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BACKGROUND: A left ventricular assist device (LVAD) is a life-saving but intensive therapy for patients with end-stage heart failure. We evaluated the healthcare consumption in a cohort of LVAD patients in our centre over 6 years. METHODS: All patients with a primary LVAD implantation at the University Medical Centre Utrecht in Utrecht, the Netherlands from 2016 through 2021 were included in this analysis. Subsequent hospital stay, outpatient clinic visits, emergency department visits and readmissions were recorded. RESULTS: During the investigated period, 226 LVADs were implanted, ranging from 32 in 2016 to 45 in 2020. Most LVADs were implanted in patients aged 40-60 years, while they were supported by or sliding on inotropes (Interagency Registry for Mechanically Assisted Circulatory Support class 2 or 3). Around the time of LVAD implantation, the median total hospital stay was 41 days. As the size of the LVAD cohort increased over time, the total annual number of outpatient clinic visits also increased, from 124 in 2016 to 812 in 2021 (pâ¯= 0.003). The numbers of emergency department visits and readmissions significantly increased in the 6year period as well, with a total number of 553 emergency department visits and 614 readmissions. Over the years, the annual number of outpatient clinic visits decreased by 1 per patient-year follow-up, while the annual numbers of emergency department visits and readmissions per patient-year remained stable. CONCLUSION: The number of patients supported by an LVAD has grown steadily over the last years, requiring a more specialised healthcare in this particular population.
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A newly identified pathogenic variant (A527G) in alpha B-crystallin (αB-crystallin) has been linked to congenital cataract and young-onset dilated cardiomyopathy (DCM) within a Dutch family, although the disease mechanism remains unclear. Four human induced pluripotent stem cell (hiPSC) clones were generated from three symptomatic patients carrying the A527G variant, and one healthy proband. Peripheral blood mononuclear cells (PBMCs) were reprogrammed using integration-free Sendai viral pluripotency vectors. The established hiPSCs clones exhibited regular ESC-like morphology, expression of pluripotency markers, and normal karyotyping. These hiPSC lines can facilitate future studies to understand the chaperone function and its role in DCM disease progression.
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Cardiac tissue engineering (cTE) has already advanced towards the first clinical trials, investigating safety and feasibility of cTE construct transplantation in failing hearts. However, the lack of well-established preservation methods poses a hindrance to further scalability, commercialization, and transportation, thereby reducing their clinical implementation. In this study, hypothermic preservation (4 °C) and two methods for cryopreservation (i.e., a slow and fast cooling approach to -196 °C and -150 °C, respectively) were investigated as potential solutions to extend the cTE construct implantation window. The cTE model used consisted of human induced pluripotent stem cell-derived cardiomyocytes and human cardiac fibroblasts embedded in a natural-derived hydrogel and supported by a polymeric melt electrowritten hexagonal scaffold. Constructs, composed of cardiomyocytes of different maturity, were preserved for three days, using several commercially available preservation protocols and solutions. Cardiomyocyte viability, function (beat rate and calcium handling), and metabolic activity were investigated after rewarming. Our observations show that cardiomyocytes' age did not influence post-rewarming viability, however, it influenced construct function. Hypothermic preservation with HypoThermosol® ensured cardiomyocyte viability and function. Furthermore, fast freezing outperformed slow freezing, but both viability and function were severely reduced after rewarming. In conclusion, whereas long-term preservation remains a challenge, hypothermic preservation with HypoThermosol® represents a promising solution for cTE construct short-term preservation and potential transportation, aiding in off-the-shelf availability, ultimately increasing their clinical applicability.
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Criopreservación , Miocitos Cardíacos , Ingeniería de Tejidos , Humanos , Miocitos Cardíacos/citología , Supervivencia Celular/efectos de los fármacos , Andamios del Tejido/química , Células Madre Pluripotentes Inducidas/citología , Células Cultivadas , Hidrogeles/química , Hidrogeles/farmacologíaRESUMEN
Cardiovascular disease (CVD) is the leading cause of morbimortality in Europe and worldwide. CVD imposes a heterogeneous spectrum of cardiac remodelling, depending on the insult nature, that is, pressure or volume overload, ischaemia, arrhythmias, infection, pathogenic gene variant, or cardiotoxicity. Moreover, the progression of CVD-induced remodelling is influenced by sex, age, genetic background and comorbidities, impacting patients' outcomes and prognosis. Cardiac reverse remodelling (RR) is defined as any normative improvement in cardiac geometry and function, driven by therapeutic interventions and rarely occurring spontaneously. While RR is the outcome desired for most CVD treatments, they often only slow/halt its progression or modify risk factors, calling for novel and more timely RR approaches. Interventions triggering RR depend on the myocardial insult and include drugs (renin-angiotensin-aldosterone system inhibitors, beta-blockers, diuretics and sodium-glucose cotransporter 2 inhibitors), devices (cardiac resynchronization therapy, ventricular assist devices), surgeries (valve replacement, coronary artery bypass graft), or physiological responses (deconditioning, postpartum). Subsequently, cardiac RR is inferred from the degree of normalization of left ventricular mass, ejection fraction and end-diastolic/end-systolic volumes, whose extent often correlates with patients' prognosis. However, strategies aimed at achieving sustained cardiac improvement, predictive models assessing the extent of RR, or even clinical endpoints that allow for distinguishing complete from incomplete RR or adverse remodelling objectively, remain limited and controversial. This scientific statement aims to define RR, clarify its underlying (patho)physiologic mechanisms and address (non)pharmacological options and promising strategies to promote RR, focusing on the left heart. We highlight the predictors of the extent of RR and review the prognostic significance/impact of incomplete RR/adverse remodelling. Lastly, we present an overview of RR animal models and potential future strategies under pre-clinical evaluation.
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Remodelación Ventricular , Humanos , Remodelación Ventricular/fisiología , Pronóstico , Enfermedades Cardiovasculares/terapia , Enfermedades Cardiovasculares/fisiopatología , Europa (Continente) , Relevancia ClínicaRESUMEN
BACKGROUND: Advanced heart failure is defined as severe cardiac dysfunction combined with hospital admissions due to heart failure and major functional limitations. Selected patients with advanced heart failure can be treated with a left ventricular assist device. Patients with the newest generation of devices have a five-year survival of approximately 60%. CASE DESCRIPTION: We describe the case of a 54-year-old patient with advanced heart failure due to coronary artery disease, who was referred from a secondary to a tertiary care center to evaluate candidacy for LVAD therapy. Due to significant multimorbidity and unhealthy lifestyle (BMI 33 kg/m2, eGFR 29 ml/min/1.73m2, smoking, peripheral vascular disease, very poorly controlled diabetes mellitus), the patient was not considered a suitable candidate. Due to a rigorous change in his lifestyle, a number of (relative) contraindications changed in such a way that an LVAD was successfully implanted in the patient with a good functional status afterwards. CONCLUSION: Candidacy for LVAD therapy is determined on an individual basis through a vigilant screening process. Eligibility for this treatment can be positively influenced by a change in lifestyle. Intensive guidance of care providers is important in this respect.
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Insuficiencia Cardíaca , Corazón Auxiliar , Estilo de Vida , Humanos , Persona de Mediana Edad , Masculino , Insuficiencia Cardíaca/terapiaRESUMEN
Heart failure (HF) is a chronic and progressive disease that often progresses to an advanced stage where conventional therapy is insufficient to relieve patients' symptoms. Despite the availability of advanced therapies such as mechanical circulatory support or heart transplantation, the complexity of defining advanced HF, which requires multiple parameters and multimodality assessment, often leads to delays in referral to dedicated specialists with the result of a worsening prognosis. In this review, we aim to explore the role of cardiac magnetic resonance (CMR) in advanced HF by showing how CMR is useful at every step in managing these patients: from diagnosis to prognostic stratification, hemodynamic evaluation, follow-up and advanced therapies such as heart transplantation. The technical challenges of scanning advanced HF patients, which often require troubleshooting of intracardiac devices and dedicated scans, will be also discussed.
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Insuficiencia Cardíaca , Humanos , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/diagnóstico , Imagen por Resonancia Cinemagnética/métodosRESUMEN
Right heart failure (RHF) following implantation of a left ventricular assist device (LVAD) is a common and potentially serious condition with a wide spectrum of clinical presentations with an unfavourable effect on patient outcomes. Clinical scores that predict the occurrence of right ventricular (RV) failure have included multiple clinical, biochemical, imaging and haemodynamic parameters. However, unless the right ventricle is overtly dysfunctional with end-organ involvement, prediction of RHF post-LVAD implantation is, in most cases, difficult and inaccurate. For these reasons optimization of RV function in every patient is a reasonable practice aiming at preparing the right ventricle for a new and challenging haemodynamic environment after LVAD implantation. To this end, the institution of diuretics, inotropes and even temporary mechanical circulatory support may improve RV function, thereby preparing it for a better adaptation post-LVAD implantation. Furthermore, meticulous management of patients during the perioperative and immediate postoperative period should facilitate identification of RV failure refractory to medication. When RHF occurs late during chronic LVAD support, this is associated with worse long-term outcomes. Careful monitoring of RV function and characterization of the origination deficit should therefore continue throughout the patient's entire follow-up. Despite the useful information provided by the echocardiogram with respect to RV function, right heart catheterization frequently offers additional support for the assessment and optimization of RV function in LVAD-supported patients. In any patient candidate for LVAD therapy, evaluation and treatment of RV function and failure should be assessed in a multidimensional and multidisciplinary manner.
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BACKGROUND: In refractory cardiogenic shock, temporary mechanical support (tMCS) may be crucial for maintaining tissue perfusion and oxygen delivery. tMCS can serve as a bridge-to-decision to assess eligibility for left ventricular assist device (LVAD) implantation or heart transplantation, or as a bridge-to-recovery. ECPELLA is a novel tMCS configuration combining venoarterial extracorporeal membrane oxygenation with Impella. The present study presents the clinical parameters, outcomes, and complications of patients supported with ECPELLA. METHODS: All patients supported with ECPELLA at University Medical Centre Utrecht between December 2020 and August 2023 were included. The primary outcome was 30-day mortality, and secondary outcomes were LVAD implantation/heart transplantation and safety outcomes. RESULTS: Twenty patients with an average age of 51 years, and of whom 70% were males, were included. Causes of cardiogenic shock were acute heart failure (due to acute coronary syndrome, myocarditis, or after cardiac surgery) or chronic heart failure, respectively 70 and 30% of cases. The median duration of ECPELLA support was 164â¯h (interquartile range 98-210). In 50% of cases, a permanent LVAD was implanted. Cardiac recovery within 30 days was seen in 30% of cases and 30-day mortality rate was 20%. ECPELLA support was associated with major bleeding (40%), haemolysis (25%), vascular complications (30%), kidney failure requiring replacement therapy (50%), and Impella failure requiring extraction (15%). CONCLUSION: ECPELLA can be successfully used as a bridge to LVAD implantation or as a bridge-to-recovery in patients with refractory cardiogenic shock. Despite a significant number of complications, 30-day mortality was lower than observed in previous cohorts.
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Background: Non-ischemic dilated cardiomyopathy (NIDCM) is a common cause of heart failure with progressive tendency. The disease occurs in one in every 2,500 individuals in the developed world, with high morbidity and mortality. However, detailed data on the role of NIDCM in heart failure in Tanzania is lacking. Aim: To characterize NIDCM in a Tanzanian cohort with respect to demographics, clinical profile, imaging findings and management. Methods: Characterization of non-ischemic dilated cardioMyOpathY in a native Tanzanian cOhort (MOYO) is a prospective cohort study of NIDCM patients seen at the Jakaya Kikwete Cardiac Institute. Patients aged ≥18 years with a clinical diagnosis of heart failure, an ejection fraction of ≤45% on echocardiography and no evidence of ischemia were enrolled. Clinical data, echocardiography, electrocardiography (ECG), coronary angiography and stress ECG information were collected from February 2020 to March 2022. Results: Of 402 patients, n = 220 (54.7%) were males with a median (IQR) age of 55.0 (41.0, 66.0) years. Causes of NIDCM were presumably hypertensive n = 218 (54.2%), idiopathic n = 116 (28.9%), PPCM n = 45 (11.2%), alcoholic n = 10 (2.5%) and other causes n = 13 (3.2%). The most common presenting symptoms were dyspnea n = 342 (85.1%), with the majority of patients presenting with New York Heart Association (NYHA) Class III n = 195 (48.5%). The mean (SD) left ventricular ejection fraction (LVEF) was 29.4% (±7.7), and severe systolic dysfunction (LVEF <30%) was common n = 208 (51.7%). Compared with other forms of DCM, idiopathic DCM patients were significantly younger, had more advanced NYHA class (p < 0.001) and presented more often with left bundle branch block on ECG (p = 0.0042). There was suboptimal use of novel guidelines recommended medications ARNI n = 10 (2.5%) and SGLT2 2-inhibitors n = 2 (0.5%). Conclusions: In our Tanzanian cohort, the majority of patients with NIDCM have an identified underlying cause, and they present at late stages of the disease. Patients with idiopathic DCM are younger with more severe disease compared to other forms of NIDCM.
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Cardiomiopatía Dilatada , Insuficiencia Cardíaca , Masculino , Humanos , Adolescente , Adulto , Femenino , Tanzanía/epidemiología , Cardiomiopatía Dilatada/diagnóstico , Cardiomiopatía Dilatada/epidemiología , Estudios Prospectivos , Volumen Sistólico , Función Ventricular Izquierda , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiologíaRESUMEN
This study aims to associate the incidence of postoperative vasoplegia and short-term survival to the implantation of various left ventricular assist devices differing in hemocompatibility and flow profiles. The overall incidence of vasoplegia was 25.3% (73/289 patients) and 30.3% (37/122), 25.0% (18/72), and 18.9% (18/95) in the axial flow (AXF), centrifugal flow (CF), and centrifugal flow with artificial pulse (CFAP) group, respectively. Vasoplegia was associated with longer intensive care (ICU) and hospital length of stay (LOS) and mortality. ICU and in-hospital LOS and 1-year mortality were the lowest in the CFAP group. Post hoc analysis resulted in a p-value of 0.43 between AXF and CF; 0.35 between CF and CFAP; and 0.06 between AXF and CFAP. Although there is a trend in diminished incidence of vasoplegia, pooled logistic regression using flow profile and variables that remained after feature selection showed that flow profile was not an independent predictor for postoperative vasoplegia.
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Corazón Auxiliar , Tiempo de Internación , Diseño de Prótesis , Vasoplejía , Función Ventricular Izquierda , Humanos , Vasoplejía/fisiopatología , Vasoplejía/etiología , Vasoplejía/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Factores de Tiempo , Resultado del Tratamiento , Incidencia , Factores de Riesgo , Adulto , Anciano , Insuficiencia Cardíaca/fisiopatología , Insuficiencia Cardíaca/mortalidad , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Implantación de Prótesis/instrumentación , Implantación de Prótesis/efectos adversos , Implantación de Prótesis/mortalidad , Estudios Retrospectivos , Mortalidad Hospitalaria , Medición de RiesgoRESUMEN
Background: The aim of this study was to assess the prevalence of frailty and other impairments in potential left ventricular assist device (LVAD) and heart transplantation (HTx) candidates by performing a preoperative comprehensive geriatric assessment (CGA) and reviewing the treatment recommendations resulting from the CGA. Methods and results: This cross-sectional study included 73 patients aged ≥40 years who received a CGA as part of the patient selection procedure for LVAD and HTx. In every patient, a conclusion comprising frailty and other impairments was formulated based on the medical, mental, functional, and social domains and recommendations were made. The mean age was 58 years (range 40-71) and 70 % were male. In 97 % of patients, at least one impairment was identified by the CGA. The most common impairments were polypharmacy, high morbidity burden, reduced renal function, osteopenia, depression, poor quality of life, reduced functionality, (risk of) malnutrition, reduced grip strength and high caregiver burden. A small proportion of the potential LVAD and HTx candidates were frail (7 % according to Fried's frailty criteria, 6 % according to the Edmonton Frail Scale) and 39 % were pre-frail. The domains for which most impairments were found and the domains for which most treatment recommendations were given matched well, with the functional domain as the frontrunner. Conclusion: This study showed that most of the potential candidates for LVAD or HTx have impairments on at least one domain of the CGA. Impairments and associated risks can contribute to the decision making process for candidacy for LVAD and HTx.
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BACKGROUND: Soluble suppression of tumorigenicity-2 (sST2) predicts mortality in patients with heart failure. The predictive value of sST2 in patients with a left ventricular assist device remains unknown. Therefore, we studied the relationship between sST2 and outcome after left ventricular assist device implantation. METHODS AND RESULTS: sST2 levels of patients with a left ventricular assist device implanted between January 2015 and December 2022 were included in this observational study. The median follow-up was 25 months, during which 1573 postoperative sST2 levels were measured in 199 patients, with a median of 29 ng/mL. Survival of patients with normal and elevated preoperative levels was compared using Kaplan-Meier analysis, which did not differ significantly (P=0.22) between both groups. The relationship between postoperative sST2, survival, and right heart failure was evaluated using a joint model, which showed a significant relationship between the absolute sST2 level and mortality, with a hazard ratio (HR) of 1.20 (95% CI, 1.10-1.130; P<0.01) and an HR of 1.22 (95% CI, 1.07-1.39; P=0.01) for right heart failure, both per 10-unit sST2 increase. The sST2 instantaneous change was not predictive for survival or right heart failure (P=0.99 and P=0.94, respectively). Multivariate joint model analysis showed a significant relationship between sST2 with mortality adjusted for NT-proBNP (N-terminal pro-B-type natriuretic peptide), with an HR of 1.19 (95% CI, 1.00-1.42; P=0.05), whereas the HR of right heart failure was not significant (1.22 [95% CI, 0.94-1.59]; P=0.14), both per 10-unit sST2 increase. CONCLUSIONS: Time-dependent postoperative sST2 predicts all-cause mortality after left ventricular assist device implantation after adjustment for NT-proBNP. Future research is warranted into possible target interventions and the optimal monitoring frequency.
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Insuficiencia Cardíaca , Corazón Auxiliar , Humanos , Pronóstico , Biomarcadores , Proteína 1 Similar al Receptor de Interleucina-1 , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Fragmentos de Péptidos , Péptido Natriurético EncefálicoRESUMEN
Aims: Non-invasive remote patient monitoring is an increasingly popular technique to aid clinicians in the early detection of worsening heart failure (HF) alongside regular follow-ups. However, previous studies have shown mixed results in the performance of such systems. Therefore, we developed and evaluated a personalized monitoring algorithm aimed at increasing positive-predictive-value (PPV) (i.e. alarm quality) and compared performance with simple rule-of-thumb and moving average convergence-divergence algorithms (MACD). Methods and results: In this proof-of-concept study, the developed algorithm was applied to retrospective data of daily bodyweight, heart rate, and systolic blood pressure of 74 HF-patients with a median observation period of 327 days (IQR: 183 days), during which 31 patients experienced 64 clinical worsening HF episodes. The algorithm combined information on both the monitored patients and a group of stable HF patients, and is increasingly personalized over time, using linear mixed-effect modelling and statistical process control charts. Optimized on alarm quality, heart rate showed the highest PPV (Personalized: 92%, MACD: 2%, Rule-of-thumb: 7%) with an F1 score of (Personalized: 28%, MACD: 6%, Rule-of-thumb: 8%). Bodyweight demonstrated the lowest PPV (Personalized: 16%, MACD: 0%, Rule-of-thumb: 6%) and F1 score (Personalized: 10%, MACD: 3%, Rule-of-thumb: 7%) overall compared methods. Conclusion: The personalized algorithm with flexible patient-tailored thresholds led to higher PPV, and performance was more sensitive compared to common simple monitoring methods (rule-of-thumb and MACD). However, many episodes of worsening HF remained undetected. Heart rate and systolic blood pressure monitoring outperformed bodyweight in predicting worsening HF. The algorithm source code is publicly available for future validation and improvement.
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Aims: The number of patients on left ventricular assist device (LVAD) support increases due to the growing number of patients with end-stage heart failure and the limited number of donor hearts. Despite improving survival rates, patients frequently suffer from adverse events such as cardiac arrhythmia and major bleeding. Telemonitoring is a potentially powerful tool to early detect deteriorations and may further improve outcome after LVAD implantation. Hence, we developed a personalized algorithm to remotely monitor HeartMate3 (HM3) pump parameters aiming to early detect unscheduled admissions due to cardiac arrhythmia or major bleeding. Methods and results: The source code of the algorithm is published in an open repository. The algorithm was optimized and tested retrospectively using HeartMate 3 (HM3) power and flow data of 120 patients, including 29 admissions due to cardiac arrhythmia and 14 admissions due to major bleeding. Using a true alarm window of 14 days prior to the admission date, the algorithm detected 59 and 79% of unscheduled admissions due to cardiac arrhythmia and major bleeding, respectively, with a false alarm rate of 2%. Conclusion: The proposed algorithm showed that the personalized algorithm is a viable approach to early identify cardiac arrhythmia and major bleeding by monitoring HM3 pump parameters. External validation is needed and integration with other clinical parameters could potentially improve the predictive value. In addition, the algorithm can be further enhanced using continuous data.
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While chronic heart failure (CHF) treatment has considerably improved patient prognosis and survival, the therapeutic management of acute heart failure (AHF) has remained virtually unchanged in the last decades. This is partly due to the scarcity of pre-clinical models for the pathophysiological assessment and, consequently, the limited knowledge of molecular mechanisms involved in the different AHF phenotypes. This scientific statement outlines the different trajectories from acute to CHF originating from the interaction between aetiology, genetic and environmental factors, and comorbidities. Furthermore, we discuss the potential molecular targets capable of unveiling new therapeutic perspectives to improve the outcome of the acute phase and counteracting the evolution towards CHF.
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Insuficiencia Cardíaca , Humanos , Enfermedad Aguda , Pronóstico , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/genética , Insuficiencia Cardíaca/terapia , Enfermedad Crónica , Factores de RiesgoRESUMEN
INTRODUCTION: From the start of the coronavirus disease 2019 (COVID-19) pandemic, international guidelines have recommended pre-operative screening for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) before heart transplantation (HTx). Due to the changing prevalence of COVID-19, the chances of false positive results have increased. Because of increased immunity in the population and evolution of SARS-CoV-2 to current Omicron variants, associated mortality and morbidity have decreased. We set out to investigate the yield and side effects of SARS-CoV-2 screening in our center. METHODS: We performed a retrospective cohort study in the University Medical Center Utrecht. The study period was from March 2019 to January 2023. All data from patients who underwent HTx were collected, including all pre-operative and post-operative SARS-CoV-2 tests. Furthermore, all clinical SARS-CoV-2 tests for the indication of potential HTx were screened. RESULTS: In the period under study, 51 patients underwent HTx. None of the recipients reported any symptoms of a viral infection. Fifty HTx recipients were screened for SARS-CoV-2. Forty-nine out of fifty patients tested negative. One patient had a false positive result, potentially delaying the HTx procedure. There were no cancelled HTx procedures due to a true positive SARS-CoV-2 test result. CONCLUSION: Pre-operative SARS-CoV-2 screening in asymptomatic HTx recipients did not lead to any true positive cases. In 2% of the cases, screening resulted in a false positive test result. With the current Omicron variants, in combination with a low-prevalence situation, we propose to abandon pre-operative SARS-CoV-2 screening and initiate a symptom-driven approach for the general viral testing of patients who are called in for a potential HTx.
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Background: Doxorubicin is an essential cancer treatment, but its usefulness is hampered by the occurrence of cardiotoxicity. Nevertheless, the pathophysiology underlying doxorubicin-induced cardiotoxicity and the respective molecular mechanisms are poorly understood. Recent studies have suggested involvement of cellular senescence. Objectives: The aims of this study were to establish whether senescence is present in patients with doxorubicin-induced cardiotoxicity and to investigate if this could be used as a potential treatment target. Methods: Biopsies from the left ventricles of patients with severe doxorubicin-induced cardiotoxicity were compared with control samples. Additionally, senescence-associated mechanisms were characterized in 3-dimensional dynamic engineered heart tissues (dyn-EHTs) and human pluripotent stem cell-derived cardiomyocytes. These were exposed to multiple, clinically relevant doses of doxorubicin to recapitulate patient treatment regimens. To prevent senescence, dyn-EHTs were cotreated with the senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol. Results: Senescence-related markers were significantly up-regulated in the left ventricles of patients with doxorubicin-induced cardiotoxicity. Treatment of dyn-EHTs resulted in up-regulation of similar senescence markers as seen in the patients, accompanied by tissue dilatation, decreased force generation, and increased troponin release. Treatment with senomorphic drugs led to decreased expression of senescence-associated markers, but this was not accompanied by improved function. Conclusions: Senescence was observed in the hearts of patients with severe doxorubicin-induced cardiotoxicity, and this phenotype can be modeled in vitro by exposing dyn-EHTs to repeated clinically relevant doses of doxorubicin. The senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol prevent senescence but do not result in functional improvements. These findings suggest that preventing senescence by using a senomorphic during doxorubicin administration might not prevent cardiotoxicity.
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BACKGROUND: Late right heart failure (LRHF) is a common complication during long-term left ventricular assist device (LVAD) support. We aimed to identify risk factors for LRHF after LVAD implantation. METHODS: Patients undergoing primary LVAD implantation between 2006 and 2019 and surviving the perioperative period were included for this study (n = 261). Univariate Cox proportional hazards analysis was used to assess the association of clinical covariates and LRHF, stratified for device type. Variables with p < 0.10 entered the multivariable model. In a subset of patients with complete echocardiography or right catheterization data, this multivariable model was extended. Postoperative cardiopulmonary exercise test data were compared in patients with and without LRHF. RESULTS: Nineteen percentage of patients suffered from LRHF after a median of 12 months, of which 67% required hospitalization. A history of atrial fibrillation (AF) (HR: 2.06 [1.08-3.93], p = 0.029), a higher preoperative body mass index (BMI) (HR: 1.07 [1.01-1.13], p = 0.023), and intensive care unit (ICU) duration (HR: 1.03 [1.00-1.06], p = 0.025) were independent predictors of LHRF in the multivariable model. A significant relation between the severity of tricuspid regurgitation (TR) and LRHF (HR: 1.91 [1.13-3.21], p = 0.016) was found in patients with echocardiographic data. Patients with LRHF demonstrated a lower maximal workload and peak VO2 at 6 months postoperatively. CONCLUSION: A history of AF, BMI, and longer ICU stay may help identify patients at high risk for LRHF. Severity of TR was significantly related to LRHF in a subset of patients.
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Insuficiencia Cardíaca , Corazón Auxiliar , Insuficiencia de la Válvula Tricúspide , Humanos , Incidencia , Resultado del Tratamiento , Estudios Retrospectivos , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/etiología , Factores de Riesgo , Corazón Auxiliar/efectos adversosRESUMEN
BACKGROUND: Circadian (24-h) rhythms are important regulators in physiology and disease, but systemic disease may disrupt circadian rhythmicity. Heart failure (HF) is a systemic disease affecting hormonal regulation. We investigate whether HF affects the rhythmic expression of melatonin and cortisol, main endocrine products of the central clock, and cardiac-specific troponin in patients. We corroborate the functionality of the peripheral clock directly in the organs of translational models, inaccessible in human participants. METHODS: We included 46 HF patients (71.7% male, median age of 60 years, NYHA class II (32.6%) or III (67.4%), ischemic cardiomyopathy (43.5%), comorbidities: diabetes 21.7%, atrial fibrillation 30.4%), and 24 matched controls. Blood was collected at seven time-points during a 24-h period (totalling 320 HF and 167 control samples) for melatonin, cortisol, and cardiac troponin T (cTnT) measurements after which circadian rhythms were assessed through cosinor analyses, both on the individual and the group level. Next, we analysed peripheral circadian clock functionality using cosinor analysis in male animal HF models: nocturnal mice and diurnal zebrafish, based on expression of core clock genes in heart, kidneys, and liver, every 4 h during a 24-h period in a light/darkness synchronised environment. FINDINGS: Melatonin and cortisol concentrations followed a physiological 24-h pattern in both patients and controls. For melatonin, acrophase occurred during the night for both groups, with significantly decreased amplitude (median 5.2 vs 8.8, P = 0.0001) and circadian variation ([maximum]/[minimum]) in heart failure patients. For cortisol, mesor showed a significant increase for HF patients (mean 331.9 vs 275.1, P = 0.017) with a difference of 56.8 (95% CI 10.3-103.3) again resulting in a relatively lower variation: median 3.9 vs 6.3 (P = 0.0058). A nocturnal blood pressure dip was absent in 77.8% of HF patients. Clock gene expression profiles (Bmal, Clock, Per, Cry) were similar and with expected phase relations in animal HF models and controls, demonstrating preserved peripheral clock functionality in HF. Furthermore, oscillations in diurnal zebrafish were expectedly in opposite phases to those of nocturnal mice. Concordantly, cTnT concentrations in HF patients revealed significant circadian oscillations. INTERPRETATION: Central clock output is dampened in HF patients while the molecular peripheral clock, as confirmed in animal models, remains intact. This emphasises the importance of taking timing into account in research and therapy for HF, setting the stage for another dimension of diagnostic, prognostic and therapeutic approaches. FUNDING: Hartstichting.