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Combined [18F]FDG PET-cardiac MRI imaging (PET/CMR) is a useful tool to assess myocardial viability and cardiac function in patients with acute myocardial infarction (AMI). Here, we evaluated the prognostic value of PET/CMR in a porcine closed-chest reperfused AMI (rAMI) model. Late gadolinium enhancement by PET/CMR imaging displayed tracer uptake defect at the infarction site by 3 days after the rAMI in the majority of the animals (group Match, n = 28). Increased [18F]FDG uptake at the infarcted area (metabolism/contractility mismatch) with reduced tracer uptake in the remote viable myocardium (group Mismatch, n = 12) 3 days after rAMI was observed in the animals with larger infarct size and worse left ventricular ejection fraction (LVEF) (34 ± 8.7 vs 42.0 ± 5.2%), with lower LVEF also at the 1-month follow-up (35.8 ± 9.5 vs 43.0 ± 6.3%). Transcriptome analyses by bulk and single-nuclei RNA sequencing of the infarcted myocardium and border zones (n = 3 of each group, and 3 sham-operated controls) revealed a strong inflammatory response with infiltration of monocytes and macrophages in the infarcted and border areas in Mismatch animals. Our data indicate a high prognostic relevance of combined PET/MRI in the subacute phase of rAMI for subsequent impairment of heart function and underline the adverse effects of an excessive activation of the innate immune system in the initial phase after rAMI.
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BACKGROUND: Mitral- and tricuspid regurgitation are associated with significant morbidity and mortality and are increasingly treated interventionally. CardioMEMS is a transcutaneously implanted pressure sensor placed in the pulmonary artery that allows invasive measurement of pulmonary artery pressure and cardiac output. METHODS: This proof-of-concept study aimed to observe hemodynamic changes as determined by CardioMEMS after transcatheter atrioventricular valve interventions, assess the additional value of CardioMEMS on top of echocardiography, and investigate a potential effect of CardioMEMS on outcome. Patients treated with transcatheter mitral- or tricuspid valve interventions (mitral: TMVR, tricuspid: TTVR) or bicaval valve implantation (bi-CAVI) were recruited. All patients were followed for 12 months. RESULTS: Thirty-six patients were included (4 with CardioMEMS, 32 controls). Patients with CardioMEMS were monitored prior to intervention and 3-12 months thereafter (one received TMVR, one bi-CAVI, one both TMVR and TTVR, and one isolated TTVR). CardioMEMS group: In both patients with TMVR and in the patient with bi-CAVI, mean pulmonary artery pressures decreased (all p < .001) and cardiac output increased significantly (both TMVR p < .001 and bi-CAVI p = .006) while functional parameters, echocardiography, and NT-proBNP were difficult to interpret, unreliable, or both. Changes after TTVR remained inconclusive. CONCLUSION: Invasive monitoring using CardioMEMS provides important information after mitral- and tricuspid valve interventions. Such data pave the way for a deeper understanding of the prerequisites for optimal patient selection and management for catheter-based interventions.
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Implante de Prótese de Valva Cardíaca , Insuficiência da Valva Mitral , Humanos , Valva Tricúspide/diagnóstico por imagem , Valva Tricúspide/cirurgia , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/cirurgia , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/métodos , Cateterismo Cardíaco , Resultado do TratamentoRESUMO
Lung ultrasound has the potential to enable standardized follow-up without radiation exposure and with lower associated costs in comparison to CT scans. It is a valuable tool to follow up on patients after a COVID-19 infection and evaluate if there is pulmonary fibrosis developing. Echocardiography, including strain imaging, is a proven tool to assess various causes of dyspnea and adds valuable information in the context of long COVID care. Including two-dimensional (2D) strain imaging, a better comprehension of myocardial damage in post-COVID syndrome can be made. Especially 2D strain imaging (left and the right ventricular strain) can provide information about prognosis.
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COVID-19 , Pneumologia , Humanos , Síndrome de COVID-19 Pós-Aguda , Áustria , Ecocardiografia , Pulmão/diagnóstico por imagemRESUMO
We have designed translational animal models to investigate cardiac profibrotic gene signatures. Domestic pigs were treated with cardiotoxic drugs (doxorubicin, DOX, n = 5 or Myocet®, MYO, n = 5) to induce replacement fibrosis via cardiotoxicity. Reactive interstitial fibrosis was triggered by LV pressure overload by artificial isthmus stenosis with stepwise developing myocardial hypertrophy and final fibrosis (Hyper, n = 3) or by LV volume overload in the adverse remodeled LV after myocardial infarction (RemoLV, n = 3). Sham interventions served as controls and healthy animals (Control, n = 3) served as a reference in sequencing study. Myocardial samples from the LV of each group were subjected to RNA sequencing. RNA-seq analysis revealed a clear distinction between the transcriptomes of myocardial fibrosis (MF) models. Cardiotoxic drugs activated the TNF-alpha and adrenergic signaling pathways. Pressure or volume overload led to the activation of FoxO pathway. Significant upregulation of pathway components enabled the identification of potential drug candidates used for the treatment of heart failure, such as ACE inhibitors, ARB, ß-blockers, statins and diuretics specific to the distinct MF models. We identified candidate drugs in the groups of channel blockers, thiostrepton that targets the FOXM1-regulated ACE conversion to ACE2, tyrosine kinases or peroxisome proliferator-activated receptor inhibitors. Our study identified different gene targets involved in the development of distinct preclinical MF protocols enabling tailoring expression signature-based approach for the treatment of MF.
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Cardiomiopatias , Insuficiência Cardíaca , Animais , Transcriptoma , Antagonistas de Receptores de Angiotensina , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Cardiomiopatias/metabolismo , Insuficiência Cardíaca/patologia , Cardiotoxicidade/patologia , Doxorrubicina/farmacologia , Fenótipo , Fibrose , Sistemas de Liberação de Medicamentos , Miocárdio/metabolismo , Modelos Animais de DoençasRESUMO
BACKGROUND: Recently, the European Society of Cardiology (ESC) and European Association for the Society of Diabetes (EASD) introduced a new cardiovascular disease (CVD) risk stratification model to aid further treatment decisions in individuals with diabetes. Our study aimed to investigate the prognostic performance of the ESC/EASD risk model in comparison to the Systematic COronary Risk Evaluation (SCORE) risk model and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in an unselected cohort of type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: A total of 1690 T2DM patients with a 10-year follow up for fatal CVD and all-cause death and a 5-year follow up for CVD and all-cause hospitalizations were analyzed. According to ESC/EASD risk criteria 25 (1.5%) patients were classified as moderate, 252 (14.9%) high, 1125 (66.6%) very high risk and 288 (17.0%) were not classifiable. Both NT-proBNP and SCORE risk model were associated with 10-year CVD and all-cause death and 5-year CVD and all-cause hospitalizations while the ESC/EASD model was only associated with 10-year all-cause death and 5-year all-cause hospitalizations. NT-proBNP and SCORE showed significantly higher C-indices than the ESC/EASD risk model for CVD death [0.80 vs. 0.53, p < 0.001; 0.64 vs. 0.53, p = 0.001] and all-cause death [0.73, 0.66 vs. 0.52, p < 0.001 for both]. The performance of SCORE improved in a subgroup without CVD aged 40-64 years compared to the unselected cohort, while NT-proBNP performance was robust across all groups. CONCLUSION: The new introduced ESC/EASD risk stratification model performed limited compared to SCORE and single NT-proBNP assessment for predicting 10-year CVD and all-cause fatal events in individuals with T2DM.
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Doenças Cardiovasculares/mortalidade , Técnicas de Apoio para a Decisão , Diabetes Mellitus Tipo 2/sangue , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Fatores Etários , Idoso , Áustria , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Causas de Morte , Comorbidade , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/mortalidade , Feminino , Fatores de Risco de Doenças Cardíacas , Hospitalização , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Sistema de Registros , Medição de Risco , Fatores de TempoRESUMO
BACKGROUND: While secondary mitral regurgitation (sMR) is associated with adverse outcome in heart failure with reduced ejection fraction (HFrEF), key pathophysiologic mechanisms remain poorly understood and might be elucidated by microRNAs (miRNA/miR), that were recently related to cardiac remodelling. This study sought to assess (i) the differences of miRNA profiles in patients with severe sMR compared to matched disease controls, (ii) the correlation between circulating miRNAs and surrogates of sMR severity as well as (iii) the prognostic implications of miRNA levels in severe sMR. MATERIALS AND METHODS: Sixty-six HFrEF patients were included, of these 44 patients with severe sMR 2:1 matched to HFrEF controls with no/mild sMR. A comprehensive set of miRNAs (miR-21, miR-29a, miR-122, miR-132, miR-133a, miR-let7i) were measured and correlated to echocardiographic sMR severity. RESULTS: miRNA patterns differed distinctly between patients with severe sMR and HFrEF controls (P < .05). Among the panel of assessed miRNAs, miR-133a correlated most strongly with surrogates of sMR severity (r = -0.41, P = .001 with sMR vena contracta width). Interestingly, elevated levels of miR-133 were associated with an increased risk for cardiovascular death and/or HF hospitalizations with and adjusted HR of 1.85 (95% CI 1.24-2.76, P = .003). CONCLUSIONS: This study unveils distinct pathophysiologic maladaptions at a cellular level in patients with severe sMR compared to no/mild sMR by showing significant differences in miRNA profiles and correlations with sMR severity, supporting the concept that sMR drives cardiac remodelling in heart failure. Moreover, the increased risk for adverse outcome in HFrEF patients with severe sMR conveyed by miR-133a might indicate irreversible myocardial damage.
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Insuficiência Cardíaca/genética , MicroRNAs/metabolismo , Insuficiência da Valva Mitral/genética , Idoso , Estudos de Casos e Controles , Ecocardiografia , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/fisiopatologia , Volume Sistólico/fisiologiaRESUMO
AIMS: The clinically investigated rationale for neprilysin (NEP)-inhibition by angiotensinreceptor-NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi. METHODS: Seventy-four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin-converting-enzyme inhibitor(ACEi)/angiotensin-receptor blocker (ARB) therapy served as control. Plasma bioactive-ADM (bio-ADM), mid-regional-pro-ADM (MR-proADM), B-typenatriuretic peptide (BNP) and N-terminal-pro-BNP (NT-proBNP) were determined at baseline, short-term, 1-year and 2-year follow up. RESULTS: Following ARNi initiation both bio-ADM and MR-proADM concentrations were significantly increased at early and long-term follow up (bio-ADM [pg/mL]: 26.0 [interquartile range {IQR}: 17.7-37.5] vs. 50.8 [IQR: 36.5-78.1] vs. 54.6 [IQR: 42.0-97.1] vs. 57.4 [IQR: 48.5-161.6]; MR-proADM [nmol/L]: 0.87 [IQR: 0.64-1.12] vs. 1.25 [IQR: 0.93-1.79] vs. 1.42 [IQR: 0.95-1.90] vs. 1.60 [IQR: 1.12-2.46], P < .0001 for all). The ratios bio-ADM/MR-proADM and BNP/NT-proBNP increased during ARNi-therapy proving improved availability of bioactive peptides. The proportional increase of bio-ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin-angiotensin system blocker therapy, i.e. ACEi or ARB (P > .05 for all), indicating that activation of the ADM-axis arises particularly from NEPinhibition. CONCLUSION: The significant increase of MR-proADM and bio-ADM together with an elevated bioADM/MR-proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM-axis represents a so far unrecognized effect of ARNi.
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Insuficiência Cardíaca Sistólica , Insuficiência Cardíaca , Adrenomedulina , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Angiotensinas , Biomarcadores , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca Sistólica/tratamento farmacológico , Humanos , Peptídeo Natriurético Encefálico , Neprilisina , Fragmentos de Peptídeos , Receptores de Angiotensina , Volume SistólicoRESUMO
Secondary mitral regurgitation and secondary tricuspid regurgitation due to heart failure (HF) remain challenging in almost every aspect: increasing prevalence, poor prognosis, notoriously elusive in diagnosis, and complexity of therapeutic management. Recently, defined HF subgroups according to three ejection fraction (EF) ranges (reduced, mid-range, and preserved) have stimulated a structured understanding of the HF syndrome but the role of secondary valve regurgitation (SVR) across the spectrum of EF remains undefined. This review expands this structured understanding by consolidating the underlying phenotype of myocardial impairment with each type of SVR. Specifically, the current understanding, epidemiological considerations, impact, public health burden, mechanisms, and treatment options of SVR are discussed separately for each lesion across the HF spectrum. Furthermore, this review identifies important gaps in knowledge, future directions for research, and provides potential solutions for diagnosis and treatment. Mastering the challenge of SVR requires a multidisciplinary collaborative effort, both, in clinical practice and scientific approach to optimize patient outcomes.
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Insuficiência Cardíaca , Insuficiência Cardíaca/etiologia , Humanos , Prevalência , Prognóstico , Sistema de Registros , Volume SistólicoRESUMO
Circular RNAs (circRNAs) are crucial in gene regulatory networks and disease development, yet circRNA expression in myocardial infarction (MI) is poorly understood. Here, we harvested myocardium samples from domestic pigs 3 days after closed-chest reperfused MI or sham surgery. Cardiac circRNAs were identified by RNA-sequencing of rRNA-depleted RNA from infarcted and healthy myocardium tissue samples. Bioinformatics analysis was performed using the CIRIfull and KNIFE algorithms, and circRNAs identified with both algorithms were subjected to differential expression (DE) analysis and validation by qPCR. Circ-RCAN2 and circ-C12orf29 expressions were significantly downregulated in infarcted tissue compared to healthy pig heart. Sanger sequencing was performed to identify the backsplice junctions of circular transcripts. Finally, we compared the expressions of circ-C12orf29 and circ-RCAN2 between porcine cardiac progenitor cells (pCPCs) that were incubated in a hypoxia chamber for different time periods versus normoxic pCPCs. Circ-C12orf29 did not show significant DE in vitro, whereas circ-RCAN2 exhibited significant ischemia-time-dependent upregulation in hypoxic pCPCs. Overall, our results revealed novel cardiac circRNAs with DE patterns in pCPCs, and in infarcted and healthy myocardium. Circ-RCAN2 exhibited differential regulation by myocardial infarction in vivo and by hypoxia in vitro. These results will improve our understanding of circRNA regulation during acute MI.
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Redes Reguladoras de Genes , Mioblastos Cardíacos/patologia , Infarto do Miocárdio/complicações , Traumatismo por Reperfusão Miocárdica/genética , RNA Circular/metabolismo , Animais , Hipóxia Celular/genética , Biologia Computacional , Angiografia Coronária , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Humanos , Mioblastos Cardíacos/metabolismo , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/genética , Traumatismo por Reperfusão Miocárdica/diagnóstico , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , RNA-Seq , Sus scrofa , Regulação para CimaRESUMO
OBJECTIVES: Neurologic outcome prediction in out-of-hospital cardiac arrest survivors is highly limited due to the lack of consistent predictors of clinically relevant brain damage. The present study aimed to identify novel biomarkers of neurologic recovery to improve early prediction of neurologic outcome. DESIGN: Prospective, single-center study, SETTING:: University-affiliated tertiary care center. PATIENTS: We prospectively enrolled 96 out-of-hospital cardiac arrest survivors into our study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Neurologic outcome was assessed by the Cerebral Performance Categories score. To identify plasma biomarkers for poor neurologic outcome (Cerebral Performance Categories score ≥ 3), we performed a three-step proteomics strategy of preselection by shotgun analyses, crosschecking in brain tissue samples, and verification by targeted proteomic analyses using a multistep statistical modeling approach. Sixty-three patients (66%) had a poor neurologic outcome. Out of a total of 299 proteins, we identified α-enolase, 14-3-3 protein ζ/δ, cofilin-1, and heat shock cognate 71 kDa protein as novel biomarkers for poor neurologic outcome. The implementation of these biomarkers into a clinical multimarker model, consisting of previously identified covariates associated to outcome, resulted in a significant improvement of neurologic outcome prediction (C-index, 0.70; explained variation, 11.9%; p for added value, 0.019). CONCLUSIONS: This study identified four novel biomarkers for the prediction of poor neurologic outcome in out-of-hospital cardiac arrest survivors. The implementation of α-enolase, 14-3-3 protein ζ/δ, cofilin-1, and heat shock cognate 71 kDa protein into a multimarker predictive model along with previously identified risk factors significantly improved neurologic outcome prediction. Each of the proteomically identified biomarkers did not only outperform current risk stratification models but may also reflect important pathophysiologic pathways undergoing during cerebral ischemia.
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Parada Cardíaca Extra-Hospitalar/sangue , Proteômica/métodos , Idoso , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/fisiopatologia , Prognóstico , Estudos ProspectivosRESUMO
As part of the TACTICS (Transnational Alliance for Regenerative Therapies in Cardiovascular Syndromes) series to enhance regenerative medicine, here, we discuss the role of preclinical studies designed to advance stem cell therapies for cardiovascular disease. The quality of this research has improved over the past 10 to 15 years and overall indicates that cell therapy promotes cardiac repair. However, many issues remain, including inability to provide complete cardiac recovery. Recent studies question the need for intact cells suggesting that harnessing what the cells release is the solution. Our contribution describes important breakthroughs and current directions in a cell-based approach to alleviating cardiovascular disease.
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Técnicas de Reprogramação Celular/métodos , Cardiopatias/terapia , Células-Tronco Pluripotentes/classificação , Transplante de Células-Tronco/métodos , Animais , Humanos , Células-Tronco Pluripotentes/citologia , Transplante de Células-Tronco/efeitos adversos , Pesquisa Translacional Biomédica/métodosRESUMO
BACKGROUND: Experimental and clinical data indicate a major influence of diabetes on atherogenesis. We aimed to assess whether the effect of diabetes on long-term mortality in asymptomatic patient with carotid stenosis is contingent upon the degree of the carotid atherosclerotic burden. METHODS: 1065 patients with neurological asymptomatic carotid atherosclerosis as evaluated by duplex sonography were prospectively followed for cause-specific mortality. RESULTS: During a median of 11.8 years, a total of 549 deaths, including 362 cardiovascular deaths, were recorded. Diabetes and glycohemoglobin A1c (Hba1c) levels were significantly associated with mortality. Diabetes displayed an independent risk for all-cause (adjusted HR 1.62; 95% CI 1.35-1.94) and cardiovascular death (adjusted HR 1.75, 95% CI 1.40-2.19). The adjusted hazard ratio per increase of 1% of Hba1c levels was 1.21 (P < 0.01) for all-cause and 1.31 (P < 0.01) for cardiovascular mortality, respectively. Patients with diabetes mellitus and a higher degree of carotid stenosis and were at great risk of adverse outcome. Only 21% of the asymptomatic diabetic patients with carotid narrowing over 50% survived, whereas 62% of the patients without diabetes and with carotid atherosclerosis below 50% were still alive after 12-years of follow-up. The high risk for all-cause and cardiovascular death of these patients remained significant after adjustment for various established cardiovascular risk factors in multivariable regression analysis (adjusted hazard ratio 2.4, P < 0.001; compared to patients without diabetes and < 50% carotid atherosclerosis). CONCLUSION: Diabetic patients with carotid stenosis ≥ 50% are at exceptional high risk for all-cause and cardiovascular death. Thus, routinely ultrasound investigation of the carotid arteries might be a valuable prognostic tool for patients with diabetes mellitus.
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Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/mortalidade , Vasos Coronários/diagnóstico por imagem , Diabetes Mellitus/mortalidade , Ultrassonografia Doppler Dupla , Idoso , Doenças Assintomáticas , Áustria/epidemiologia , Biomarcadores/sangue , Glicemia/metabolismo , Causas de Morte , Diabetes Mellitus/sangue , Diabetes Mellitus/diagnóstico , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND: Secondary mitral regurgitation (sMR) drives adverse cardiac remodelling in patients with heart failure with reduced ejection fraction (HFrEF). Progression in severity over time contributes to a transition towards more advanced HF stages. Early identification of patients at risk for sMR progression remains challenging. We therefore sought to assess a broad spectrum of neurohumoral biomarkers in patients with HFrEF to explore their ability to predict progression of sMR. METHODS: A total of 249 HFrEF patients were enrolled. Biomarkers encompassing key neurohumoral pathways in heart failure were sampled at baseline, and sMR progression was assessed over 3 years of follow-up. RESULTS: Of 191 patients with nonsevere sMR at baseline, 18% showed progressive sMR within three years after study enrolment. Progression of sMR was associated with higher levels of MR-proADM (adj.OR 2.25, 95% CI 1.29-3.93; P = .004), MR-proANP (adj.OR 1.84, 95% CI 1.14-3.00; P = .012), copeptin (adj.OR 1.66, 95% CI 1.04-2.67; P = .035) and CT-pro-ET1 (adj.OR 1.68, 95% CI 1.06-2.68; P = .027) but not with NT-proBNP (P = .54). CONCLUSION: Increased plasma levels of neurohumoral cardiac biomarkers are predictors of sMR progression in patients with HFrEF and add easily available incremental prognostic information for risk stratification. Importantly, NT-proBNP was not useful to predict progressive sMR in the present analysis. On the contrary, MR-proANP, primarily produced in the atria, copeptin partly triggered by intra-cardiac and intra-arterial pressures and MR-proADM, a marker of forward failure and peripheral released vasoactive CT-proET1, increase based on a progressive loading burden by sMR and may thus serve as better predictors of sMR progression.
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Adrenomedulina/sangue , Fator Natriurético Atrial/sangue , Endotelina-1/sangue , Glicopeptídeos/sangue , Insuficiência Cardíaca Sistólica/sangue , Insuficiência da Valva Mitral/sangue , Fragmentos de Peptídeos/sangue , Precursores de Proteínas/sangue , Idoso , Biomarcadores , Doença Crônica , Progressão da Doença , Ecocardiografia , Feminino , Insuficiência Cardíaca Sistólica/complicações , Insuficiência Cardíaca Sistólica/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/etiologia , Peptídeo Natriurético Encefálico/sangue , Fenótipo , Prognóstico , Medição de Risco , Volume SistólicoRESUMO
AIM: GDF-15 is an established cardiovascular risk marker but is equally implicated in tumour biology. Elevated levels of GDF-15 have indeed been observed in distinct tumour entities. This study aimed to explore the relation of GDF-15 to other cardiac biomarkers and the general association of GDF-15 on prognosis in an unselected cohort of treatment-naïve cancer patients. METHODS: We prospectively enrolled 555 consecutive patients at time of diagnosis of malignant disease prior receiving anticancer therapy. Plasma GDF-15 concentrations were determined alongside other cardiac and routine laboratory markers. All-cause mortality was defined as primary endpoint. RESULTS: GDF-15 levels were 338 ng/L (IQR:205-534) for the total cohort, and values were comparable for different tumour entities except breast cancer. Metastatic disease was characterized by higher plasma GDF-15 [435 ng/L (IQR:279-614) vs 266 ng/L (IQR:175-427), P < .001]. GDF-15 correlated positively with inflammatory status reflected by CRP, SAA and IL-6 [r = .31, P < .001, r = .23, P < .001 and r = .14, P = .002] and cardiac biomarkers as NT-proBNP, hsTnT, MR-proADM and CT-proET-1 [r = .46; r = .46; r = .59 and r = .50; P < .001 for all]. GDF-15 was significantly associated with all-cause mortality after multivariate adjustment [adj.HR for ln(GDF-15) 1.78, 95%CI:1.47-2.16, P < .001]. There was a significant interaction between solid and haematological malignancies with loss of association of GDF-15 with outcome in myelodysplastic and myeloproliferative disease. CONCLUSIONS: Elevated plasma GDF-15 is associated with progressing disease severity and poor prognosis in solid tumours of treatment-naïve cancer patients. GDF-15 increase is accompanied by worsening systemic inflammation and a subclinical functional impairment of different organs including the heart. GDF-15 represents a promising target for our pathophysiologic understanding in cardio-oncology linking conditions of both cardiac and neoplastic disease.
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Fator 15 de Diferenciação de Crescimento/sangue , Mortalidade , Neoplasias/sangue , Adrenomedulina/sangue , Idoso , Neoplasias da Mama/sangue , Proteína C-Reativa/metabolismo , Causas de Morte , Endotelina-1/sangue , Feminino , Neoplasias Gastrointestinais/sangue , Glicopeptídeos , Humanos , Interleucina-6/sangue , Neoplasias Pulmonares/sangue , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/sangue , Transtornos Mieloproliferativos/sangue , Peptídeo Natriurético Encefálico/sangue , Metástase Neoplásica , Fragmentos de Peptídeos/sangue , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Precursores de Proteínas/sangue , Proteína Amiloide A Sérica/metabolismo , Troponina T/sangueRESUMO
Aims: Significant efforts are currently undertaken to reduce functional mitral regurgitation (FMR) in patients with chronic heart failure in the hope to improve prognosis. We aimed to assess the prognostic impact of FMR in heart failure with reduced ejection fraction (HFrEF) under optimal medical therapy (OMT) and various conditions of HFrEF. We further intended to identify a heart failure phenotype, where FMR is most likely a driving force and not a mere bystander of the disease. Methods and results: We prospectively included 576 consecutive HFrEF patients into our long-term observational study. Functional [i.e. New York Heart Association (NYHA) class], echocardiographic, invasive haemodynamic, and biochemical (i.e. NT-proBNP, MR-proANP, MR-proADM, CT-proET-1, copeptin) measurements were performed at baseline. During a median follow-up of 62 months (interquartile range 52-76), 47% of patients died. Severe FMR was a significant predictor of mortality [hazard ratio (HR) 1.76, 95% confidence interval (CI) 1.34-2.30; P < 0.001], independent of clinical (adjusted HR 1.61, 95% CI 1.22-2.12; P = 0.001), and echocardiographic (adjusted HR 1.46, 95% CI 1.09-1.94; P = 0.01) confounders, OMT (adjusted HR 1.81, 95% CI 1.25-2.63; P = 0.002), and neurohumoral activation (adjusted HR 1.38, 95% CI 1.03-1.84; P = 0.03). Subanalysis revealed that severe FMR was associated with poor outcome in an intermediate-failure phenotype of HFrEF i.e. patients with NYHA class II (adjusted HR 2.17, 95% CI 1.07-4.44; P = 0.03) and III (adjusted HR 1.80, 95% CI 1.17-2.77; P = 0.008), moderately reduced left ventricular function (adjusted HR 2.37, 95% CI 1.36-4.12; P = 0.002), and within the second quartile (871-2360 pg/mL) of NT-proBNP (adjusted HR 2.16, 95% CI 1.22-3.86; P = 0.009). Conclusion: In a patient cohort under OMT, the adverse prognostic impact of FMR is given predominantly in a sub-cohort of a specific intermediate-failure phenotype-well-defined functionally, haemodynamically, biochemically, and morphologically.
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Insuficiência Cardíaca , Insuficiência da Valva Mitral , Idoso , Doença Crônica , Feminino , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/epidemiologia , Insuficiência da Valva Mitral/fisiopatologia , Prognóstico , Volume Sistólico/fisiologiaRESUMO
The impact of excess viral RNA on myocardial function and morphology in the setting of acute human immunodeficiency virus (HIV) infection remains unknown. In this study, 49 patients with acute HIV infection showed increased levels of N-terminal prohormone of brain natriuretic peptide, a surrogate of myocardial function, which decreased with viral suppression and normalization of systemic inflammation (79 pg/mL vs 28 pg/mL; P < .001). A comparable change was seen with levels of troponin T, a marker of morphologic myocardial damage (4.9 ng/L vs 1.5 ng/L; P < .001). In conclusion, we observed significant functional and morphological myocardial impairment during acute HIV infection, fueled by inflammatory activation and extensive viral replication, resulting in a reversible subclinical inflammatory cardiomyopathy.
Assuntos
Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Infecções por HIV/patologia , HIV/isolamento & purificação , Peptídeo Natriurético Encefálico/sangue , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Troponina T/sangue , Carga ViralRESUMO
BACKGROUND: Blockade of the renin-angiotensin system (RAS) represents a main strategy in the therapy of heart failure with reduced ejection fraction (HFrEF), but the role of active renin concentration (ARC) for guiding therapy in the presence of an RAS blockade remains to be established. This study assessed angiotensin profiles of HFrEF patients with distinct RAS activations as reflected by ARC. METHODS: Two cohorts of stable chronic HFrEF patients on optimal medical treatment (OMT) were enrolled. We assessed ARC and all known circulating angiotensin metabolites, including AngI and AngII, by mass spectrometry to investigate the effect of different therapy modalities. Low- and high-renin HFrEF patients were identified by ARC screening and subsequently characterized by their angiotensin profiles. RESULTS: Although different modes of RAS blockade resulted in typical AngII/AngI ratios, concentrations of (AngI+AngII) strongly correlated with ARC [r = 0.95, P < 0.001] independent of therapy mode. Despite RAS blocker treatment with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin II type 1 receptor blockers (ARB), which anticipated ARC upregulation, about 30% of patients showed lower/normal range ARC values. ARC did not correlate with N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations and New York Heart Association (NYHA) stages. Angiotensin concentrations were profoundly diminished for the low-ARC group compared with the high-ARC group: AngI [6.4 ng/L (IQR: 2.1-12.5) vs 537.9 ng/L (IQR: 423.1-728.4), P < 0.001 for ACE-I; and 4.5 ng/L (IQR: 1.4-11.2) vs 203.0 ng/L (IQR: 130.2-247.9), P = 0.003 for ARB] and AngII [<1.4 ng/L (IQR: <1.4-1.5) vs 6.1 ng/L (IQR: 2.0-11.1), P = 0.002 for ACE-I and 4.7 ng/L (IQR: <1.4-12.3) vs 206.4 ng/L (IQR: 142.2-234.4), P < 0.001 for ARB]. CONCLUSIONS: In addition to NT-proBNP and NYHA stages, ARC enables classification of HFrEF patients receiving OMT into more distinguished neurohumoral HFrEF phenotypes, offering a rationale for adaptive therapeutic interventions.
Assuntos
Insuficiência Cardíaca/tratamento farmacológico , Renina/sangue , Idoso , Angiotensina I/sangue , Angiotensina II/sangue , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Feminino , Insuficiência Cardíaca/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Fenótipo , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
Deleterious inflammatory responses are seen to be the trigger of heart failure in myocarditis and therapies directed towards immunomodulation have been assumed to be beneficial. The objective of the present review was to systematically assess the effect of immunomodulation in lymphocytic myocarditis. Studies were included if diagnosis of lymphocytic myocarditis was based on EMB as well as on the exclusion of other etiologies of heart failure and if the patients had at least moderately decreased left ventricular ejection fraction (< 45%). All immunomodulatory treatments at any dose that target the cause of myocarditis leading to cardiomyopathy were included. Retrieval of PUBMED, SCOPUS, Cochrane Central Register of Controlled Trials, and LILACs from January 1950 to January 2016 revealed 444 abstracts of which nine studies with a total of 612 patients were included. As primary effectivity endpoint, a change in left ventricular ejection was chosen. No benefits of corticosteroids or intravenous immunoglobulin alone were reported. Immunoadsorption and subsequent IVIG substitution was associated with a greater improvement in left ventricular ejection fraction (LVEF) in one study. Single studies found a beneficial effect of interferon and statins on LVEF. We performed a meta-analysis for the combination of corticosteroids with immunosuppressants and found a non-significant increase of LVEF of + 13.06% favoring combined treatment (95%CI 1.71 to + 27.84%, p = 0.08). The current evidence does not support the routine use of immunosuppression in traditional lymphocytic myocarditis. Nevertheless, in histologically proven virus-negative myocarditis of high-risk patients, combined immunosuppression might be beneficial. Future research should focus on translation of these effects to clinical outcome.
Assuntos
Fatores Imunológicos/uso terapêutico , Imunomodulação , Imunossupressores/uso terapêutico , Linfócitos/patologia , Miocardite/terapia , Humanos , Linfócitos/imunologia , Miocardite/imunologia , Resultado do TratamentoRESUMO
BACKGROUND: Premature myocardial infarction (≤40 years) represents a rare disease with a distinct risk factor profile and a lipid phenotype that is characterized by a predominance of elevated triglyceride-rich lipoproteins. So far high-density and low-density lipoproteins remain the primary targets for risk stratification and treatment evaluation in coronary artery disease, but this strategy might be insensitive in patients with premature myocardial infarction. AIM: Aim of this study was to investigate the predictive value of different lipid fractions on long-term cardiovascular outcome in patients with premature myocardial infarction. METHODS: We prospectively enrolled 102 consecutive AMI survivors (≤40 years) in this prospective multicentre study and investigated the influence of the familial combined hypercholesterolaemia phenotype and a corresponding multimarker panel of different lipid fractions on cardiovascular outcome. RESULTS: Total cholesterol, non-HDL cholesterol, remnant cholesterol and Apo B lipoprotein were significantly higher in patients experiencing MACE as compared to those who did not. The familial combined hypercholesterolaemia phenotype was associated with an unfavourable cardiovascular outcome even after adjustment for potential cofounders (adjusted HR 3.04,95% CI, 1.26-7.34, P = 0.013). Remnant cholesterol revealed the strongest association with MACE (adj.HR 1.94, 95%CI. 1.30-2.99, P = 0.001). Interestingly LDL and HDL revealed no significant impact on cardiovascular outcome in this study cohort. CONCLUSION: Non-HDL and remnant cholesterol are strongly associated with an unfavourable outcome in patients with premature myocardial infarction and might be the preferred treatment target for lipid-lowering therapy.
Assuntos
Hiperlipoproteinemia Tipo II/complicações , Metabolismo dos Lipídeos/fisiologia , Infarto do Miocárdio/sangue , Adulto , Apolipoproteínas B/metabolismo , Austrália/epidemiologia , Estudos de Casos e Controles , HDL-Colesterol/metabolismo , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/mortalidade , Masculino , Infarto do Miocárdio/mortalidade , Estudos Prospectivos , Medição de RiscoRESUMO
BACKGROUND: The underlying reasons for the highly inconsistent clinical outcome data for omega-3-polyunsaturated fatty acids (n3-PUFAs) supplementation in patients with cardiac disease have not been understood yet. The aim of this prospective, randomized, double-blind, placebo controlled study was to determine the effects of oral treatment with n3-PUFAs on the anti-oxidant capacity of HDL in heart failure (HF) patients. METHODS: A total of 40 patients with advanced HF of nonischaemic origin, defined by NT-proBNP levels of >2000 pg/mL, NYHA class III or IV and a LVEF <35% who were on stable optimized medical therapy for ≥3 months, were consecutively enrolled into this prospective, double-blind, placebo-controlled trial and randomized in a 1:1:1 fashion to receive 1 g/day or 4 g/day of n3-PUFA, or placebo, respectively, for 12 weeks. RESULTS: After 12 weeks of treatment, the anti-oxidant function of HDL, measured by the HDL inflammatory index, was found significantly impaired in the treatment group in a dose-dependent fashion with 0.67 [IQR 0.49-1.04] for placebo vs 0.71 [IQR 0.55-1.01] for 1 g/day n3-PUFA vs 0.98 [IQR 0.73-1.16] for 4 g/day n3-PUFA (P for trend = 0.018). CONCLUSION: We provide evidence for an adverse effect of n3-PUFA supplementation on anti-oxidant function of HDL in nonischaemic heart failure patients, establishing a potential mechanistic link for the controversial outcome data on n3-PUFA supplementation.