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OBJECTIVES: End-stage renal disease is associated with a high risk of cardiovascular disease. We compared the concentration and prognostic ability of high sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) and cardiac myosin-binding protein C (cMyC) among stable hemodialysis patients. METHODS: Patients were sampled before and after hemodialysis. We measured hs-cTnI, hs-cTnT and cMyC and used Cox regressions to assess the association between quartiles of concentrations and all-cause mortality and a combination of cardiovascular events and all-cause mortality during follow-up. RESULTS: A total of 307 patients were included, 204 males, mean age 66 years (SD 14). Before dialysis, 299 (99â¯%) had a hs-cTnT concentration above the 99th percentile, compared to 188 (66â¯%) for cMyC and 35 (11â¯%) for hs-cTnI. Hs-cTnT (23â¯%, p<0.001) and hs-cTnI (15â¯%, p=0.049) but not cMyC (4â¯%, p=0.256) decreased during dialysis. Follow-up was a median of 924 days (492-957 days); patients in the 3rd and 4th quartiles of hs-cTnT (3rd:HR 3.0, 95â¯% CI 1.5-5.8, 4th:5.2, 2.7-9.8) and the 4th quartile of hs-cTnI (HR 3.8, 2.2-6.8) had an increased risk of mortality. Both were associated with an increased risk of the combined endpoint for patients in the 3rd and 4th quartiles. cMyC concentrations were not associated with risk of mortality or cardiovascular event. CONCLUSIONS: Hs-cTnT was above the 99th percentile in almost all patients. This was less frequent for hs-cTnI and cMyC. High cTn levels were associated with a 3-5-fold higher mortality. This association was not present for cMyC. These findings are important for management of hemodialysis patients.
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Infarto del Miocardio , Masculino , Humanos , Anciano , Estudios de Cohortes , Biomarcadores , Infarto del Miocardio/diagnóstico , Troponina T , Diálisis Renal , Troponina IRESUMEN
Takotsubo syndrome (TTS) is a severe but reversible acute heart failure syndrome that occurs following high catecholaminergic stress. TTS patients are similar to those with acute coronary syndrome, with chest pain, dyspnoea and ST segment changes on electrocardiogram, but are characterised by apical akinesia of the left ventricle, with basal hyperkinesia in the absence of culprit coronary artery stenosis. The pathophysiology of TTS is not completely understood and there is a paucity of evidence to guide treatment. The mechanisms of TTS are thought to involve catecholaminergic myocardial stunning, microvascular dysfunction, increased inflammation and changes in cardiomyocyte metabolism. Here, we summarise the available literature to focus on the molecular basis for the pathophysiology of TTS to advance the understanding of the condition.
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Síndrome Coronario Agudo , Cardiomiopatía de Takotsubo , Humanos , Cardiomiopatía de Takotsubo/etiología , Electrocardiografía , Arritmias Cardíacas , Ventrículos CardíacosRESUMEN
Engagement of the sarcoplasmic reticulum (SR) Ca2+ stores for excitation-contraction (EC)-coupling is a fundamental feature of cardiac muscle cells. Extracellular matrix (ECM) proteins that form the extracellular scaffolding supporting cardiac contractile activity are thought to play an integral role in the modulation of EC-coupling. At baseline, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) show poor utilisation of SR Ca2+ stores, leading to inefficient EC-coupling, like developing or human CMs in cardiac diseases such as heart failure. We hypothesised that integrin ligand-receptor interactions between ECM proteins and CMs recruit the SR to Ca2+ cycling during EC-coupling. hiPSC-CM monolayers were cultured on fibronectin-coated glass before 24 h treatment with fibril-forming peptides containing the integrin-binding tripeptide sequence arginine-glycine-aspartic acid (2 mM). Micropipette application of 40 mM caffeine in standard or Na+/Ca2+-free Tyrode's solutions was used to assess the Ca2+ removal mechanisms. Microelectrode recordings were conducted to analyse action potentials in current-clamp. Confocal images of labelled hiPSC-CMs were analysed to investigate hiPSC-CM morphology and ultrastructural arrangements in Ca2+ release units. This study demonstrates that peptides containing the integrin-binding sequence arginine-glycine-aspartic acid (1) abbreviate hiPSC-CM Ca2+ transient and action potential duration, (2) increase co-localisation between L-type Ca2+ channels and ryanodine receptors involved in EC-coupling, and (3) increase the rate of SR-mediated Ca2+ cycling. We conclude that integrin-binding peptides induce recruitment of the SR for Ca2+ cycling in EC-coupling through functional and structural improvements and demonstrate the importance of the ECM in modulating cardiomyocyte function in physiology.
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Células Madre Pluripotentes Inducidas , Retículo Sarcoplasmático , Arginina/metabolismo , Ácido Aspártico/metabolismo , Cafeína/farmacología , Calcio/metabolismo , Fibronectinas/metabolismo , Glicina/metabolismo , Humanos , Integrinas/metabolismo , Ligandos , Miocitos Cardíacos/metabolismo , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Retículo Sarcoplasmático/metabolismoRESUMEN
Current clinical guidelines emphasize the unmet need for technological innovations to guide physician decision-making and to transit from conventional care to personalized cardiovascular medicine. Biomarker-guided cardiovascular therapy represents an interesting approach to inform tailored treatment selection and monitor ongoing efficacy. However, results from previous publications cast some doubts about the clinical applicability of biomarkers to direct individualized treatment. In recent years, the non-coding human transcriptome has emerged as a new opportunity for the development of novel therapeutic strategies and biomarker discovery. Non-coding RNA (ncRNA) signatures may provide an accurate molecular fingerprint of patient phenotypes and capture levels of information that could complement traditional markers and established clinical variables. Importantly, ncRNAs have been identified in body fluids and their concentrations change with physiology and pathology, thus representing promising non-invasive biomarkers. Previous publications highlight the translational applicability of circulating ncRNAs for diagnosis and prognostic stratification within cardiology. Numerous independent studies have also evaluated the potential of the circulating non-coding transcriptome to predict and monitor response to cardiovascular treatment. However, this field has not been reviewed in detail. Here, we discuss the state-of-the-art research into circulating ncRNAs, specifically microRNAs and long non-coding RNAs, to support clinical decision-making in cardiovascular therapy. Furthermore, we summarize current methodological and conceptual limitations and propose future steps for their incorporation into personalized cardiology. Despite the lack of robust population-based studies and technical barriers, circulating ncRNAs emerge as a promising tool for biomarker-guided therapy.
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Biomarcadores/sangre , Enfermedades Cardiovasculares , MicroARN Circulante/sangre , Medicina de Precisión/métodos , ARN no Traducido/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/terapia , HumanosAsunto(s)
Cardiología , Sistema Cardiovascular , Neoplasias , Humanos , Corazón , Neoplasias/terapiaRESUMEN
Heart failure with preserved ejection fraction (HFpEF) is increasingly prevalent and now accounts for half of all heart failure cases. This rise is largely attributed to growing rates of obesity, hypertension, and diabetes. Despite its prevalence, the pathophysiological mechanisms of HFpEF are not fully understood. The heart, being the most energy-demanding organ, appears to have a compromised bioenergetic capacity in heart failure, affecting all phenotypes and aetiologies. While metabolic disturbances in heart failure with reduced ejection fraction (HFrEF) have been extensively studied, similar insights into HFpEF are limited. This review collates evidence from both animal and human studies, highlighting metabolic dysregulations associated with HFpEF and its risk factors, such as obesity, hypertension, and diabetes. We discuss how changes in substrate utilisation, oxidative phosphorylation, and energy transport contribute to HFpEF. By delving into these pathological shifts in myocardial energy production, we aim to reveal novel therapeutic opportunities. Potential strategies include modulating energy substrates, improving metabolic efficiency, and enhancing critical metabolic pathways. Understanding these aspects could be key to developing more effective treatments for HFpEF.
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AIMS: The trials upon which recommendations for the use of cardiac resynchronization therapy (CRT) in heart failure used optimal medical therapy (OMT) before sodium-glucose co-transporter 2 inhibitors (SGLT2i). Moreover, the SGLT2i heart failure trials included only a small proportion of participants with CRT, and therefore, it remains uncertain whether SGLT2i should be considered part of OMT prior to CRT. METHODS AND RESULTS: We compared electrocardiogram (ECG) and echocardiographic responses to CRT as well as hospitalization and mortality rates in consecutive patients undergoing implantation at a large tertiary centre between January 2019 to June 2022 with and without SGLT2i treatment. Three hundred seventy-four participants were included aged 74.0 ± 11.5 years (mean ± standard deviation), with a left ventricular ejection fraction (LVEF) of 31.8 ± 9.9% and QRS duration of 161 ± 29 ms. The majority had non-ischaemic cardiomyopathy (58%) and were in NYHA Class II/III (83.6%). These characteristics were similar between patients with (n = 66) and without (n = 308) prior SGLT2i treatment. Both groups demonstrated similar evidence of response to CRT in terms of QRS duration shortening, and improvements in LVEF, left ventricular end-diastolic inner-dimension (LVIDd) and diastolic function (E/A and e/e'). While there was no difference in rates of hospitalization (for heart failure or overall), mortality was significantly lower in patients treated with SGLT2i compared with those who were not (6.5 vs. 16.6%, P = 0.049). CONCLUSIONS: We observed an improvement in mortality in patients undergoing CRT prescribed SGLT2i compared with those not prescribed SGLT2i, despite similar degrees of reverse remodelling. The authors recommend starting SGLT2i prior to CRT implantation, where it does not delay implantation.
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Terapia de Resincronización Cardíaca , Insuficiencia Cardíaca , Inhibidores del Cotransportador de Sodio-Glucosa 2 , Humanos , Inhibidores del Cotransportador de Sodio-Glucosa 2/uso terapéutico , Masculino , Femenino , Terapia de Resincronización Cardíaca/métodos , Anciano , Insuficiencia Cardíaca/terapia , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Resultado del Tratamiento , Volumen Sistólico/fisiología , Estudios Retrospectivos , Función Ventricular Izquierda/fisiología , Ecocardiografía , Electrocardiografía , Estudios de Seguimiento , Tasa de Supervivencia/tendenciasRESUMEN
OBJECTIVE: Takotsubo syndrome (TTS) is an acute heart failure syndrome which resembles acute coronary syndrome (ACS) at presentation. Differentiation requires coronary angiography, but where this does not occur immediately, cardiac biomarkers may provide additional utility. We performed a meta-analysis to compare troponin and natriuretic peptides (NPs) in TTS and ACS to determine if differences in biomarker profile can aid diagnosis. METHODS: We searched five literature databases for studies reporting NPs (Brain NP (BNP)/NT-pro-BNP) or troponin I/T in TTS and ACS, identifying 28 studies for troponin/NPs (5618 and 1145 patients, respectively). RESULTS: Troponin was significantly lower in TTS than ACS (standardised mean difference (SMD) -0.86; 95% CI, -1.08 to -0.64; p<0.00001), with an absolute difference of 75 times the upper limit of normal (×ULN) higher in ACS than TTS. Conversely, NPs were significantly higher in TTS (SMD 0.62; 95% CI, 0.44 to 0.80; p<0.00001) and 5.8×ULN greater absolutely. Area under the curve (AUC) for troponin in ACS versus TTS was 0.82 (95% CI, 0.70 to 0.93), and 0.92 (95% CI, 0.80 to 1.00) for ST-segment elevation myocardial infarction versus TTS. For NPs, AUC was 0.69 (95% CI, 0.48 to 0.89). Combination of troponin and NPs with logistic regression did not improve AUC. Recursive Partitioning and Regression Tree analysis calculated a troponin threshold ≥26×ULN that identified 95% cases as ACS where and specificity for ACS were 85.71% and 53.57%, respectively, with 94.32% positive predictive value and 29.40% negative predictive value. CONCLUSIONS: Troponin is lower and NPs higher in TTS versus ACS. Troponin had greater power than NPs at discriminating TTS and ACS, and with troponin ≥26×ULN patients are far more likely to have ACS.
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Síndrome Coronario Agudo , Cardiomiopatía de Takotsubo , Humanos , Síndrome Coronario Agudo/diagnóstico , Troponina , Cardiomiopatía de Takotsubo/diagnóstico , Péptidos Natriuréticos , Biomarcadores , Troponina TRESUMEN
The advent of immunological therapies has revolutionized the treatment of solid and haematological cancers over the last decade. Licensed therapies which activate the immune system to target cancer cells can be broadly divided into two classes. The first class are antibodies that inhibit immune checkpoint signalling, known as immune checkpoint inhibitors (ICIs). The second class are cell-based immune therapies including chimeric antigen receptor T lymphocyte (CAR-T) cell therapies, natural killer (NK) cell therapies, and tumour infiltrating lymphocyte (TIL) therapies. The clinical efficacy of all these treatments generally outweighs the risks, but there is a high rate of immune-related adverse events (irAEs), which are often unpredictable in timing with clinical sequalae ranging from mild (e.g. rash) to severe or even fatal (e.g. myocarditis, cytokine release syndrome) and reversible to permanent (e.g. endocrinopathies).The mechanisms underpinning irAE pathology vary across different irAE complications and syndromes, reflecting the broad clinical phenotypes observed and the variability of different individual immune responses, and are poorly understood overall. Immune-related cardiovascular toxicities have emerged, and our understanding has evolved from focussing initially on rare but fatal ICI-related myocarditis with cardiogenic shock to more common complications including less severe ICI-related myocarditis, pericarditis, arrhythmias, including conduction system disease and heart block, non-inflammatory heart failure, takotsubo syndrome and coronary artery disease. In this scientific statement on the cardiovascular toxicities of immune therapies for cancer, we summarize the pathophysiology, epidemiology, diagnosis, and management of ICI, CAR-T, NK, and TIL therapies. We also highlight gaps in the literature and where future research should focus.
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The coronavirus disease 2019 (COVID-19) pandemic has resulted in over 6 million deaths and significant morbidity across the globe. Alongside common respiratory symptoms, COVID-19 is associated with a variety of cardiovascular complications in the acute and post-acute phases of infection. The suggested pathophysiological mechanisms that underlie these complications include direct viral infection of the myocardium via the angiotensin-converting enzyme 2 (ACE2) protein and a cytokine release syndrome that results in indirect inflammatory damage to the heart. Patients with pre-existing cardiovascular disease and co-morbidities are generally more susceptible to the cardiac manifestations of COVID-19. However, studies have identified a variety of complications in low-risk individuals, including young adults and children. Myocarditis and paediatric inflammatory multisystem syndrome temporally associated with COVID-19 (PIMS) are among the adverse events reported in the acute phase of infection. Furthermore, patients have reported cardiac symptoms persisting beyond the acute phase in post-COVID syndrome. This review summarises the acute and chronic cardiac consequences of COVID-19 in low-risk patients, explores the pathophysiology behind them, and discusses new predictive factors for poor outcomes.
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COVID-19 , Cardiopatías , COVID-19/complicaciones , Niño , Cardiopatías/etiología , Humanos , Pandemias , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria SistémicaRESUMEN
Cardiac fibroblasts regulate the development of the adult cardiomyocyte phenotype and cardiac remodeling in disease. We investigate the role that cardiac fibroblasts-secreted extracellular vesicles (EVs) have in the modulation of cardiomyocyte Ca2+ cycling-a fundamental mechanism in cardiomyocyte function universally altered during disease. EVs collected from cultured human cardiac ventricular fibroblasts were purified by centrifugation, ultrafiltration and size-exclusion chromatography. The presence of EVs and EV markers were identified by dot blot analysis and electron microscopy. Fibroblast-conditioned media contains liposomal particles with a characteristic EV phenotype. EV markers CD9, CD63 and CD81 were highly expressed in chromatography fractions that elute earlier (Fractions 1-15), with most soluble contaminating proteins in the later fractions collected (Fractions 16-30). Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were treated with fibroblast-secreted EVs and intracellular Ca2+ transients were analyzed. Fibroblast-secreted EVs abbreviate the Ca2+ transient time to peak and time to 50% decay versus serum-free controls. Thus, EVs from human cardiac fibroblasts represent a novel mediator of human fibroblast-cardiomyocyte interaction, increasing the efficiency of hiPSC-CM Ca2+ handling.
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Vesículas Extracelulares , Células Madre Pluripotentes Inducidas , Calcio/metabolismo , Vesículas Extracelulares/metabolismo , Fibroblastos , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Miocitos Cardíacos/metabolismoRESUMEN
Aims: To evaluate the clinical feasibility of implementing the 2020 ESC 0/1â hr algorithm for rapid rule-out/rule-in of acute coronary syndrome (ACS). Methods and results: Data were collected retrospectively from 5496 patients in 2020 and 7363 patients in 2021 who received cardiac troponin measurements through the ACS algorithm in acute care settings within a large tertiary cardiac centre in the United Kingdom. This period overlapped the introduction of the 2020 ESC 0/1â hr algorithm. After exclusion of haemolysis, 1905 patients underwent repeat troponin measurement within the study period in 2020 and 2658 in 2021. Median time to repeat was significantly reduced from 3â h 14â min for intermediate low risk patients (5-12â ng/L) in 2020 to 1â h 22â min in 2021, and from 3â h 30â min to 1â h 59â min in intermediate high-risk patients (12-51â ng/L). Less than 15% of patients requiring repeat testing had dynamic changes in troponin of sufficient magnitude to change their initial risk category. Of all patients, 58.1% of patients in 2020 were ultimately classified as 'low risk', 19.2% deemed 'ACS likely', and 22.7% as 'ACS possible', with similar distributions in 2021. Conclusion: Whilst an efficient algorithm, our study demonstrates multi-faceted, practical limitations of achieving the 1â h target for the triage of patients with suspected ACS. Despite challenges predominantly of logistic nature, the algorithm enables rapid, streamlined, and efficient triage of large patient cohorts. Further work is required to streamline this process and achieve the targeted 1â h repeat in a resource-constrained healthcare environment, which would invariably require second blood draw before the result of first, as recommended by the ESC.
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[This corrects the article DOI: 10.3389/fcvm.2022.869585.].
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Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40-41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.
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AIMS: Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and in the absence of culprit coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS. METHODS AND RESULTS: miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal), cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavß subunit), RGS4 (regulator of G-protein signalling 4), and G-protein subunit Gß (GNB1) as underlying these effects. CONCLUSION: miR-16 and miR-26a sensitize the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future.
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MicroARN Circulante , MicroARNs , Infarto del Miocardio , Cardiomiopatía de Takotsubo , Animales , Epinefrina , MicroARNs/genética , Infarto del Miocardio/complicaciones , Infarto del Miocardio/genética , Miocitos Cardíacos , Ratas , Cardiomiopatía de Takotsubo/inducido químicamente , Cardiomiopatía de Takotsubo/complicaciones , Cardiomiopatía de Takotsubo/genéticaRESUMEN
This is the first part of a scientific statement from the Heart Failure Association (HFA) of the European Society of Cardiology focused upon the pathophysiology of Takotsubo syndrome and is complimentary to the previous HFA position statement on Takotsubo syndrome which focused upon clinical management. In part 1 we provide an overview of the pathophysiology of Takotsubo syndrome and fundamental questions to consider. We then review and discuss the central role of catecholamines and the sympathetic nervous system in the pathophysiology, and the direct effects of high surges in catecholamines upon myocardial biology including ß-adrenergic receptor signalling, G-protein coupled receptor kinases, cardiomyocyte calcium physiology, myofilament physiology, cardiomyocyte gene expression, myocardial electrophysiology and arrhythmogenicity, myocardial inflammation, metabolism and energetics. The integrated effects upon ventricular haemodynamics are discussed and integrated into the pathophysiological model.
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Cardiología , Insuficiencia Cardíaca , Cardiomiopatía de Takotsubo , Catecolaminas , Humanos , Sistema Nervioso SimpáticoRESUMEN
While the first part of the scientific statement on the pathophysiology of Takotsubo syndrome was focused on catecholamines and the sympathetic nervous system, in the second part we focus on the vascular pathophysiology including coronary and systemic vascular responses, the role of the central and peripheral nervous systems during the acute phase and abnormalities in the subacute phase, the gender differences and integrated effects of sex hormones, genetics of Takotsubo syndrome including insights from microRNA studies and inducible pluripotent stem cell models of Takotsubo syndrome. We then discuss the chronic abnormalities of cardiovascular physiology in survivors, the limitations of current clinical and preclinical studies, the implications of the knowledge of pathophysiology for clinical management and future perspectives and directions of research.
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Cardiología , Insuficiencia Cardíaca , MicroARNs , Cardiomiopatía de Takotsubo , Hormonas Esteroides Gonadales , Insuficiencia Cardíaca/genética , Humanos , Cardiomiopatía de Takotsubo/genéticaRESUMEN
Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be a novel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more data are needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.5 cm × 1.5 cm × 1.5 mm) consisting of up to 20 million human induced pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) embedded in a fibrin-based hydrogel was developed. A rabbit myocardial infarction model was then established to test for feasibility and efficacy. Our data showed that hPSC-CMs in EHTs became more aligned over 28 days and had improved contraction kinetics and faster calcium transients. Blinded echocardiographic analysis revealed a significant improvement in function in infarcted hearts that received EHTs, along with reduction in infarct scar size by 35%. Vascularization from the host to the patch was observed at week 1 and stable to week 4, but electrical coupling between patch and host heart was not observed. In vivo telemetry recordings and ex vivo arrhythmia provocation protocols showed that the patch was not pro-arrhythmic. In summary, EHTs improved function and reduced scar size without causing arrhythmia, which may be due to the lack of electrical coupling between patch and host heart.