased by 0.10±0.20 mm Hg/d and 0.16±0.15 mm Hg/d, respectively. During these periods, impedance decreased by 3.8±5.4 Ω ( P P P P r =−0.48±0.25). Within 30 days preceding a major HF event, this correlation improved to r =−0.58±0.24. Conclusions— Decompensated HF develops based on hemodynamic derangements and is preceded by significant changes in intrathoracic impedance and right ventricular pressures during the month prior to a major clinical event. Impedance and pressure changes are moderately correlated. Future research may establish the complementary contribution of both parameters to guide diagnosis and management of patients with HF by implantable devices.

Prolonged exercise can induce cardiac fatigue, which is characterized by biomarker release and impaired myocardial function. The impact on ventricular electrophysiology is largely unknown.The objective of this study was to examine changes in ventricular repolarization after a 30-km cross-country race in runners agedor=55 years.Fifteen healthy participants (62 +/- 5 years) were assessed using biomarkers (N-terminal pro-brain natriuretic peptide [NT-proBNP], troponin T [TnT]), tissue Doppler echocardiography, and vectorcardiography at baseline, within 1 hour postrace and on days 1 and 6 postrace.During the race, NT-proBNP increased from 42 ng/L (interquartile range 25-117) to 187 ng/L (113-464), and TnT increased from undetectable levels to 0.03 microg/L (0.015-0.05). Global strain (19.1% +/- 2.2%) decreased on day 1 (17.2% +/- 1.8%) and day 6 (17.9% +/- 1.5%; P.01). QT(c) increased from 431 +/- 15 ms prerace to 445 +/- 22 ms postrace and 445 +/- 15 ms on day 1 (P.05), mainly because of an increased T(peak-end) interval (prerace 108 +/- 13 ms, postrace 127 +/- 43 ms, day 1 127 +/- 43 ms; P.05). Postrace, T(area) (baseline 75 +/- 26 microVs) peaked on day 1 (105 +/- 42 microVs) and remained high on day 6 (89 +/- 37 microVs; P.05). Runners with higher baseline NT-proBNP developed greater impairment of myocardial velocities (rho = -0.68 to -0.54; P.05) and a larger increase in T(area) (rho = 0.73; P.01).Cardiac fatigue induced by prolonged exertion is associated with sustained abnormalities in ventricular repolarization. Runners with higher baseline NT-proBNP are especially liable to such alterations of cardiac function.

Background Regular enhanced external counterpulsation (EECP) improves exercise capacity possibly through a training effect, but the roles of oxygen consumption (VO 2 ) vs. direct EECP effects (diastolic augmentation, DA-ratio), and their relation to cardiac index (CI) during EECP are unknown. Methods We studied eight patients with angina pectoris (median [range] age 72 [53-85], 25% women), who underwent EECP for 35 daily sessions. Before, during and after the first and last sessions, we assessed VO 2 , DA-ratio and CI. Results At first EECP, CI increased from 2.2 (1.7-2.9) L/min/m 2 prior to EECP to 3.0 (2.2-3.8) during EECP (p=0.011), and returned to 2.4 (0.8-3.0). Similarly, VO 2 increased during EECP and returned to baseline after EECP. These patterns were reproduced at the last EECP session. Absolute values of CI and VO 2 correlated with each other during but not prior to or after EECP. The increase in CI correlated with the increase in VO 2 by trend: (first session, r 0.52, p=0.19; second session r 0.69, p=0.09), but not with DA-ratio. Conclusions Acutely during EECP, there is an increase in cardiac output that is unrelated to direct EECP effects but related to, and may be secondary to, an increase in peripheral O 2 demand. This may represent a training effect.

Objective: To investigate the clinical feasibility (technical feasibility and patient-/clinician adherence) of remote telemonitoring, using a mobile phone, in an international and diverse HF population. Methods: HF patients from five centers in the USA, India and Sweden were equipped with a blood pressure apparatus, digital weight scale and a mobile phone device with custom made software for remote telemonitoring (Vitalbeat®). Patients were asked to record and transmit daily information on body weight, blood pressure and pulse rate as well as symptoms and adherence to medical therapy for 90 days. The primary endpoint, for assessment of general feasibility was defined as % of days with a combination of successful data transmission from patients and data read by clinicians. Acceptable clinical feasibility was a priori set as ≥ 66% of days meeting the primary endpoint. A survey was used to assess patients’ opinions about the remote monitoring system. Data was analyzed according to Intention to treat. Results: 46 HF patients were included (India=20, USA=13, Sweden=13; 59±16yrs; 84% male; NYHA-class 2.4±0.8) and followed for a total of 4410 days. The primary endpoint occurred in 3178 days (77%) and 34/46 patients (74%) exceeded the cut-off ≥ 66% of days meeting endpoint criteria. In the majority of patients (n=28; 61 %) the primary endpoint was met ≥ 90% of the days, and in 6 patients (13%) 66-89% of the days.Twelve patients (26%) opted to drop out of the study prematurely or were hospitalized for HF related causes. Compared to patients with acceptable clinical feasibility (≥ 66%), patients with less than acceptable feasibility (< 66%) were older (72±12 vs. 56±15 yrs, p=0.003) and more likely to be followed at a center in USA or Sweden (p=0.02 vs. Indian centers). The monitoring system was described as user friendly by 91 % of patients. Conclusion: This study shows that remote telemonitoring using a mobile phone is clinically feasible in an international and diverse heart failure population. However, monitoring was less feasible in elderly patients and depended on the geographic location. Further studies are warranted to assess whether clinical feasibility can improve with improved software/hardware design and/or patient selection.

Aims: To evaluate the long-term clinical outcome and device performance of cardiac resynchronization therapy in a consecutive sample of patients with moderate to severe heart failure. Methods and Results: Between 1998 and 2000, forty consecutive patients with drug-refractory heart failure due to ischemic or idiopathic dilated cardiomyopathy were selected for cardiac resynchronization therapy (CRT). After successful implantation of the coronary sinus lead (n = 35, 88%), patients were followed every sixth month by New York Heart Association (NYHA) functional class, the 6-minute walking test (6´ walk), quality of life (QoL, Minnesota), and pacemaker control. NYHA-class and 6´ walk were significantly improved after 6 months and continued to improve gradually until 36 months of follow-up. The QoL improvement at 6 months was sustained over 3 years. After 3 years, the β-blocker dose could be increased in 10/23 patients as compared to baseline. Nine patients had to be re-operated. Coronary sinus lead thresholds were stable over time. Conclusion: The clinical improvements by CRT are sustained over 3 years of follow-up. In the setting of a University Medical Center, CRT can be applied in clinical routine with excellent clinical outcome, acceptable implantation success, and stable device performance over time.

Aims It has been suggested that cardiac resynchronization therapy (CRT) is less utilized, dyssynchrony occurs at narrower QRS, and CRT is more beneficial in women compared with men. We tested the hypotheses that (i) CRT is more underutilized and (ii) QRS prolongation and left bundle branch block (LBBB) are more harmful in women. Methods and results We studied 14 713 patients (28% women) with left ventricular ejection fraction (LVEF)

Age is not a contraindication to cardiac resynchronization therapy (CRT), but the prevalence and prognostic impact of QRS prolongation with intraventricular conduction delay (IVCD) and left bundle branch block (LBBB), as well as CRT utilization, may differ with age. We tested the hypotheses that in the elderly: (i) IVCD and LBBB are more prevalent, (ii) IVCD and LBBB are more harmful, and (iii) CRT is underutilized.We studied 14 713 patients with ejection fraction ≤39% in the Swedish Heart Failure Registry and divided into age groups ≤65 years, 66-80 years and80 years. Among 13 782 patients without CRT, IVCD was present in the three age groups in 11% vs. 15% vs. 19% and LBBB was present in 20% vs. 27% vs. 28%, respectively, (P 0.001). The multivariable hazard ratio (HR) for all-cause mortality over a median (interquartile range) follow-up of 29 (12-53) months for IVCD vs. narrow QRS was 1.31 (1.06-1.63, P = 0.013) in the ≤65 year group, 1.32 (1.17-1.47, P 0.001) in the 66-80 year group, and 1.26 (1.21-1.41, p 0.001) in the80 year group. For LBBB vs. narrow QRS it was 1.29 (1.07-1.56, P = 0.009), 1.17 (1.06-1.30, P = 0.002), and 1.10 (0.99-1.22, P = 0.091), respectively. The adjusted P for interaction between age and QRS morphology was 0.664. In the three age groups, CRT was present in 6% vs. 8% vs. 4% and absent but with indication in 23% vs. 32% vs. 37%, respectively (P 0.001).Both IVCD and LBBB were more common with increasing age and were similarly strong independent predictors of mortality and in all ages. The underutilization of CRT was worse with increasing age.

We aimed at testing the hypothesis that spinal cord stimulation (SCS) reduces cardiac sympathetic nerve activity in patients with heart failure (HF). Patients with HF (NYHA -class III, EF ≤35%, QRS < 120 ms) were randomly assigned to SCS ON for 6 weeks followed by a 6-week OFF period, or vice

Heart failure is now considered an epidemic. In patients with heart failure, electrical and mechanical dyssynchrony, evident primarily as prolongation of the QRS-complex on the surface electrocardiogram, is associated with detrimental effects on the cardiovascular system at several levels. In the past 10 years, studies have demonstrated that by stimulating both cardiac ventricles simultaneously, or almost simultaneously [cardiac resynchronization therapy (CRT)], the adverse effects of dyssynchrony can be overcome. Here, we provide a comprehensive overview of different aspects of CRT including the rationale behind and evidence for efficacy of the therapy. Issues with regard to gender effects and patient follow-up as well as a number of unresolved concerns will also be discussed.

Background Sex comparisons between girls and boys in response to exercise in trained adolescents are missing and we investigated similarities and differences as a basis for clinical interpretation and guidance. Methods A total of 24 adolescent females and 27 adolescent males aged 13–19 years underwent a maximal bicycle exercise stress test with measurement of cardiovascular variables, cardiac output, lung volumes, metabolic factors/lactate concentrations and breath-by-breath monitoring of ventilation, and determination of peak VO2. Results Maximum heart rate was similar in females (191 ± 9 bpm) and males (194 ± 7 bpm), cardiac index at maximum exercise was lower in females (7.0 ± 1.0 l/min/m2) than in males (8.3 ± 1.4 l/min/m2, P 2 was lower in females (2.37 ± 0.34 l/min) than in males (3.38 ± 0.49 l/min, P 2 was normalized to leg muscle mass sex differences disappeared (females: 161 ± 21 ml/min/kg vs. males: 170 ± 23 ml/min/kg). The increase in cardiac index during exercise is the key factor responsible for the greater peak VO2 in adolescent boys compared to girls. Conclusions Differences in peak VO2 in adolescent boys and girls disappear when peak VO2 is normalized to estimated leg muscle mass and therefore provide a tool to conduct individual and intersex comparisons of fitness when evaluating adolescent athletes in aerobic sports.

Aims Cardiac resynchronization therapy (CRT) improves prognosis in patients with moderate-to-severe heart failure, reduced left ventricular ejection fraction, and wide QRS complexes. However, CRT may be under-utilized in women and data on long-term follow-up are still scarce. The aim was to investigate long-term mortality and hospitalization and prognostic impact of gender after CRT. Methods and results Data on 619 consecutive patients (19% women) that received CRT at a single centre between 1998 and 2008 were collected from electronic medical records and national death and hospitalization registries up to 2010. The primary endpoint was death of any cause and the secondary endpoint was combined death of any cause or heart failure hospitalization. Over a mean follow-up of 1320 ± 786 days, 215 (35%) patients reached the primary endpoint and 437 (71%) the secondary endpoint. Overall, 1-, 5-, and 10-year survivals were 91, 63, and 39%, respectively. Female gender was the only independent predictor of all-cause mortality; hazard ratio (HR) 0.44 [95% confidence interval (CI), 0.21–0.90; P = 0.025]. Women also had a trend towards lower risk for the secondary endpoint, HR 0.68 (95% CI, 0.45–1.04; P = 0.072). Conclusion In this registry analysis, patients with CRT had similarly high short-term survival to those in controlled trials, and this favourable prognosis was sustained over the long term.Women had lower all-cause mortality than men.

The present study investigates the adaptation of the central circulation to ultraendurance exercise, including the relative contributions of changes in stroke volume (SV) and arteriovenous oxygen difference to the increased oxygen pulse (VO2/HR).We evaluated subjects undergoing 12 h of mixed exercise at controlled intensity (n=8) and a 53-h adventure race (n=20). HR, oxygen uptake (VO2), and cardiac output determined using noninvasive gas rebreathing were measured during cycling at a fixed work rate after 0, 4, 8, and 12 h and 0, 20, and 53 h of continuous exercise in the 12- and 53-h protocols, respectively.The central circulation changed in several steps in response to ultraendurance exercise. Compared with initial levels, VO2 was increased at every time point measured. The increase was attributed to peripheral adaptations, confirmed by a close correlation between change in VO2 and change in arteriovenous oxygen difference. The first step of the circulatory response was typical of normal (early) cardiovascular drift, with increased HR and concomitantly decreased SV and VO2/HR, occurring during the first 4-6 h. The second step, which continued until approximately 12 h, included reversed HR drift, with normalization of SV and VO2/HR. When exercise continued until 50 h, late cardiovascular drift was noted, characterized by increased VO2/HR (indicating more efficient energy distribution), decreased peripheral resistance, increased SV, and decreased work of the heart. Because cardiac output was maintained at all time points, we interpret the changes as physiologically appropriate adaptations to ultraendurance exercise.

Aims The aim of this study was to study the haemodynamic effect of atrioventricular delay (AVD) modifications within a narrow range in different body positions and during exercise in patients receiving cardiac resynchronization therapy (CRT). Methods The previously optimized AVD was shortened and prolonged by 40 ms in 27 CRT patients and 9 controls without heart failure. Cardiac output (CO) was measured by inert gas rebreathing (Innocor) as the average over different body positions (left-lateral, supine, sitting, standing, and exercise). In eight CRT patients with an implantable haemodynamic monitor, the estimated pulmonary artery diastolic pressure (ePAD) was analysed. Results The magnitude of CO response to AVD changes was greater in CRT patients than in controls (0.25 vs. 0.20 L/min, P < 0.05), varied substantially between individuals (range: 0.12–0.56 L/min), and correlated with left atrial size ( r = 0.61, P < 0.001). On average, AVD shortening decreased CO slightly (0.07 ± 0.17 L/min) and increased ePAD (1.1 ± 0.8 mmHg, both P < 0.05), whereas prolongation had no significant effect. Conclusion The haemodynamic response to AVD modifications within a narrow range is larger in CRT patients than in normal controls and varies substantially between individuals. These findings suggest that optimal AVD tuning is clinically important in selected patients.