Cellular Senescence, Mitochondrial Dysfunction, and Their Link to Cardiovascular Disease.

Cardiovascular diseases (CVDs), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disability. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, an increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to an even greater health and economic burden as the global average life expectancy increases and consequently the world's population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction including energy starvation and oxidative stress, mitochondria dynamics imbalance, cell apoptosis, mitophagy, and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.

Exogenous Transforming Growth Factor-ß1 and Its Helminth-Derived Mimic Attenuate the Heart's Inflammatory Response to Ischemic Injury and Reduce Mature Scar Size.

Coronary reperfusion after acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage ischemic heart muscle. However, subsequent inflammatory responses within the infarct lead to further loss of viable myocardium. Transforming growth factor (TGF)-ß1 is a potent anti-inflammatory cytokine released in response to tissue injury. The aim of this study was to investigate the protective effects of TGF-ß1 after MI. In patients with STEMI, there was a significant correlation (P = 0.003) between higher circulating TGF-ß1 levels at 24 hours after MI and a reduction in infarct size after 3 months, suggesting a protective role of early increase in circulating TGF-ß1. A mouse model of cardiac ischemia reperfusion was used to demonstrate multiple benefits of exogenous TGF-ß1 delivered in the acute phase. It led to a significantly smaller infarct size (30% reduction, P = 0.025), reduced inflammatory infiltrate (28% reduction, P = 0.015), lower intracardiac expression of inflammatory cytokines IL-1ß and chemokine (C-C motif) ligand 2 (>50% reduction, P = 0.038 and 0.0004, respectively) at 24 hours, and reduced scar size at 4 weeks (21% reduction, P = 0.015) after reperfusion. Furthermore, a low-fibrogenic mimic of TGF-ß1, secreted by the helminth parasite Heligmosomoides polygyrus, had an almost identical protective effect on injured mouse hearts. Finally, genetic studies indicated that this benefit was mediated by TGF-ß signaling in the vascular endothelium.

Fractalkine/CX3CR1 in Dilated Cardiomyopathy: A Potential Future Target for Immunomodulatory Therapy?

Dilated cardiomyopathy (DCM) is a cardiac condition with structural and functional impairment, where either the left ventricle or both ventricular chambers are enlarged, coinciding with reduced systolic pump function (reduced ejection fraction, rEF). The prevalence of DCM is more than 1:250 individuals, and mortality largely due to heart failure in two-third of cases, and sudden cardiac death in one-third of patients. Damage to the myocardium, whether from a genetic or environmental cause such as viruses, triggers inflammation and recruits immune cells to the heart to repair the myocardium. Examination of myocardial biopsy tissue often reveals an inflammatory cell infiltrate, T lymphocyte (T cell) infiltration, or other activated immune cells. Despite medical therapy, adverse outcomes for DCM remain. The evidence base and existing literature suggest that upregulation of CX3CR1, migration of immune cells, together with cytomegalovirus (CMV) seropositivity is associated with worse outcomes in patients with dilated cardiomyopathy. We hypothesise that this potentially occurs through cardiac inflammation and fibrosis, resulting in adverse remodelling. Immune modulators to target this pathway may potentially improve outcomes above and beyond current guideline-recommended therapy.

Microvascular Obstruction in Acute Myocardial Infarction, a Potential Therapeutic Target.

Microvascular obstruction (MVO) is a recognised phenomenon following mechanical reperfusion in patients presenting with ST-segment elevation myocardial infarction (STEMI). Invasive and non-invasive modalities to detect and measure the extent of MVO vary in their accuracy, suggesting that this phenomenon may reflect a spectrum of pathophysiological changes at the level of coronary microcirculation. The importance of detecting MVO lies in the observation that its presence adds incremental risk to patients following STEMI treatment. This increased risk is associated with adverse cardiac remodelling seen on cardiac imaging, increased infarct size, and worse patient outcomes. This review provides an outline of the pathophysiology, clinical implications, and prognosis of MVO in STEMI. It describes historic and novel pharmacological and non-pharmacological therapies to address this phenomenon in conjunction with primary PCI.

Arginine Vasopressin Plays a Role in Microvascular Dysfunction After ST-Elevation Myocardial Infarction.

Background Coronary microvascular dysfunction (CMD) predicts mortality after ST-elevation-myocardial infarction (STEMI). Arginine vasopressin (AVP) may be implicated, but data in humans are lacking, and no study has investigated the link between arginine vasopressin and invasive measures of CMD. Methods and Results We invasively assessed CMD in 55 patients with STEMI treated with primary percutaneous coronary intervention (PPCI), by measuring the index of microcirculatory resistance after PPCI. In a separate group of 45 patients with STEMI/PPCI, recruited for a clinical trial, we measured infarct size and microvascular obstruction with cardiac magnetic resonance (CMR) imaging at 1 week and 12 weeks post-STEMI. Serum copeptin was measured at 4 time points before and after PPCI in all patients with STEMI. Plasma copeptin levels fell from 92.5 pmol/L before reperfusion to 6.4 pmol/L at 24 hours. Copeptin inversely correlated with diastolic, but not systolic, blood pressure (r=-0.431, P=0.001), suggesting it is released in response to myocardial ischemia. Persistently raised copeptin at 24 hours was correlated with higher index of microcirculatory resistance (r=0.372, P=0.011). Patients with microvascular obstruction on early CMR imaging showed a trend toward higher admission copeptin, which was not statistically significant. Copeptin levels were not associated with infarct size on either early or late CMR. Conclusions Patients with CMD after STEMI have persistently elevated copeptin at 24 hours, suggesting arginine vasopressin may contribute to microvascular dysfunction. Arginine vasopressin receptor antagonists may represent a novel therapeutic option in patients with STEMI and CMD.

Clinical outcomes of coronary intravascular lithotripsy in patients with stent failure (COIL registry).

BACKGROUND: Intravascular lithotripsy (IVL) has been demonstrated to be an effective treatment of calcified de novo coronary lesions. Safety data on the use of IVL within stented segments are lacking. We sought to evaluate the safety, feasibility, and long-term outcomes of IVL in patients with stent failure. METHODS: This was a retrospective multi-centre registry that included consecutive patients with stent failure who had undergone IVL treatment. The primary efficacy endpoint was procedural success defined as residual stenosis <30% (determined by quantitative coronary angiography analysis) in patients who survived hospital admission without in-hospital adverse events. Major adverse cardiovascular events (MACE) were defined as the composite endpoints of cardiovascular death, spontaneous myocardial infarction, and target vessel revascularisation at one-year follow up. RESULTS: 102 patients were included in this study. Mean age was 73 ± 9 years and 81% were male. The duration from previous stent implantation and IVL treatment was 24 (interquartile range 7-76) months, of which 10.8% received IVL for acute under-expanded stent. IVL treatment allowed significant improvement in both minimal lumen diameter (1.14 ± 0.60 to 2.53 ± 0.59, P < 0.001) and degree of stenosis (66.8 ± 19.9 to 20.3 ± 11.3%, P < 0.001). The rate of procedural success was 78.4% (80/102 of patients). The one-year MACE was 15.7%. Ostial disease (HR 5.16; 95% CI 1.19 to 22.33; P = 0.028) and lesion length (HR 1.05; 95% CI 1.01 to 1.10; P = 0.010) were independently associated with one-year MACE. CONCLUSIONS: In patients with stent failure, IVL is a safe and feasible treatment for this high-risk group.

Modification of the GRACE Risk Score for Risk Prediction in Patients With Acute Coronary Syndromes.

Importance: The Global Registry of Acute Coronary Events (GRACE) risk score, a guideline-recommended risk stratification tool for patients presenting with acute coronary syndromes (ACS), does not consider the extent of myocardial injury. Objective: To assess the incremental predictive value of a modified GRACE score incorporating high-sensitivity cardiac troponin (hs-cTn) T at presentation, a surrogate of the extent of myocardial injury. Design, Setting, and Participants: This retrospectively designed longitudinal cohort study examined 3 independent cohorts of 9803 patients with ACS enrolled from September 2009 to December 2017; 2 ACS derivation cohorts (Heidelberg ACS cohort and Newcastle STEMI cohort) and an ACS validation cohort (SPUM-ACS study). The Heidelberg ACS cohort included 2535 and the SPUM-ACS study 4288 consecutive patients presenting with a working diagnosis of ACS. The Newcastle STEMI cohort included 2980 consecutive patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Data were analyzed from March to June 2023. Exposures: In-hospital, 30-day, and 1-year mortality risk estimates derived from an updated risk score that incorporates continuous hs-cTn T at presentation (modified GRACE). Main Outcomes and Measures: The predictive value of continuous hs-cTn T and modified GRACE risk score compared with the original GRACE risk score. Study end points were all-cause mortality during hospitalization and at 30 days and 1 year after the index event. Results: Of 9450 included patients, 7313 (77.4%) were male, and the mean (SD) age at presentation was 64.2 (12.6) years. Using continuous rather than binary hs-cTn T conferred improved discrimination and reclassification compared with the original GRACE score (in-hospital mortality: area under the receiver operating characteristic curve [AUC], 0.835 vs 0.741; continuous net reclassification improvement [NRI], 0.208; 30-day mortality: AUC, 0.828 vs 0.740; NRI, 0.312; 1-year mortality: AUC, 0.785 vs 0.778; NRI, 0.078) in the derivation cohort. These findings were confirmed in the validation cohort. In the pooled population of 9450 patients, modified GRACE risk score showed superior performance compared with the original GRACE risk score in terms of reclassification and discrimination for in-hospital mortality end point (AUC, 0.878 vs 0.780; NRI, 0.097), 30-day mortality end point (AUC, 0.858 vs 0.771; NRI, 0.08), and 1-year mortality end point (AUC, 0.813 vs 0.797; NRI, 0.056). Conclusions and Relevance: In this study, using continuous rather than binary hs-cTn T at presentation, a proxy of the extent of myocardial injury, in the GRACE risk score improved the mortality risk prediction in patients with ACS.

Effector T cell chemokine IP-10 predicts cardiac recovery and clinical outcomes post-myocardial infarction.

Background and aims: Preclinical data suggest that activation of the adaptive immune system is critical for myocardial repair processes in acute myocardial infarction. The aim of the present study was to determine the clinical value of baseline effector T cell chemokine IP-10 blood levels in the acute phase of ST-segment elevation myocardial infarction (STEMI) for the prediction of the left ventricular function changes and cardiovascular outcomes after STEMI. Methods: Serum IP-10 levels were retrospectively quantified in two independent cohorts of STEMI patients undergoing primary percutaneous coronary intervention. Results: We report a biphasic response of the effector T cell trafficking chemokine IP-10 characterized by an initial increase of its serum levels in the acute phase of STEMI followed by a rapid reduction at 90min post reperfusion. Patients at the highest IP-10 tertile presented also with more CD4 effector memory T cells (CD4 TEM cells), but not other T cell subtypes, in blood. In the Newcastle cohort (n=47), patients in the highest IP-10 tertile or CD4 TEM cells at admission exhibited an improved cardiac systolic function 12 weeks after STEMI compared to patients in the lowest IP-10 tertile. In the Heidelberg cohort (n=331), STEMI patients were followed for a median of 540 days for major adverse cardiovascular events (MACE). Patients presenting with higher serum IP-10 levels at admission had a lower risk for MACE after adjustment for traditional risk factors, CRP and high-sensitivity troponin-T levels (highest vs. rest quarters: HR [95% CI]=0.420 [0.218-0.808]). Conclusion: Increased serum levels of IP-10 in the acute phase of STEMI predict a better recovery in cardiac systolic function and less adverse events in patients after STEMI.

Fractalkine Signalling (CX3CL1/CX3CR1 Axis) as an Emerging Target in Coronary Artery Disease.

Acute myocardial infarction (MI) is the most common and dramatic complication of atherosclerosis, which, despite successful reperfusion therapy, can lead to incident heart failure (HF). HF occurs when the healing process is impaired due to adverse left ventricular remodelling, and can be the result of so-called ischaemia/reperfusion injury (IRI), visualised by the development of intramyocardial haemorrhage (IMH) or microvascular obstruction (MVO) in cardiac MRI. Thus far, translation of novel pharmacological strategies from preclinical studies to target either IRI or HF post MI have been largely unsuccessful. Anti-inflammatory therapies also carry the risk of affecting the immune system. Fractalkine (FKN, CX3CL1) is a unique chemokine, present as a transmembrane protein on the endothelium, or following cleavage as a soluble ligand, attracting leukocyte subsets expressing the corresponding receptor CX3CR1. We have shown previously that the fractalkine receptor CX3CR1 is associated with MVO in patients undergoing primary PCI. Moreover, inhibition of CX3CR1 with an allosteric small molecule antagonist (KAND567) in the rat MI model reduces acute infarct size, inflammation, and IMH. Here we review the cellular biology of fractalkine and its receptor, along with ongoing studies that introduce CX3CR1 as a future target in coronary artery disease, specifically in patients with myocardial infarction.

Senescent cardiomyocytes contribute to cardiac dysfunction following myocardial infarction.

Myocardial infarction is a leading cause of morbidity and mortality. While reperfusion is now standard therapy, pathological remodelling leading to heart failure remains a clinical problem. Cellular senescence has been shown to contribute to disease pathophysiology and treatment with the senolytic navitoclax attenuates inflammation, reduces adverse myocardial remodelling and results in improved functional recovery. However, it remains unclear which senescent cell populations contribute to these processes. To identify whether senescent cardiomyocytes contribute to disease pathophysiology post-myocardial infarction, we established a transgenic model in which p16 (CDKN2A) expression was specifically knocked-out in the cardiomyocyte population. Following myocardial infarction, mice lacking cardiomyocyte p16 expression demonstrated no difference in cardiomyocyte hypertrophy but exhibited improved cardiac function and significantly reduced scar size in comparison to control animals. This data demonstrates that senescent cardiomyocytes participate in pathological myocardial remodelling. Importantly, inhibition of cardiomyocyte senescence led to reduced senescence-associated inflammation and decreased senescence-associated markers within other myocardial lineages, consistent with the hypothesis that cardiomyocytes promote pathological remodelling by spreading senescence to other cell-types. Collectively this study presents the demonstration that senescent cardiomyocytes are major contributors to myocardial remodelling and dysfunction following a myocardial infarction. Therefore, to maximise the potential for clinical translation, it is important to further understand the mechanisms underlying cardiomyocyte senescence and how to optimise senolytic strategies to target this cell lineage.

Senescent cardiomyocytes contribute to cardiac dysfunction following myocardial infarction.

Myocardial infarction is a leading cause of morbidity and mortality. While reperfusion is now standard therapy, pathological remodeling leading to heart failure remains a clinical problem. Cellular senescence has been shown to contribute to disease pathophysiology and treatment with the senolytic navitoclax attenuates inflammation, reduces adverse myocardial remodeling and results in improved functional recovery. However, it remains unclear which senescent cell populations contribute to these processes. To identify whether senescent cardiomyocytes contribute to disease pathophysiology post-myocardial infarction, we established a transgenic model in which p16 (CDKN2A) expression was specifically knocked-out in the cardiomyocyte population. Following myocardial infarction, mice lacking cardiomyocyte p16 expression demonstrated no difference in cardiomyocyte hypertrophy but exhibited improved cardiac function and significantly reduced scar size in comparison to control animals. This data demonstrates that senescent cardiomyocytes participate in pathological myocardial remodeling. Importantly, inhibition of cardiomyocyte senescence led to reduced senescence-associated inflammation and decreased senescence-associated markers within other myocardial lineages, consistent with the hypothesis that cardiomyocytes promote pathological remodeling by spreading senescence to other cell-types. Collectively this study presents a novel demonstration that senescent cardiomyocytes are major contributors to myocardial remodeling and dysfunction following a myocardial infarction. Therefore, to maximize the potential for clinical translation, it is important to further understand the mechanisms underlying cardiomyocyte senescence and how to optimize senolytic strategies to target this cell lineage.

The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation.

Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury.

Heart Disease and Ageing: The Roles of Senescence, Mitochondria, and Telomerase in Cardiovascular Disease.

During ageing molecular damage leads to the accumulation of several hallmarks of ageing including mitochondrial dysfunction, cellular senescence, genetic instability and chronic inflammation, which contribute to the development and progression of ageing-associated diseases including cardiovascular disease. Consequently, understanding how these hallmarks of biological ageing interact with the cardiovascular system and each other is fundamental to the pursuit of improving cardiovascular health globally. This review provides an overview of our current understanding of how candidate hallmarks contribute to cardiovascular diseases such as atherosclerosis, coronary artery disease and subsequent myocardial infarction, and age-related heart failure. Further, we consider the evidence that, even in the absence of chronological age, acute cellular stress leading to accelerated biological ageing expedites cardiovascular dysfunction and impacts on cardiovascular health. Finally, we consider the opportunities that modulating hallmarks of ageing offer for the development of novel cardiovascular therapeutics.

Activation of telomerase by TA-65 enhances immunity and reduces inflammation post myocardial infarction.

Myocardial infarction (MI) accelerates immune ageing characterised by lymphopenia, expansion of terminally differentiated CD8+ T-lymphocytes (CD8+ TEMRA) and inflammation. Pre-clinical data showed that TA-65, an oral telomerase activator, reduced immune ageing and inflammation after MI. We conducted a double blinded randomised controlled pilot trial evaluating the use of TA-65 to reduce immune cell ageing in patients following MI. Ninety MI patients aged over 65 years were randomised to either TA-65 (16 mg daily) or placebo for 12 months. Peripheral blood leucocytes were analysed by flow cytometry. The pre-defined primary endpoint was the proportion of CD8+ T-lymphocytes which were CD8+ TEMRA after 12 months. Secondary outcomes included high-sensitivity C-reactive protein (hsCRP) levels. Median age of participants was 71 years. Proportions of CD8+ TEMRA did not differ after 12 months between treatment groups. There was a significant increase in mean total lymphocyte count in the TA-65 group after 12 months (estimated treatment effect: + 285 cells/µl (95% CI: 117-452 cells/ µ l, p < 0.004), driven by significant increases from baseline in CD3+, CD4+, and CD8+ T-lymphocytes, B-lymphocytes and natural killer cells. No increase in lymphocyte populations was seen in the placebo group. At 12 months, hsCRP was 62% lower in the TA-65 group compared to placebo (1.1 vs. 2.9 mg/L). Patients in the TA-65 arm experienced significantly fewer adverse events (130 vs. 185, p = 0.002). TA-65 did not alter CD8+ TEMRA but increased all major lymphocyte subsets and reduced hsCRP in elderly patients with MI after 12 months.

Very Early Discharge After Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction: Mortality Outcomes at Six Months.

BACKGROUND: Current guidelines recommend that low risk patients presenting with ST-segment elevation myocardial infarction (STEMI) and undergoing uncomplicated primary percutaneous coronary intervention (PPCI) can be discharged home in 48-72 h. We report the safety of early discharge in STEMI patients undergoing uncomplicated PPCI after 24-h stay in-hospital. METHODS: We performed a retrospective analysis of prospectively collected data of consecutive patients presenting with STEMI between January 2014 and December 2020. One- and 6-month mortality rates were compared between patients who underwent next day (early discharge group) and two days in-hospital stay (standard discharge group). RESULTS: Of 6119 STEMI patients, 4033 were included in the analysis, of whom 1674 (42 %) underwent early discharge. Patients in the early discharge group were younger, more likely to be male, and had a lower peak troponin. Both groups had similar ischemia- and door-to-balloon time, but anterior STEMI were less frequent in the early discharge group. The 1- and 6-month mortality rate for the whole cohort was 0.6 % and 1.3 %, respectively. After adjustment, there were no significant differences in the 1-month [HR 0.54; 95 % CI (0.20 to 1.47), P = 0.23] and 6-month mortality [HR 0.73; 95 % CI (0.38 to 1.41), P = 0.35] between early and standard discharge groups. Age, admission heart rate and chronic obstructive lung disease were identified as independent predictors of 6-month mortality in patients who underwent early discharge strategy. CONCLUSION: Our data confirms safety of next day discharge of patients presenting with STEMI after successful PPCI and uncomplicated post-procedural course.

Cathepsin S Levels and Survival Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes.

BACKGROUND: Patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are at high residual risk for long-term cardiovascular (CV) mortality. Cathepsin S (CTSS) is a lysosomal cysteine protease with elastolytic and collagenolytic activity that has been involved in atherosclerotic plaque rupture. OBJECTIVES: The purpose of this study was to determine the following: 1) the prognostic value of circulating CTSS measured at patient admission for long-term mortality in NSTE-ACS; and 2) its additive value over the GRACE (Global Registry of Acute Coronary Events) risk score. METHODS: This was a single-center cohort study, consecutively recruiting patients with adjudicated NSTE-ACS (n = 1,112) from the emergency department of an academic hospital. CTSS was measured in serum using enzyme-linked immunosorbent assay. All-cause mortality at 8 years was the primary endpoint. CV death was the secondary endpoint. RESULTS: In total, 367 (33.0%) deaths were recorded. CTSS was associated with increased risk of all-cause mortality (HR for highest vs lowest quarter of CTSS: 1.89; 95% CI: 1.34-2.66; P < 0.001) and CV death (HR: 2.58; 95% CI: 1.15-5.77; P = 0.021) after adjusting for traditional CV risk factors, high-sensitivity C-reactive protein, left ventricular ejection fraction, high-sensitivity troponin-T, revascularization and index diagnosis (unstable angina/ non-ST-segment elevation myocardial infarction). When CTSS was added to the GRACE score, it conferred significant discrimination and reclassification value for all-cause mortality (Delta Harrell's C: 0.03; 95% CI: 0.012-0.047; P = 0.001; and net reclassification improvement = 0.202; P = 0.003) and CV death (AUC: 0.056; 95% CI: 0.017-0.095; P = 0.005; and net reclassification improvement = 0.390; P = 0.001) even after additionally considering high-sensitivity troponin-T and left ventricular ejection fraction. CONCLUSIONS: Circulating CTSS is a predictor of long-term mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score.

Immunosenescence profiles of lymphocyte compartments and multiple long-term conditions (multimorbidity) in very old adults: The Newcastle 85+ Study.

Immunosenescence, a decline in immune system function, has been linked to several age-related diseases and ageing syndromes. Very old adults (aged ≥ 85 years) live with multiple long-term conditions (MLTC, also known as multimorbidity)-a complex phenomenon of poor health defined by either counts, indices, or patterns, but little is known about the relationship between an ageing immune system and MLTC in this age group. We utilised baseline data from the Newcastle 85+ Study to investigate the associations between previously defined immunosenescence profiles of lymphocyte compartments and MLTC counts and patterns (from 16 chronic diseases/ageing syndromes). Seven hundred and three participants had MLTC and complete data for all 16 conditions, a median and mean of 5 (range 2-11) and 62.2% had ≥ 5 conditions. Three distinct MLTC patterns emerged by clustering: Cluster 1 ('Low frequency cardiometabolic-cerebrovascular diseases', n = 209), Cluster 2 ('High ageing syndromes-arthritis', n = 240), and Cluster 3 ('Hypertensive-renal impairment', n = 254). Although having a more senescent phenotype, characterised by higher frequency of CD4 and CD8 senescence-like effector memory cells and lower CD4/CD8 ratio, was not associated with MLTC compared with less senescent phenotype, the results warrant further investigation, including whether immunosenescence drives change in MLTC and influences MLTC severity in late adulthood.

Longer leukocyte telomere length is associated with myeloid inflammation and increased mortality after transcatheter aortic valve replacement.

Aims: Inflammatory activation of leukocytes may limit prognosis of patients (pts) with severe aortic valve stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). Leukocyte telomere length (LTL) is a marker of proliferative capacity and inflammatory responsiveness but the impact of LTL on the prognosis in AS remains elusive. The aim of this study was to analyse the association of LTL with inflammatory markers and prognosis of pts undergoing TAVR. Methods and results: LTL was analysed using quantitative real-time PCR in 285 consecutive pts (median age 82 years) undergoing TAVR and correlated with 18-month all-cause mortality. C-reactive protein was significantly elevated in pts with the longest LTL (P = 0.017), paralleled by increased procalcitonin (PCT) serum levels (P = 0.0006). This inflammatory reaction was accompanied by increased myeloid cells in the highest LTL tertile, mainly a rise in circulating neutrophils (P = 0.0025) and monocytes (P = 0.01). Multivariate analysis revealed LTL (HR 2.6, 95%CI 1.4-5.1, P= 0.004) and PCT levels (HR 4.3, 95%CI 1.7-11.0, P = 0.003) as independent predictors of mortality. Conclusions: Longer LTL is associated with increased mortality after TAVR. This might be explained by enhanced proliferative capacity of cells resulting in myeloid and systemic inflammation. Our findings suggest that targeting the specific inflammation pathways could present a novel strategy to augment survival in selected patients with degenerative aortic stenosis.

Clinical frailty, and not features of acute infection, is associated with late mortality in COVID-19: a retrospective cohort study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is associated with excess mortality after hospital discharge. Identification of patients at increased risk of death following hospital discharge is needed to guide clinical monitoring and early intervention. Herein, we aimed to identify predictors of early vs. late mortality in COVID-19 patients. METHODS: A total of 471 patients with polymerase chain reaction-confirmed COVID-19 were followed up for 9 months [median (inter-quartile range) of follow-up time: 271 (14) days] after hospital admission. COVID-19-related signs and symptoms, laboratory features, co-morbidities, Coronavirus Clinical Characterisation Consortium (4C) mortality and Clinical Frailty Scale (CFS) scores were analysed by logistic regression for association with early (28 day) vs. late mortality. Receiver operating characteristic (ROC) analysis was used to determine the discriminative value of 4C and CFS scores for early vs. late mortality. RESULTS: A total of 120 patients died within 28 days from hospital admission. Of the remaining 351 patients, 41 died within the next 8 months. Respiratory failure, systemic inflammation, and renal impairment were associated with early mortality, while active cancer and dementia were associated with late mortality, after adjustment for age and sex. 4C mortality score and CFS were associated with both early [odds ratio (OR) (95% confidence interval-CI): 4C: 1.34 (1.25-1.45); CFS: 1.49 (1.33-1.66)] and late [OR (95% CI): 4C: 1.23 (1.12-1.36); CFS: 2.04 (1.62-2.56)] mortality. After adjustment for CFS, the association between 4C and late mortality was lost. By ROC analysis, 4C mortality score was superior to CFS for 28 day mortality [area under the curve (AUC) (95% CI): 0.779 (0.732-0.825) vs. 0.723 (0.673-0.773), respectively; P = 0.039]. In contrast, CFS had higher predictive value for late mortality compared with 4C mortality score [AUC (95% CI): 0.830 (0.776-0.883) vs. 0.724 (0.650-0.798), respectively; P = 0.007]. CONCLUSIONS: In our cohort, late mortality in COVID-19 patients is more strongly associated with premorbid clinical frailty than with severity of the acute infection phase.