Rivaroxaban versus vitamin K antagonist treatment on the progression of coronary calcification: the IRIVASC-trial.

Vitamin K antagonists (VKA) remain the only option of anticoagulation for people with mechanical valve replacement and due to their wider availability and lower acquisition costs, VKA's remain widely used in low- and middle-income countries. It has been suggested that prolonged use of VKAs can increase the development of vascular and valvular calcification, though this effect has not been examined in larger randomized prospective trials. This investigator-initiated multicenter, prospective, randomized, open-label interventional trial randomized patients with baseline coronary or valvular calcification and an indication for prolonged oral anticoagulation therapy to Marcumar or Rivaroxaban. Patients were followed-up through repeat coronary computed tomographies to measure the progression of coronary and valvular calcification for up to 24 months. 192 patients were randomized between 2013 and 2018 to receive either Rivaroxaban or Marcumar and followed for up to 24 months. Coronary calcification significantly increased over time although there was no significant difference in progression between the groups after 12 and 24 months as measured by the Agatston score [360.7 (90.2; 1075.3) vs 380.4 (136.4; 1546.9) p = 0.69], the volume score [295.8 (93.0; 995.3) vs 335.5 (128.7; 1316.9) p = 0.95] and the mass score [58.5 (15.9; 172.0) vs 71.1 (24.8; 257.3) p = 0.5]. Dephosphorylated, uncarboxylated matrix Gla Protein (Dp-ucMGP) significantly decreased in the VKA group [Δ dp-uc MGP - 95.2 (- 554.1; 156.0) vs 231.3 (- 59.7; 388.1) p < 0.001]. There does not appear to be a relevant effect of vitamin K inhibition by the vitamin K antagonist marcumar upon coronary calcification.

The Surprise Question and clinician-predicted prognosis: systematic review and meta-analysis.

BACKGROUND: The Surprise Question, 'Would you be surprised if this person died within the next year?' is a simple tool that can be used by clinicians to identify people within the last year of life. This review aimed to determine the accuracy of this assessment, across different healthcare settings, specialties, follow-up periods and respondents. METHODS: Searches were conducted of Medline, Embase, AMED, PubMed and the Cochrane Central Register of Controlled Trials, from inception until 01 January 2024. Studies were included if they reported original data on the ability of the Surprise Question to predict survival. For each study (including subgroups), sensitivity, specificity, positive and negative predictive values and accuracy were determined. RESULTS: Our dataset comprised 56 distinct cohorts, including 68 829 patients. In a pooled analysis, the sensitivity of the Surprise Question was 0.69 ((0.64 to 0.74) I2=97.2%), specificity 0.69 ((0.63 to 0.74) I2=99.7%), positive predictive value 0.40 ((0.35 to 0.45) I2=99.4%), negative predictive value 0.89 ((0.87 to 0.91) I2=99.7%) and accuracy 0.71 ((0.68 to 0.75) I2=99.3%). The prompt performed best in populations with high event rates, shorter timeframes and when posed to more experienced respondents. CONCLUSIONS: The Surprise Question demonstrated modest accuracy with considerable heterogeneity across the population to which it was applied and to whom it was posed. Prospective studies should test whether the prompt can facilitate timely access to palliative care services, as originally envisioned. PROSPERO REGISTRATION NUMBER: CRD32022298236.

Is conduction system pacing a panacea for pacemaker therapy?

INTRODUCTION: While supported by robust evidence and decades of clinical experience, right ventricular apical pacing for bradycardia is associated with a risk of progressive left ventricular dysfunction. Cardiac resynchronization therapy for heart failure with reduced ejection fraction can result in limited electrical resynchronization due to anatomical constraints and epicardial stimulation. In both settings, directly stimulating the conduction system below the atrio-ventricular node (either the bundle of His or the left bundle branch area) has potential to overcome these limitations. Conduction system pacing has met with considerable enthusiasm in view of the more physiological electrical conduction pattern, is rapidly becoming the preferred option of pacing for bradycardia, and is gaining momentum as an alternative to conventional biventricular pacing. AREAS COVERED: This article provides a review of the current efficacy and safety data for both people requiring treatment for bradycardia and the management of heart failure with conduction delay and discusses the possible future roles for conduction system pacing in routine clinical practice. EXPERT OPINION: Conduction system pacing might be the holy grail of pacemaker therapy without the disadvantages of current approaches. However, hypothesis and enthusiasm are no match for robust data, demonstrating at least equivalent efficacy and safety to standard approaches.

Diabetes mellitus does not alter mortality or hospitalisation risk in patients with newly diagnosed heart failure with preserved ejection fraction: Time to rethink pathophysiological models of disease progression.

INTRODUCTION: Type 2 diabetes is a common and adverse prognostic co-morbidity for patients with heart failure with reduced ejection fraction (HFrEF). The effect of diabetes on long-term outcomes for heart failure with preserved ejection fraction (HFpEF) is less established. METHODS: Prospective cohort study of patients referred to a regional HF clinic with newly diagnosed with HFrEF and HFpEF according to the 2016 European Society of Cardiology guidelines. The association between diabetes, all-cause mortality and hospitalisation was quantified using Kaplan-Meier or Cox regression analysis. RESULTS: Between 1st May 2012 and 1st May 2013, of 960 unselected consecutive patients referred with suspected HF, 464 and 314 patients met the criteria for HFpEF and HFrEF respectively. Within HFpEF and HFrEF groups, patients with diabetes were more frequently male and in both groups patients with diabetes were more likely to be treated with ß-adrenoceptor antagonists and angiotensin converting enzyme inhibitors. After adjustment for age, sex, medical therapy and co-morbidities, diabetes was associated with increased mortality in individuals with HFrEF (HR 1.46 95% CI: 1.05-2.02; p = .023), but not in those with HFpEF (HR 1.26 95% CI 0.92-1.72; p = .146). CONCLUSION: In unselected patients with newly diagnosed HF, diabetes is not an adverse prognostic marker in patients with HFpEF, but is in HFrEF.

Studying Adipose Endothelial Cell/Adipocyte Cross-Talk in Human Subcutaneous Adipose Tissue.

Microvascular endothelial cells (MVECs) have many critical roles, including control of vascular tone, regulation of thrombosis, and angiogenesis. Significant heterogeneity in endothelial cell (EC) genotype and phenotype depends on their vascular bed and host disease state. The ability to isolate MVECs from tissue-specific vascular beds and individual patient groups offers the opportunity to directly compare MVEC function in different disease states. Here, using subcutaneous adipose tissue (SAT) taken at the time of insertion of cardiac implantable electronic devices (CIED), we describe a method for the isolation of a pure population of functional human subcutaneous adipose tissue MVEC (hSATMVEC) and an experimental model of hSATMVEC-adipocyte cross-talk. hSATMVEC were isolated following enzymatic digestion of SAT by incubation with anti-CD31 antibody-coated magnetic beads and passage through magnetic columns. hSATMVEC were grown and passaged on gelatin-coated plates. Experiments used cells at passages 2-4. Cells maintained classic features of EC morphology until at least passage 5. Flow cytometric assessment showed 99.5% purity of isolated hSATMVEC, defined as CD31+/CD144+/CD45-. Isolated hSATMVEC from controls had a population doubling time of approximately 57 h, and active proliferation was confirmed using a cell proliferation imaging kit. Isolated hSATMVEC function was assessed using their response to insulin stimulation and angiogenic tube-forming potential. We then established an hSATMVEC-subcutaneous adipocyte co-culture model to study cellular cross-talk and demonstrated a downstream effect of hSATMVEC on adipocyte function. hSATMVEC can be isolated from SAT taken at the time of CIED insertion and are of sufficient purity to both experimentally phenotype and study hSATMVEC-adipocyte cross-talk.

A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models.

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as an anti-fibrotic target using a predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, a small-molecule TNIK inhibitor, which exhibits desirable drug-like properties and anti-fibrotic activity across different organs in vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects in addition to its anti-fibrotic profile, validated in multiple in vivo studies. Its safety and tolerability as well as pharmacokinetics were validated in a randomized, double-blinded, placebo-controlled phase I clinical trial (NCT05154240) involving 78 healthy participants. A separate phase I trial in China, CTR20221542, also demonstrated comparable safety and pharmacokinetic profiles. This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline.

Sodium-glucose cotransporter 2 inhibitors influence skeletal muscle pathology in patients with heart failure and reduced ejection fraction.

AIMS: Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF. METHODS AND RESULTS: Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment. CONCLUSIONS: Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology.

Integration of implantable device therapy in patients with heart failure. A clinical consensus statement from the Heart Failure Association (HFA) and European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC).

Implantable devices form an integral part of the management of patients with heart failure (HF) and provide adjunctive therapies in addition to cornerstone drug treatment. Although the number of these devices is growing, only few are supported by robust evidence. Current devices aim to improve haemodynamics, improve reverse remodelling, or provide electrical therapy. A number of these devices have guideline recommendations and some have been shown to improve outcomes such as cardiac resynchronization therapy, implantable cardioverter-defibrillators and long-term mechanical support. For others, more evidence is still needed before large-scale implementation can be strongly advised. Of note, devices and drugs can work synergistically in HF as improved disease control with devices can allow for further optimization of drug therapy. Therefore, some devices might already be considered early in the disease trajectory of HF patients, while others might only be reserved for advanced HF. As such, device therapy should be integrated into HF care programmes. Unfortunately, implementation of devices, including those with the greatest evidence, in clinical care pathways is still suboptimal. This clinical consensus document of the Heart Failure Association (HFA) and European Heart Rhythm Association (EHRA) of the European Society of Cardiology (ESC) describes the physiological rationale behind device-provided therapy and also device-guided management, offers an overview of current implantable device options recommended by the guidelines and proposes a new integrated model of device therapy as a part of HF care.

The CINCH-FMR postmarket registry: Real-world long-term outcomes with percutaneous mitral valve repair with the Carillon Mitral Contour System®.

BACKGROUND: The Carillon® Mitral Contour System® has been studied in 4 prospective controlled studies in the treatment of functional mitral regurgitation (FMR) where it has been found to reduce mitral regurgitation, reduce left ventricular and atrial volumes, and be associated with improvements in clinical parameters. AIMS: The CINCH post-market registry is designed to evaluate immediate, mid-term and long-term outcomes from a post-approval study of the Carillon® device evaluated in real-world practice. METHODS: The CINCH post-market registry is a single-arm study of percutaneous mitral annuloplasty with the Carillon device in patients with functional (secondary) mitral regurgitation and symptomatic congestive heart failure when utilized in real-world conditions. Patient selection, echocardiographic hemodynamic measurements, and patient follow-up requirements were performed per standard of care at each institution. RESULTS: A total of 101 patients treated with the Carillon device at 13 sites in Germany were enrolled in the CINCH registry. The mean age was 75 ± 9 years, 57 % were male, and patient presentation included primarily NYHA class III (69 %) with MR grade 3 (68 %). Over 5 years of follow-up, all-cause mortality was 40.1 %, the incidence of HFH was 53.9 %, and the composite outcome of HFH or death was 66.4 %. At each follow-up interval through 5 years, statistically significant reductions in NYHA class (p < 0.05) and MR grade (p < 0.01) were reported. CONCLUSIONS: In this "real world" registry of the Carillon Mitral Contour System, procedural safety and medium-term follow-up outcomes is similar to the outcomes seen in the prospective, controlled clinical trials, despite being used in populations of patients that extend outside of those studied in the trials. The use of this therapy in patients with atrial functional mitral regurgitation, and heart failure with preserved ejection fraction, was notable, since these types of patients were excluded from the prospective, controlled trials. This supports possible additional patient populations who might benefit from this type of mechanical therapy. The safety profile of this therapy in this registry and in the earlier trials may support a potential role in earlier forms of secondary mitral regurgitation.

Outcomes following cardiac resynchronisation therapy in older people.

INTRODUCTION: Older patients may be less likely to receive cardiac resynchronisation therapy (CRT) for the management of heart failure. We aimed to describe the differences in clinical response, complications, and subsequent outcomes following CRT implantation compared to younger patients. METHODS: We conducted a retrospective cohort study of unselected, consecutive patients implanted with CRT devices between March 2008 and July 2017. We recorded complications, symptomatic and echocardiographic response, hospitalisation for heart failure, and all-cause mortality comparing patients aged <70, 70-79 and ≥ 80 years. RESULTS: Five hundred and seventy-four patients (median age 76 years [interquartile range 68-81], 73.3% male) received CRT. At baseline, patients aged ≥80 years had worse symptoms, were more likely to have co-morbidities, and less likely to be receiving comprehensive medical therapy, although left ventricular function was similar. Older patients were less likely to receive CRT-defibrillators compared to CRT-pacemakers. Complications were infrequent and not more common in older patients. Age was not a predictor of symptomatic or echocardiographic response to CRT (67.2%, 71.2% and 62.6% responders in patients aged <70, 70-79 and ≥ 80 years, respectively; P = 0.43), and time to first heart failure hospitalisation was similar across age groups (P = 0.28). Ten-year survival was lower for older patients (49.9%, 23.9% and 6.8% in patients aged <70, 70-79 and ≥ 80 years, respectively; P < 0.001). CONCLUSIONS: The benefits of CRT on symptoms and left ventricular function were not different in older patients despite a greater burden of co-morbidities and less optimal medical therapy. These findings support the use of CRT in an ageing population.

Efficacy and Safety of Low-Dose Protamine in Reducing Bleeding Complications during TAVI: A Propensity-Matched Comparison.

OBJECTIVES: We aimed to evaluate the efficacy and safety of low-dose protamine in reducing access site-related complications during Transcatheter Aortic Valve Implantation (TAVI) as compared to full-dose protamine. BACKGROUND: Access site-related complications represent an independent predictor of poor outcomes of TAVI. Data regarding heparin reversal with protamine and the dosage needed to prevent bleeding complications are scarce among patients undergoing TAVI. METHODS: A total of 897 patients were retrospectively included in the study. Patients who underwent percutaneous coronary intervention within 4 weeks before or concomitantly with TAVI (n = 191) were given 0.5 mg protamine for each 100 units of unfractionated heparin. All other patients (n = 706) were considered as a control group and 1 mg protamine for each 100 units of heparin was administered. RESULTS: The combined intra-hospital endpoint of death, life-threatening major bleeding, and major vascular complications were significantly more frequent in patients receiving low-dose protamine [29 (15.2%) vs. 50 (7.1%), p < 0.001]. After propensity matching (n = 130 for each group) for relevant clinical characteristics including anti-platelet therapy [19 (14.6%) vs. 6 (4.6%), p = 0.006], low-dose protamine predicted the combined endpoint (OR 3.54, 95%-CI 1.36-9.17, p = 0.009), and even in multivariable analysis, low-dose protamine continued to be a predictor of the combined endpoint in the matched model (OR 3.07, 95%-CI 1.17-8.08, p = 0.023) alongside baseline hemoglobin. CONCLUSIONS: In this propensity-matched retrospective analysis, a low-dose protamine regime is associated with a higher rate of major adverse events compared to a full-dose protamine regime following transfemoral TAVI.

Percutaneous mitral annuloplasty with the Carillon device: Outcomes in proportionate and disproportionate functional mitral regurgitation.

BACKGROUND: It has been suggested that the disparity of outcomes between the studies of transcutaneous edge-to-edge repair (TEER) for functional mitral regurgitation (FMR) in heart failure with reduced ejection fraction (HFrEF) could be due to systematic differences in the populations studied. One proposal is that there are 2 broad groups: those with proportional FMR who respond less favorably, and those in whom the FMR is greater than expected (disproportionate) FMR where edge-to-edge TEER seems to be more effective. Whether this grouping is relevant for other percutaneous interventions for FMR is unknown. OBJECTIVES: We sought to compare clinical and echocardiographic outcomes of patients with HFrEF and proportionate and disproportionate FMR treated with indirect annuloplasty using the Carillon device. METHODS: This is a pooled analysis from 3 trials of patients with FMR. Key patient eligibility in these trials specified persistent grade 2+ to 4+ FMR with >5.5 cm left ventricular (LV) end-diastolic diameter (LVEDD) and reduced ejection fraction. Patients with an effective regurgitant orifice area/LV end-diastolic volume (EROA/LVEDV) ratio under 0.15 were assigned to the proportionate FMR group (n = 74;65%) and those with a ratio above 0.15 were classed as having disproportionate FMR (n = 39;35%). RESULTS: At 12 months following treatment, both groups showed improvements in all MR variables including regurgitation volume, EROA and vena contracta. Moreover, in patients with proportionate MR there were clinically relevant and statistically significant improvements in LV volumes and diameters. There was no independent relationship between the degree of proportionality as a continuous variable and the remodeling response to Carillon therapy (change in LVEDV r = 0.17; change in LVESV r = 0.14). CONCLUSION: Percutaneous mitral annuloplasty with the Carillon device reduces MR in patients with both proportionate and disproportionate FMR, and also results in LV reverse remodeling in those with proportionate FMR. The effect on remodeling remains to be verified in a large-scale trial.

Atrial secondary mitral regurgitation: prevalence, characteristics, management, and long-term outcomes.

BACKGROUND: The prevalence, clinical characteristics, management and long-term outcomes of patients with atrial secondary mitral regurgitation (ASMR) are not well described. METHODS: We performed a retrospective, observational study of consecutive patients with grade III/IV MR determined by transthoracic echocardiography. The aetiology of MR was grouped as being either primary (due to degenerative mitral valve disease), ventricular SMR (VSMR: due to left ventricular dilatation/dysfunction), ASMR (due to LA dilatation), or other. RESULTS: A total of 388 individuals were identified who had grade III/IV MR; of whom 37 (9.5%) had ASMR, 113 (29.1%) had VSMR, 193 had primary MR (49.7%), and 45 (11.6%) were classified as having other causes. Compared to MR of other subtypes, patients with ASMR were on average older (median age 82 [74-87] years, p < 0.001), were more likely to be female (67.6%, p = 0.004) and usually had atrial fibrillation (83.8%, p = 0.001). All-cause mortality was highest in patients with ASMR (p < 0.001), but similar to that in patients with VSMR once adjusted for age and sex (hazard ratio [HR] 0.81, 95% confidence interval [CI] 0.52-1.25). Hospitalisation for worsening heart failure was more commonly observed in those with ASMR or VSMR (p < 0.001) although was similar between these groups when age and sex were accounted for (HR 0.74, 95% CI 0.34-1.58). For patients with ASMR, the only variables associated with outcomes were age and co-morbidities. CONCLUSIONS: ASMR is a prevalent and distinct disease process associated with a poor prognosis, with much of this related to older age and co-morbidities.

Cost-effectiveness of an insertable cardiac monitor in a high-risk population in the US.

BACKGROUND: Insertable cardiac monitors (ICMs) are a clinically effective means of detecting atrial fibrillation (AF) in high-risk patients, and guiding the initiation of non-vitamin K oral anticoagulants (NOACs). Their cost-effectiveness from a US clinical payer perspective is not yet known. The objective of this study was to evaluate the cost-effectiveness of ICMs compared to standard of care (SoC) for detecting AF in patients at high risk of stroke (CHADS2 ≥ 2), in the US. METHODS: Using patient data from the REVEAL AF trial (n = 393, average CHADS2 score = 2.9), a Markov model estimated the lifetime costs and benefits of detecting AF with an ICM or with SoC (specifically intermittent use of electrocardiograms and 24-h Holter monitors). Ischemic and hemorrhagic strokes, intra- and extra-cranial hemorrhages, and minor bleeds were modelled. Diagnostic and device costs, costs of treating stroke and bleeding events and medical therapy-specifically costs of NOACs were included. Costs and health outcomes, measured as quality-adjusted life years (QALYs), were discounted at 3% per annum, in line with standard practice in the US setting. One-way deterministic and probabilistic sensitivity analyses (PSA) were undertaken. RESULTS: Lifetime per-patient cost for ICM was $31,116 versus $25,330 for SoC. ICMs generated a total of 7.75 QALYs versus 7.59 for SoC, with 34 fewer strokes projected per 1000 patients. The model estimates a number needed to treat of 29 per stroke avoided. The incremental cost-effectiveness ratio was $35,528 per QALY gained. ICMs were cost-effective in 75% of PSA simulations, using a $50,000 per QALY threshold, and a 100% probability of being cost-effective at a WTP threshold of $150,000 per QALY. CONCLUSIONS: The use of ICMs to identify AF in a high-risk population is likely to be cost-effective in the US healthcare setting.

Improving the management of left ventricular thrombus in a tertiary cardiology centre: a quality improvement project.

Left ventricular (LV) thrombus is an increasingly recognised complication following anterior myocardial infarction and non-ischaemic cardiomyopathy. Whilst vitamin K antagonists (VKA) remain the only approved therapeutic option to reduce the risk of systemic thromboembolism including stroke, the off-label use of direct oral anticoagulants (DOACs) is becoming an attractive alternative.We aimed to improve the diagnosis and management of LV thrombus at a tertiary cardiology centre using quality improvement methodology. Outcomes included increasing the use of DOACs from 25% to 70% over a period of 1 year and shorten length of time from diagnosis to repeat imaging to within 3-6 months as recommended by guidelines.During the first Plan-Do-Study-Action (PDSA) cycle, we identified 84 patients diagnosed with LV thrombus between 1 December 2012 and 30 June 2018. The majority (74%) were prescribed VKA. Repeat imaging occurred in 89% of patients, but only 55% using the same modality. The mean duration between diagnosis and repeat imaging was 233±251 days. There were no significant differences between VKA and DOAC in terms of thrombus resolution, systemic embolisation or clinically significant bleeding. We published trust-wide guidelines on the management of LV thrombus with recommendations supporting the use of DOACs and appropriate follow-up imaging. A second PDSA cycle undertaken between 1 October 2019 and 31 March 2020 identified a further 20 patients. DOAC use increased to 70% and 70% of patients underwent follow-up imaging following a mean duration of 140±61 days, although in only 36% using the same modality.Using quality improvement methodology, we confirmed safe and efficient use of DOAC in the setting of LV thrombus. We published trust guidelines supporting their use, which was associated with an increase in DOAC use and in earlier follow-up imaging in line with our recommendations.