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Heart failure with preserved ejection fraction (HFpEF) is characterized by obesity, hypertension, diabetes mellitus and chronic kidney disease. Obese ZSF1 rats, a model of HFpEF, exhibit multiple such comorbidities that can disturb cardiac function. Little attention has been paid to how these comorbidities affect renal disease in ZSF1 rats. HFpEF is found predominantly in women in whom obesity and hypertension are particularly prevalent. Therefore, we characterized renal phenotype in female and male, lean and obese, ZSF1 rats and investigated additional effects of worsened hypertension on disease severity. Systolic blood pressure and renal function were assessed biweekly from 12 to 26 weeks. From 19 weeks, rats were implanted with either a deoxycorticosterone acetate pellet and fed high salt diet (DS) or a placebo pellet and fed normal salt diet. At 26 weeks, terminal GFR was assessed via inulin clearance under isoflurane. Renal sections were processed for histological analysis. Lean and obese ZSF1 rats, both female and male, were mildly hypertensive (systolic blood pressure 140-150 mmHg). All obese ZSF1 rats showed HFpEF. In female normoglycemic ZSF1 rats, obesity associates with mild proteinuria, decreased glomerular filtration rate and glomerular hypertrophy. DS-worsened hypertension enhanced proteinuria and triggered glomerulosclerosis. Male obese ZSF1 rats were hyperglycemic and showed proteinuria, glomerular hypertrophy and sclerosis, and tubulo-interstitial damage. DS-worsened hypertension aggravated this phenotype in male ZSF1 rats. In conclusion, female obese ZSF1 rats develop mild renal dysfunction and DS-worsened hypertension compromises renal function and structure in normoglycemic female obese ZSF1 rats as in hyperglycemic male obese ZSF1 rats.

Purpose of Review The prevalence of cancer therapy-related cardiac dysfunction (CTRCD) is increasing due to improved cancer survival. Serial monitoring of cardiac function is essential to detect CTRCD, guiding timely intervention strategies. Multigated radionuclide angiography (MUGA) has been the main screening tool using left ventricular ejection fraction (LVEF) to monitor cardiac dysfunction. However, transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR) may be more suitable for serial assessment. We aimed to assess the concordance between different non-radiating imaging modalities with MUGA to determine whether they can be used interchangeably. Recent Findings In order to identify relevant studies, a PubMed search was performed. We included cross-sectional studies comparing MUGA LVEF to that of 2D TTE, 3D TTE, and CMR. From 470 articles, 22 were selected, comprising 1017 patients in total. Among others, this included three 3D TTE, seven 2D harmonic TTE + contrast (2DHC), and seven CMR comparisons. The correlations and Bland-Altman limits of agreement varied for CMR but were stronger for 3D TTE and 2DHC. Summary Our findings suggest that MUGA and CMR should not be used interchangeably whereas 3D TTE and 2DHC are appropriate alternatives following an initial MUGA scan. We propose a multimodality diagnostic imaging strategy for LVEF monitoring in patients undergoing cancer treatment.

Timing chemotherapy on the basis of the body's intrinsic circadian clock—ie, chronomodulated chemotherapy—might improve efficacy and reduce treatment toxicity. This systematic review summarises the available clinical evidence on the effects of chronomodulated chemotherapy from randomised, controlled trials in adult patients with cancer, published between the date of database inception and June 1, 2021. This study complies with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was registered on the International Prospective Register of Systematic Reviews (CRD42020177878). The protocol was published on Oct 21, 2020, before study initiation. The primary outcome measures comprised toxicity incidence, overall survival, progression-free survival, and objective response rate. Of 1455 identified abstracts, 18 studies including 2547 patients were selected. Studies were heterogeneous in study design, treatment, and population. 14 (77%) of 18 studies reported differences among groups in toxicity. 11 (61%) studies reported that chronomodulated chemotherapy resulted in a significant decrease in toxicity while maintaining anti-cancer activity. Two (11%) studies showed that chronomodulated chemotherapy reduced some toxic effects but increased others, and one (6%) study reported worse toxicity outcomes than standard chemotherapy. Three (17%) studies reported improved efficacy (survival measures, objective response rate, or time to treatment failure) of chronomodulated chemotherapy, and no studies reported a decrease in efficacy. In conclusion, most studies provide evidence of the reduction of toxicity resulting from chronomodulated chemotherapy, while efficacy is maintained. More and larger, carefully designed, randomised, controlled trials are needed to provide recommendations for clinical practice.

Aims Judicious patient selection for cardiac resynchronization therapy (CRT) may further enhance treatment response. Progress has been made by using improved markers of electrical dyssynchrony and mechanical discoordination, using QRSAREA, and systolic rebound stretch of the septum (SRSsept) or systolic stretch index (SSI), respectively. To date, the relation between these measurements has not yet been investigated. Methods and results A total of 240 CRT patients were prospectively enrolled from six centres. Patients underwent standard 12-lead electrocardiography, and echocardiography, at baseline, 6-month, and 12-month follow-up. QRSAREA was derived using vectorcardiography, and SRSsept and SSI were measured using strain-analysis. Reverse remodelling was measured as the relative decrease in left ventricular end-systolic volume, indexed to body surface area (ΔLVESVi). Sustained response was defined as ≥15% decrease in LVESVi, at both 6- and 12-month follow-up. QRSAREA and SRSsept were both strong, multivariable adjusted, variables associated with reverse remodelling. SRSsept was associated with response, but only in patients with QRSAREA ≥ 120 μVs (AUC = 0.727 vs. 0.443). Combined presence of SRSsept ≥ 2.5% and QRSAREA ≥ 120 μVs significantly increased reverse remodelling compared with high QRSAREA alone (ΔLVESVi 38 ± 21% vs. 22 ± 21%). As a result, 92% of left bundle branch block (LBBB)-patients with combined electrical and mechanical dysfunction were ‘sustained’ volumetric responders, as opposed to 51% with high QRSAREA alone. Conclusion Parameters of mechanical dyssynchrony are better associated with response in the presence of a clear underlying electrical substrate. Combined presence of high SRSsept and QRSAREA, but not high QRSAREA alone, ensures a sustained response after CRT in LBBB patients.

Background Type 2 diabetes is a condition associated with a state of low-grade inflammation caused by adipose tissue dysfunction and insulin resistance. High sensitive-CRP (hs-CRP) is a marker for systemic low-grade inflammation and higher plasma levels have been associated with cardiovascular events in various populations. The aim of the current study is to evaluate the relation between hs-CRP and incident cardiovascular events and all-cause mortality in high-risk type 2 diabetes patients. Methods Prospective cohort study of 1679 type 2 diabetes patients included in the Second Manifestations of ARTerial disease (SMART). Cox proportional hazard models were used to evaluate the risk of hs-CRP on cardiovascular events (composite of myocardial infarction, stroke and vascular mortality) and all-cause mortality. Hs-CRP was log-transformed for continuous analyses. Findings were adjusted for age, sex, BMI, current smoking and alcohol use, non-HDL-cholesterol and micro-albuminuria. Results 307 new cardiovascular events and 343 deaths occurred during a median follow-up of 7.8 years (IQR 4.2–11.1). A one unit increase in log(hs-CRP) was related to an increased vascular- and all-cause mortality risk (HR 1.21, 95% CI 1.01–1.46 and HR 1.26, 95% CI 1.10–1.45 respectively). No relation was found between log(hs-CRP) and myocardial infarction or stroke. The relations were similar in patients with and without previous vascular disease. Conclusion Low grade inflammation, as measured by hs-CRP, is an independent risk factor for vascular- and all-cause mortality but not for cardiovascular events in high-risk type 2 diabetes patients. Chronic low-grade inflammation may be a treatment target to lower residual cardiovascular risk in type 2 diabetes patients.

We present a young patient who had to undergo 5 mitral valve replacements (MVR) because of a repetitive immune-mediated noninfectious endocarditis. The patient was treated with multiple anti-inflammatory drugs and high-dose prednisone. After the fifth MVR, the patient remained in stable condition using Anakinra after 22 months of follow-up. (Level of Difficulty: Advanced.), Central Illustration

Cardiac rehabilitation (CR) has evolved as an important part of the treatment of patients with cardiovascular disease. However, to date, its full potential is fairly underutilised. This review discusses new developments in CR aimed at improving participation rates and long-term effectiveness in the general cardiac population. It consecutively highlights new or challenging target groups, new delivery modes and new care pathways for CR programmes. These new or challenging target groups include patients with atrial fibrillation, obesity and cardiovascular disease, chronic coronary syndromes, (advanced) chronic heart failure with or without intracardiac devices, women and frail elderly patients. Also, the current evidence regarding cardiac telerehabilitation and loyalty programmes is discussed as new delivery modes for CR. Finally, this paper discusses novel care pathways with the integration of CR in residual risk management and transmural care pathways. These new developments can help to make optimal use of the benefits of CR. Therefore we should seize the opportunities to reshape current CR programmes, broaden their applicability and incorporate them into or combine them with other cardiovascular care programmes/pathways.

Objectives This study aimed to perform an external validation of the value of right ventricular (RV) deformation patterns and RV mechanical dispersion in patients with arrhythmogenic cardiomyopathy (AC). Secondly, this study assessed the association of these parameters with life-threatening ventricular arrhythmia (VA). Background Subtle RV dysfunction assessed by echocardiographic deformation imaging is valuable in AC diagnosis and risk prediction. Two different methods have emerged, the RV deformation pattern recognition and RV mechanical dispersion, but these have neither been externally validated nor compared. Methods We analyzed AC probands and mutation-positive family members, matched from 2 large European referral centers. We performed speckle tracking echocardiography, whereby we classified the subtricuspid deformation patterns from normal to abnormal and assessed RV mechanical dispersion from 6 segments. We defined VA as sustained ventricular tachycardia, appropriate implantable cardioverter-defibrillator therapy, or aborted cardiac arrest. Results We included 160 subjects, 80 from each center (43% proband, 55% women, age 41 ± 17 years). VA had occurred in 47 (29%) subjects. In both cohorts, patients with a history of VA showed abnormal deformation patterns (96% and 100%) and had greater RV mechanical dispersion (53 ± 30 ms vs. 30 ± 21 ms; p Conclusions We externally validated 2 RV dysfunction parameters in AC. Adding RV mechanical dispersion to RV deformation patterns significantly improved the association with life-threatening VA, indicating incremental value.

Objectives This study aimed to explore echocardiographic characteristics of phospholamban (PLN) p.Arg14del mutation carriers to investigate whether structural and/or functional abnormalities could be identified before onset of symptoms. Background Carriers of the genetic PLN p.Arg14del mutation may develop arrhythmogenic and/or dilated cardiomyopathy. Overt disease is preceded by a pre-symptomatic phase of variable length in which disease expression seems to be absent. Methods PLN p.Arg14del mutation carriers with an available echocardiogram were included. Mutation carriers were classified as pre-symptomatic if they had no history of ventricular arrhythmias (VAs), a premature ventricular complex count of Results The final study population consisted of 281 PLN p.Arg14del mutation carriers, 139 of whom were classified as pre-symptomatic. In comparison to control subjects, pre-symptomatic mutation carriers had lower global longitudinal strain and higher LV mechanical dispersion (both p Conclusions Global and regional LV mechanical alterations in PLN p.Arg14del mutation carriers precede arrhythmic symptoms and overt structural disease. Pre-symptomatic mutation carriers with normal deformation patterns in the apex are at low risk of developing VA within 3 years, whereas mutation carriers with apical PSS appear to be at higher risk.

Background According to the current guidelines of the European Society of Cardiology, patients with left-sided infective endocarditis are treated with intravenous antibiotics for 4–6 weeks, leading to extensive hospital stay and high costs. Recently, the Partial Oral Treatment of Endocarditis (POET) trial suggested that partial oral treatment is effective and safe in selected patients. Here, we investigated if such patients are seen in our daily clinical practice. Methods We enrolled 119 adult patients diagnosed with left-sided infective endocarditis in a retrospective, observational study. We identified those that would be eligible for switching to partial oral antibiotic treatment as defined in the POET trial (e.g. stable clinical condition without signs of infection). Secondary objectives were to provide insight into the time until each patient was eligible for partial oral treatment, and to determine parameters of longer hospital stay and/or need for extended intravenous antibiotic treatment. Results Applying the POET selection criteria, the condition of 38 patients (32%) was stable enough to switch them to partial oral treatment, of which 18 (47.3%), 8 (21.1%), 9 (23.7%) and 3 patients (7.9%) were eligible for switching after 10, 14, 21 days or 28 days of intravenous treatment, respectively. Conclusion One-third of patients who presented with left-sided endocarditis in routine clinical practice were possible candidates for switching to partial oral treatment. This could have major implications for both the patient’s quality of life and healthcare costs. These results offer an interesting perspective for implementation of such a strategy, which should be accompanied by a prospective cost-effectiveness analysis.

Aims Patient selection for cardiac resynchronization therapy (CRT) may be enhanced by evaluation of systolic myocardial stretching. We evaluate whether systolic septal rebound stretch (SRSsept) derived from speckle tracking echocardiography is a predictor of reverse remodelling after CRT and whether it holds additive predictive value over the simpler visual dyssynchrony assessment by apical rocking (ApRock). Methods and results The association between SRSsept and change in left ventricular end-systolic volume (ΔLVESV) at 6 months of follow-up was assessed in 200 patients. Subsequently, the additive predictive value of SRSsept over the assessment of ApRock was evaluated in patients with and without left bundle branch block (LBBB) according to strict criteria. SRSsept was independently associated with ΔLVESV (β 0.221, P = 0.002) after correction for sex, age, ischaemic cardiomyopathy, QRS morphology and duration, and ApRock. A high SRSsept (≥optimal cut-off value 2.4) also coincided with more volumetric responders (ΔLVESV ≥ −15%) than low SRSsept in the entire cohort (70.0% and 56.4%), in patients with strict LBBB (83.3% vs. 56.7%, P = 0.024), and non-LBBB (70.7% vs. 46.3%, P = 0.004). Moreover, in non-LBBB patients, SRSsept held additional predictive information over the assessment of ApRock alone since patients that showed ApRock and high SRSsept were more often volumetric responder than those with ApRock but low SRSsept (82.8% vs. 47.4%, P = 0.001). Conclusion SRSsept is strongly associated with CRT-induced reduction in left ventricular end-systolic volume and holds additive prognostic information over QRS morphology and ApRock. Our data suggest that CRT patient selection may be improved by assessment of SRSsept, especially in the important subgroup without strict LBBB. Clinical trial registration The MARC study was registered at clinicaltrials.gov: NCT01519908.

Background Different disease stages of arrhythmogenic right ventricular cardiomyopathy (ARVC) can be identified by right ventricle (RV) longitudinal deformation (strain) patterns. This requires assessment of the onset of shortening, (systolic) peak strain, and postsystolic index, which is time‐consuming and prone to inter‐ and intra‐observer variability. The aim of this study was to design and validate an algorithm to automatically classify RV deformation patterns. Methods We developed an algorithm based on specific local characteristics from the strain curves to detect the parameters required for classification. Determination of the onset of shortening by the algorithm was compared to manual determination by an experienced operator in a dataset containing 186 RV strain curves from 26 subjects carrying a pathogenic plakophilin‐2 (PKP2) mutation and 36 healthy subjects. Classification agreement between operator and algorithm was solely based on differences in onset shortening, as the remaining parameters required for classification of RV deformation patterns could be directly obtained from the strain curves. Results The median difference between the onset of shortening determined by the experienced operator and by the automatic detector was 5.3 ms [inter‐quartile range (IQR) 2.7–8.6 ms]. 96% of the differences were within 1 time frame. Both methods correlated significantly with ρ = 0.97 (P

Background: Patients treated for non-Hodgkin lymphoma are at risk of cardiovascular adverse events, with the risk of heart failure being particularly high. A regimen of cyclophosphamide, doxorubicin, vincristine, and prednisone, with (R-CHOP) or without (CHOP) rituximab is the standard first-line treatment for aggressive non-Hodgkin lymphoma, and doxorubicin and cyclophosphamide are both associated with left ventricular dysfunction. The aim of this systematic review and meta-analysis was to evaluate the cardiovascular toxicity of this regimen. Methods: We systematically searched PubMed, EMBASE, and the Cochrane Library from database inception to June 3, 2019, for clinical trials and observational studies in adult patients with non-Hodgkin lymphoma (diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma, and non-Hodgkin lymphoma not otherwise specified) that received first-line treatment with R-CHOP or CHOP. Studies reporting on cardiovascular adverse events and treatment-related cardiovascular mortality were included. Abstracts and articles not written in English were excluded. The main outcomes were the proportion of patients with grade 3–4 cardiovascular adverse events and heart failure. Meta-analyses of one-sample proportions were done in all patients receiving CHOP or R-CHOP. Subgroup analyses on summary estimates were done to determine the effect of number of CHOP or R-CHOP cycles, cycle interval, age, and sex. Findings: Of 2314 identified entries, 137 studies (21 211 patients) published between April, 1984, and June, 2019 were eligible (9541 patients treated with CHOP, 11 293 patients treated with R-CHOP, 377 both regimens used in the study; median follow-up 39·0 months [IQR 25·5–52·8]). From the included studies, 85 subgroups were treated with CHOP, 76 with R-CHOP, and in four studies both CHOP and R-CHOP were used without a subdivision in separate groups. The pooled proportion for grade 3–4 cardiovascular adverse events, based on 77 studies (n=14 351 patients), was 2·35% (95% CI 1·81–2·93; heterogeneity test Q=326·21; τ 2=0·0042; I 2=71·40%; p

OBJECTIVE: Left ventricular (LV) hypertrophy is the most common cardiac alteration in patients with chronic kidney disease (CKD). Normalization of hypertension in CKD patients receiving a healthy kidney allograft often reverses LV hypertrophy, but effects on LV fibrosis remain unclear. To study causal interactions between graft and environment on LV hypertrophy, fibrosis and inflammation, we applied cross-kidney transplantation METHODS:: Orthotopic transplantation was performed after inducing CKD in rats by two-third bilateral ablation of kidney mass: Healthy kidney (K) donor to healthy heart (H) recipient (healthy-K→healthy-H); CKD-K→healthy-H; healthy-K→CKD-H; CKD-K→CKD-H; N= 6 per group.RESULTS: At week 6 after transplantation, mean arterial pressure (MAP) and LV mass index (LVMI) increased in CKD-K versus healthy-K irrespective of recipient. Contrarily, LV fibrosis was more severe in CKD-H versus healthy-H recipients irrespective of graft. Indeed, MAP and plasma creatinine correlated with LVMI but not with LV fibrosis. Increased LVMI in CKD-K→CKD-H not accompanied by cardiomyocyte cross-sectional area gain is consistent with eccentric remodelling. Cardiac RNA sequencing found a strong transcriptional response associated with LV fibrosis but only sparse changes associated with LV hypertrophy. This response was, among others, characterized by changes in extracellular matrix (ECM) and inflammatory gene expression.CONCLUSION: LVMI reversed and MAP and renal function were normalized early after transplantation of a healthy kidney. However, LV fibrosis persisted, dissociating LV hypertrophy from LV fibrosis within 6 weeks. Elucidating cardiac ECM dynamics in CKD patients, although challenging, appears promising.

Background Heart failure (HF) and chronic obstructive pulmonary disease (COPD) often remain undiagnosed in older individuals, although both disorders inhibit functionality and impair health. The aim of the study was to assess the effectiveness of a case-finding strategy of these disorders. Methods This is a clustered randomized trial; 18 general practices from the vicinity of Utrecht, the Netherlands, were randomly allocated to a case-finding strategy or usual care. Multimorbid community subjects (≥65 years) with dyspnea or reduced exercise tolerance were eligible for inclusion. The case-finding strategy consisted of history taking, physical examination, blood tests, electrocardiography, spirometry, and echocardiography. Subsequent treatment decisions were at the discretion of the general practitioner. Questionnaires regarding health status and functionality were filled out at baseline and after 6 months of follow-up. Information regarding changes in medication and health care use during the 6 months follow-up was extracted. Results A total of 829 participants were randomized: 389 in the case-finding strategy group and 440 in the usual care group. More patients in the case-finding group received a new diagnosis of HF or COPD than the usual care group (cumulative incidence 34% vs 2% and 17% vs. 2%, respectively). Scores for health status, functionality, and health care use were similar between the 2 strategies after 6 months of follow-up. Conclusions A case-finding strategy applied in primary care to multimorbid older people with dyspnea or reduced exercise tolerance resulted in a number of new diagnoses of HF and COPD but did not result in short-term improvement of health status compared to usual care.

Arrhythmogenic cardiomyopathy (AC) is an inherited cardiomyopathy characterized by progressive fibro-fatty replacement of the myocardium. Previous studies suggest that progression of structural disease is uncommon during early stages of AC, whereas electrical disease progression is seen more

Background Left ventricular false tendons (LVFTs) are common. There is conflicting evidence whether LVFTs have clinically important electrophysiological effects. The aim of this study was to investigate, in a highly active population: 1) the prevalence of LVFTs, 2) the association between LVFTs and abnormalities on the resting 12-lead-electrocardiograms (ECG) and 3) the association of LVFTs with ventricular arrhythmias. Methods A retrospective cohort study was performed using data from military personnel in active service who were referred to the Cardiology Department of the Central Military Hospital in Utrecht, The Netherlands, in 2017. Data of resting 12-lead-electrocardiography, transthoracic echocardiography, ambulatory ECG monitoring, exercise testing, the prevalence of traditional cardiovascular risk factors and relevant clinical data were obtained from the electronic patient data charts. Results In total, 125 subjects were included in the analysis. The overall prevalence of LVFTs was 40% and the they were predominantly located from the mid-IVS top the apical segment of the LV (type 4). Non-significant T-Wave Abnormalities (NS-TWA) were significantly more prevalent in subjects with LVFTs and were predominantly localized in the lateral leads. There was no increased risk of any arrhythmia. Follow-up data of 3.2 years showed no difference in the occurrence of major adverse cardiac events. Conclusion In this highly active group subjects, the presence of an LVFT did not yield an increased arrhythmogenic risk compared to subjects without a LVFT.

Background: Current guidelines on the management of infective endocarditis (IE) recommend follow-up blood cultures (FUBCs) to identify persistent bacteraemia, as this has prognostic value and guides treatment decisions. While persistent bacteraemia frequently occurs in Staphylococcus aureus bacteraemia and IE, its prevalence and impact in non-staphylococcal IE is largely unknown. We determined prevalence and prognostic value of persistent bacteraemia in non-staphylococcal IE. Methods: We conducted a retrospective analysis of all patients diagnosed with definite non-staphylococcal endocarditis according to the modified Duke Criteria in two university hospital endocarditis registries We determined the prevalence and prognostic value of persistent bacteraemia. Results: Of the included 159 patients 70 (44%) had prosthetic valve endocarditis (PVE). A median number of two [IQR 1–3] FUBCs were taken during the first week, with 134/159 (84%) having at least one FUBC in the first four days. Seven patients (4,4%) had persistent bacteraemia 48 h after start of antibiotic treatment: 5/70 patients (7.1%) with PVE and 2/89 (2.2%) with native valve endocarditis. Among 97 patients with streptococcal IE, nine patients with HACEK IE and six patients with Cutibacterium IE, no persistent bacteraemia was observed. Enterococcus faecalis was the causative microorganism in five patients with persistent bacteraemia, the other two had non-HACEK Gram-negative endocarditis. Conclusion: Persistent bacteraemia in non-staphylococcal endocarditis was rare. It was more frequently observed in PVE and was restricted to more resilient microorganisms such as enterococci and non-HACEK Gram-negative bacteria. Routine collection of FUBCs in patients with streptococcal endocarditis has a low yield and may require re-evaluation.

Aims: The histopathology of mitral valve (MV) tissues have been reported in necropsy and retrospective studies. We prospectively studied the histopathological changes in rheumatic mitral stenosis using advanced techniques and corroborated these with clinical presentation, pathogenesis, and management. Methods: From January 2020 to February 2021, surgically excised rheumatic stenotic MV from 54 Tanzanian patients were studied. These were examined using hematoxylin-eosin, von Kossa staining, and immunohistochemistry. Results: The median (range) age of patients was 39 (14–57) years with 34 (63%) females. Secondary prophylaxis was given to 7 (13%) patients and 2 (3.7%) had evidence of rheumatic fever (RF). With hematoxylin-eosin, 37 (68.5%) specimens showed fibrinoid degeneration (FD), 44 (81.5%) leucocytic infiltrates, 6 (11.1%) Aschoff nodules, 30 (55.6%) calcification, and 39 (72.2%) fibrosis. Thirty-five (64.8%) specimens were positive to von Kossa. The proportion of specimens positive for CD3, CD20, CD68, and CD8 were 46 (85.2%), 35 (64.8%), 39 (72.2%), and 8 (14.8%) respectively. Valvular calcium was high among older patients, males and with a higher trans-MV gradient. The degree of inflammatory cellular infiltration was associated with valvular calcification, FD with ARF, leucocytic infiltrates with disease duration of

PurposeThe Utrecht Cardiovascular Cohort–Second Manifestations of Arterial Disease (UCC-SMART) Study is an ongoing prospective single-centre cohort study with the aim to assess important determinants and the prognosis of cardiovascular disease progression. This article provides an update of the rationale, design, included patients, measurements and findings from the start in 1996 to date.ParticipantsThe UCC-SMART Study includes patients aged 18–90 years referred to the University Medical Center Utrecht, the Netherlands, for management of cardiovascular disease (CVD) or severe cardiovascular risk factors. Since September 1996, a total of 14 830 patients have been included. Upon inclusion, patients undergo a standardised screening programme, including questionnaires, vital signs, laboratory measurements, an ECG, vascular ultrasound of carotid arteries and aorta, ankle-brachial index and ultrasound measurements of adipose tissue, kidney size and intima–media thickness. Outcomes of interest are collected through annual questionnaires and adjudicated by an endpoint committee.Findings to dateBy May 2022, the included patients contributed to a total follow-up time of over 134 000 person-years. During follow-up, 2259 patients suffered a vascular endpoint (including non-fatal myocardial infarction, non-fatal stroke and vascular death) and 2794 all-cause deaths, 943 incident cases of diabetes and 2139 incident cases of cancer were observed up until January 2020. The UCC-SMART cohort contributed to over 350 articles published in peer-reviewed journals, including prediction models recommended by the 2021 European Society of Cardiology CVD prevention guidelines.Future plansThe UCC-SMART Study guarantees an infrastructure for research in patients at high cardiovascular risk. The cohort will continue to include about 600 patients yearly and follow-up will be ongoing to ensure an up-to-date cohort in accordance with current healthcare and scientific knowledge. In the near future, UCC-SMART will be enriched by echocardiography, and a food frequency questionnaire at baseline enabling the assessment of associations between nutrition and CVD and diabetes.

Introduction: Cardiac resynchronization therapy (CRT) is an established therapy for patients with heart failure with reduced ejection fraction (HFrEF). Women appear to respond differently to CRT, yet it remains unclear whether this is inherent to the female sex itself, or due to other patient characteristics. In this study, we aimed to investigate sex differences in response to CRT. Methods: This is a post-hoc analysis of a prospective, multicenter study (MARC) in the Netherlands, studying HFrEF patients with an indication for CRT according to the guidelines (n = 240). Primary outcome measures are left ventricular ejection fraction (LVEF) and left ventricular end systolic volume (LVESV) at 6 months follow-up. Results were validated in an independent retrospective Belgian cohort (n = 818). Results: In the MARC cohort 39% were women, and in the Belgian cohort 32% were women. In the MARC cohort, 70% of the women were responders (defined as >15% decrease in LVESV) at 6 months, compared to 55% of men (p = 0.040) (79% vs. 67% in the Belgian cohort, p = 0.002). Women showed a greater decrease in LVESV %, LVESV indexed to body surface area (BSA) %, and increase in LVEF (all p < 0.05). In regression analysis, after adjustment for BSA and etiology, female sex was no longer associated with change in LVESV % and LVESV indexed to BSA % and LVEF % (p > 0.05 for all). Results were comparable in the Belgian cohort. Conclusions: Women showed a greater echocardiographic response to CRT at 6 months follow-up. However, after adjustment for BSA and ischemic etiology, no differences were found in LV-function measures or survival, suggesting that non-ischemic etiology is responsible for greater response rates in women treated with CRT. The MARC study was performed within the framework of the CTMM, the Centre for Translational Molecular Medicine (www.ctmm.nl), project COHFAR (Congestive Heart Failure and Arrhythmias, grant 01C–203), and supported by the Dutch Heart Foundation.

Objectives: Investigate if the amount of reverse remodelling after CRT coincides with blood biomarker changes. Background: Blood biomarkers are predictors of heart failure, but sparse data exist on the correlation between blood biomarkers changes and reverse remodelling. Methods: Fourteen blood biomarkers, reflecting collagen turnover (PIIINP, CICP, MMP-9, TIMP-1, ICTP), inflammation (hsCRP, IL-6), myocardial stretch and injury (NT-proBNP, hsTroponin-T), inflammatory-, fibrotic- and apoptotic pathways (Galectin-3, ST2, GDF-15) and renal function (creatinine, BUN), were assessed before and six months after CRT in 213 patients from the Markers and Response to CRT study. Additionally, baseline peripheral venous (PV) and coronary sinus (CS) samples were compared. Patients were divided in 4 groups based on indexed left ventricular end systolic volume change (LVESVi): no remodelling, lower, middle, and upper tertile. Results: Mean age was 66±10 years, 62% were men, 42% had ischemic aetiology. 169 patients experienced LVESVi reduction: lower tertile 12% (5-16%), middle tertile 32% (25-37%), upper tertile 53% (44-58%). Collagen markers increased in all groups. Inflammation markers remained in normal range. hsTroponin-T decreased in all groups. Renal markers showed no clinical significant change. GDF-15, ST2 and Galectin-3 remained elevated, showing no distinct pattern. Only NT-proBNP changes corresponded to LVESVi reduction (β -1.72, P Conclusions: NT-proBNP changes are associated with amount of reverse remodelling 6 months after CRT. Thirteen other blood biomarkers, reflecting, among others, collagen turnover, fibrotic- and apoptotic pathways, are not. CS and PV samples correspond well, CS sampling does not seem to provide additional information in assessing reverse remodelling.

Introduction: Judicious patient selection for CRT may further enhance treatment response. Progress has been made by using improved markers of electrical dyssynchrony and mechanical discoordination, using QRS AREA , and systolic rebound stretch of the septum (SRSsept) or systolic stretch index (SSI), respectively. Hypothesis: We hypothesize that the presence of combined electrical and mechanical dysfunction are of added benefit in predicting a sustained CRT-response. Methods: A total of 240 CRT patients were prospectively enrolled from six centers. Patients underwent standard 12-lead electrocardiography, and echocardiography, at baseline, 6 month, and 12 month follow-up. QRS AREA was derived using vectorcardiography, and SRSsept and SSI were measured using strain-analysis. Reverse remodelling was measured as the relative decrease in left ventricular end-systolic volume, indexed to body surface area (ΔLVESVi). Sustained response was defined as ≥ 15% decrease in LVESVi, at both 6 and 12 month follow-up. Presence of left bundle branch block (LBBB) was determined according to strict American Heart Association criteria. Results: QRS AREA and SRSsept were both strong, multivariably adjusted, predictors of reverse remodelling. The presence of SRSsept ≥ 2.5%, in addition to QRS AREA ≥ 120 μVs, significantly increased the extent of reverse remodelling when compared to high QRS AREA alone (ΔLVESVi 38±21 versus 22±21%). As a result, 100% of LBBB-patients and 74% of non-LBBB patients with combined electrical and mechanical dysfunction were sustained volumetric responders, as opposed to 53% and 46% with high QRS AREA alone, respectively. Conclusions: In patients with high QRS AREA , concomitant presence of high SRSsept significantly increases 6-month remodelling after CRT. Combined presence of high SRSsept and QRS AREA , but not high QRS AREA alone, is of importance in order to ensure a sustained response after CRT in LBBB patients.

Backgrounds The majority of risk factors for cardiovascular diseases (CVDs) are modifiable. Continuous monitoring and control of these factors could significantly reduce the risk of CVDs-related morbidity and mortality. This study estimated the prevalence of modifiable risk factors in Indonesia and its co-occurence of multiple risk factors stratified by prior CVDs diagnosis status and sex. Methods Adult participants (> 15 years, N = 36,329, 57% women) with median age of 40 years were selected from a nationwide Indonesian cross-sectional study called Basic Health Research or Riset Kesehatan Dasar (Riskesdas) conducted in 2018. Thirteen risk factors were identified from the study, including smoking, a high-risk diet, inadequate fruit and vegetable consumption, a low physical activity level, the presence of mental-emotional disorders, obesity, a high waist circumference (WC), a high waist-to-height ratio (WtHR), hypertension, diabetes, a high total cholesterol level, a high low-density lipoprotein (LDL) cholesterol level, and a low high-density lipoprotein (HDL) cholesterol level. Age-adjusted prevalence ratios stratified by CVDs status and sex were calculated using Poisson regression with the robust covariance estimator. Results CVDs were found in 3% of the study population. Risk factor prevalence in the overall population ranged from 5.7 to 96.5% for diabetes and inadequate fruit and vegetable consumption respectively. Smoking, a high-risk food diet, and a low HDL cholesterol level were more prevalent in men, whereas a low physical activity level, the presence of mental-emotional disorders, obesity, a high WC, a high WtHR, hypertension, diabetes, a high total cholesterol level, and a high LDL cholesterol level were more prevalent in women. Approximately 22% of men and 18% of women had at least 4 risk factors, and these proportions were higher in participants with prior CVDs diagnosis. Conclusions There is a high prevalence of modifiable risk factors in the Indonesian adult population. Sex, age, and the presence of CVD are major determinants of the variations in risk factors. The presence of multiple risk factors, which are often inter-related, requires a comprehensive approach through health promotion, lifestyle modification and patient education.

IntroductionAchieving optimal placement of the left ventricular (LV) lead in cardiac resynchronisation therapy (CRT) is a prerequisite in order to achieve maximum clinical benefit, and is likely to help avoid non-response. Pacing outside scar tissue and targeting late activated segments may improve outcome. The present study will be the first randomised controlled trial to compare the efficacy of real-time image-guided LV lead delivery to conventional CRT implantation. In addition, to estimate the cost-effectiveness of targeted lead implantation, an early decision analytic model was developed, and described here.Methods and analysisA multicentre, interventional, randomised, controlled trial will be conducted in a total of 130 patients with a class I or IIa indication for CRT implantation. Patients will be stratified to ischaemic heart failure aetiology and 1:1 randomised to either empirical lead placement or live image-guided lead placement. Ultimate lead location and echocardiographic assessment will be performed by core laboratories, blinded to treatment allocation and patient information. Late gadolinium enhancement cardiac magnetic resonance imaging (CMR) and CINE-CMR with feature-tracking postprocessing software will be used to semi-automatically determine myocardial scar and late mechanical activation. The subsequent treatment file with optimal LV-lead positions will be fused with the fluoroscopy, resulting in live target-visualisation during the procedure. The primary endpoint is the difference in percentage of successfully targeted LV-lead location. Secondary endpoints are relative percentage reduction in indexed LV end-systolic volume, a hierarchical clinical endpoint, and quality of life. The early analytic model was developed using a Markov-model, consisting of seven mutually exclusive health states.Ethics and disseminationThe protocol was approved by the Medical Research Ethics Committee Utrecht (NL73416.041.20). All participants are required to provide written informed consent. Results will be submitted to peer-reviewed journals.Trial registration numberNCT05053568; Trial NL8666.

Background/Purpose Heart failure with preserved ejection fraction (HFpEF) is currently hard to treat, and more prevalent in women as compared to men. Therefore, focus on prevention is key. Concentric remodelling is considered a pre-stage of HFpEF, yet knowledge on distributions and risk factor relations are scarce. Therefore, we identified the prevalence of early remodelling in women and men, and studied risk factors for early remodelling in women and men at risk for heart failure. Methods Clinical and echocardiographic data from 880 individuals, included in the HELPFul cohort were analysed (mean age 62.9 ±SD 9.3 years, 68.6% women). Relative wall thickness was calculated with the formula (2*LVPWD)/LVEDD and expressed as percentage. Concentric remodelling was defined as a relative wall thickness >42%. The relationship of classical cardiovascular risk factors, anthropometric -, lifestyle -, and pregnancy factors with relative wall thickness was tested using uni- and multivariable analyses for women and men separately. The association of continuous variables with relative wall thickness was analysed per standard deviation (SD) increase. Results Relative wall thickness was similar for both men (mean 43.2 ±SD 9.5) and women (mean 42.6 ±SD 8.1). Concentric remodelling (RWT >42%) was present in 49.1% of the population. Multivariable analyses showed that age, heart rate, systolic blood pressure, hypertension, and the usage of antihypertensive medication were independently associated with relative wall thickness in women. In men, heart rate and hypertension were independently associated with relative wall thickness. No associations were found for lifestyle factors such as smoking and alcohol intake. In women, there was no significant association of hypertensive pregnancy disorders and gestational diabetes with relative wall thickness. When relative wall thickness was dichotomized with >42% as cut-off for concentric remodelling the same risk factors remained independently associated in women. Per SD increase age, systolic blood pressure, heart rate, a diagnosis of hypertension and usage of antihypertensive medication were associated with an increased risk of concentric remodelling (OR=1.39 (95% CI: 1.18–1.64), 1.27 (95% CI: 1.05–1.53), 1.32 (95% CI: 1.10–1.58), 1.61 (95% CI: 1.09–2.36) and 1.67 (95% CI: 1.16–2.43), respectively) (Figure 1). In men, only a diagnosis of hypertension was a risk factor for concentric remodelling (OR=1.80 (95% CI: 1.05–3.06)). Conclusion Left ventricular concentric remodelling was as common in women as in men visiting outpatient cardiology clinics and found in half of the population. No sex-specific -, or lifestyle related risk factors could be identified. A relation with hypertension was evident in both sexes, but surprisingly no association of hypertensive pregnancy disorders was found. Concentric remodelling in women and men remains a common, but poorly understood, phenomenon that warrants further attention. Funding Acknowledgement Type of funding sources: None.

Clinical screening of the relatives of patients with genetic cardiomyopathies is challenging, as they often lack detectable cardiac abnormalities at presentation. Life-threatening adverse events can already occur in these early stages of disease, so sensitive tools to reveal the earliest signs of disease are needed. The utility of echocardiographic deformation imaging for early detection has been explored for this population in multiple studies but has not been broadly implemented in clinical practice. The authors discuss contemporary evidence on the utility of deformation imaging in relatives of patients with genetic cardiomyopathies. The available body of data shows that deformation imaging reveals early disease-specific abnormalities in dilated cardiomyopathy, hypertrophic cardiomyopathy, and arrhythmogenic cardiomyopathy. Deformation imaging seems promising to enhance the screening and follow-up protocols in relatives, and the authors propose measures to accelerate its implementation in clinical care.

Introduction: Computational models of the cardiovascular system are widely used to simulate cardiac (dys)function. Personalization of such models for patient-specific simulation of cardiac function remains challenging. Measurement uncertainty affects accuracy of parameter estimations. In this study, we present a methodology for patient-specific estimation and uncertainty quantification of parameters in the closed-loop CircAdapt model of the human heart and circulation using echocardiographic deformation imaging. Based on patient-specific estimated parameters we aim to reveal the mechanical substrate underlying deformation abnormalities in patients with arrhythmogenic cardiomyopathy (AC).Methods: We used adaptive multiple importance sampling to estimate the posterior distribution of regional myocardial tissue properties. This methodology is implemented in the CircAdapt cardiovascular modeling platform and applied to estimate active and passive tissue properties underlying regional deformation patterns, left ventricular volumes, and right ventricular diameter. First, we tested the accuracy of this method and its inter- and intraobserver variability using nine datasets obtained in AC patients. Second, we tested the trueness of the estimation using nine in silico generated virtual patient datasets representative for various stages of AC. Finally, we applied this method to two longitudinal series of echocardiograms of two pathogenic mutation carriers without established myocardial disease at baseline.Results: Tissue characteristics of virtual patients were accurately estimated with a highest density interval containing the true parameter value of 9% (95% CI [0–79]). Variances of estimated posterior distributions in patient data and virtual data were comparable, supporting the reliability of the patient estimations. Estimations were highly reproducible with an overlap in posterior distributions of 89.9% (95% CI [60.1–95.9]). Clinically measured deformation, ejection fraction, and end-diastolic volume were accurately simulated. In presence of worsening of deformation over time, estimated tissue properties also revealed functional deterioration.Conclusion: This method facilitates patient-specific simulation-based estimation of regional ventricular tissue properties from non-invasive imaging data, taking into account both measurement and model uncertainties. Two proof-of-principle case studies suggested that this cardiac digital twin technology enables quantitative monitoring of AC disease progression in early stages of disease.