RESUMO
BACKGROUND: The effects of temporary mechanical circulatory support with a microaxial flow pump on mortality among patients with ST-segment elevation myocardial infarction (STEMI) complicated by cardiogenic shock remains unclear. METHODS: In an international, multicenter, randomized trial, we assigned patients with STEMI and cardiogenic shock to receive a microaxial flow pump (Impella CP) plus standard care or standard care alone. The primary end point was death from any cause at 180 days. A composite safety end point was severe bleeding, limb ischemia, hemolysis, device failure, or worsening aortic regurgitation. RESULTS: A total of 360 patients underwent randomization, of whom 355 were included in the final analysis (179 in the microaxial-flow-pump group and 176 in the standard-care group). The median age of the patients was 67 years, and 79.2% were men. Death from any cause occurred in 82 of 179 patients (45.8%) in the microaxial-flow-pump group and in 103 of 176 patients (58.5%) in the standard-care group (hazard ratio, 0.74; 95% confidence interval [CI], 0.55 to 0.99; P = 0.04). A composite safety end-point event occurred in 43 patients (24.0%) in the microaxial-flow-pump group and in 11 (6.2%) in the standard-care group (relative risk, 4.74; 95% CI, 2.36 to 9.55). Renal-replacement therapy was administered to 75 patients (41.9%) in the microaxial-flow-pump group and to 47 patients (26.7%) in the standard-care group (relative risk, 1.98; 95% CI, 1.27 to 3.09). CONCLUSIONS: The routine use of a microaxial flow pump with standard care in the treatment of patients with STEMI-related cardiogenic shock led to a lower risk of death from any cause at 180 days than standard care alone. The incidence of a composite of adverse events was higher with the use of the microaxial flow pump. (Funded by the Danish Heart Foundation and Abiomed; DanGer Shock ClinicalTrials.gov number, NCT01633502.).
Assuntos
Coração Auxiliar , Infarto do Miocárdio com Supradesnível do Segmento ST , Choque Cardiogênico , Idoso , Feminino , Humanos , Masculino , Coração Auxiliar/efeitos adversos , Incidência , Choque Cardiogênico/etiologia , Choque Cardiogênico/mortalidade , Choque Cardiogênico/cirurgia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Resultado do Tratamento , Circulação Assistida/efeitos adversos , Circulação Assistida/instrumentação , Circulação Assistida/métodosRESUMO
Growing evidence suggests the crucial involvement of inflammation in the pathogenesis of pulmonary hypertension (PH). The current study analyzed the expression of interleukin (IL)-17a and IL-22 as potential biomarkers for PH in a preclinical rat model of PH as well as the serum levels in a PH patient collective. PH was induced by monocrotalin (60 mg/kg body weight s.c.) in 10 Sprague Dawley rats (PH) and compared to 6 sham-treated controls (CON) as well as 10 monocrotalin-induced, macitentan-treated rats (PH_MAC). Lung and cardiac tissues were subjected to histological and immunohistochemical analysis for the ILs, and their serum levels were quantified using ELISA. Serum IL levels were also measured in a PH patient cohort. IL-22 expression was significantly increased in the lungs of the PH and PH_MAC groups (p = 0.002), whereas increased IL17a expression was demonstrated only in the lungs and RV of the PH (p < 0.05) but not the PH_MAC group (p = n.s.). The PH group showed elevated serum concentrations for IL-22 (p = 0.04) and IL-17a (p = 0.008). Compared to the PH group, the PH_MAC group demonstrated a decrease in IL-22 (p = 0.021) but not IL17a (p = n.s.). In the PH patient collective (n = 92), increased serum levels of IL-22 but not IL-17a could be shown (p < 0.0001). This elevation remained significant across the different etiological groups (p < 0.05). Correlation analysis revealed multiple significant relations between IL-22 and various clinical, laboratory, functional and hemodynamic parameters. IL-22 could serve as a promising inflammatory biomarker of PH with potential value for initial diagnosis, functional classification or even prognosis estimation. Its validation in larger patients' cohorts regarding outcome and survival data, as well as the probability of promising therapeutic target structures, remains the object of further studies.
Assuntos
Hipertensão Pulmonar , Humanos , Animais , Ratos , Ratos Sprague-Dawley , Hipertensão Pulmonar/diagnóstico , Interleucina 22 , Biomarcadores , Ensaio de Imunoadsorção EnzimáticaRESUMO
BACKGROUND: Effective diuretic regimens using loop diuretics in patients with acute decompensated heart failure are often limited by the development of worsening kidney function. Sodium-glucose cotransporter-2 inhibitors induce glucosuria and sodium excretion with nephroprotective effects in patients with stable heart failure but their role in acute decompensated heart failure is unclear. METHODS: In this single-center, prospective, double-blind, placebo-controlled, randomized study, we randomly assigned patients with acute decompensated heart failure to empagliflozin 25 mg daily or placebo in addition to standard decongestive treatments that included loop diuretics. The primary end point was cumulative urine output over 5 days. Secondary end points included diuretic efficiency, dynamics in markers of kidney function and injury, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: Sixty patients were randomized within 12 hours of hospitalization for acute decompensated heart failure. Addition of empagliflozin daily to standard medical treatment of acute decompensated heart failure resulted in a 25% increase in cumulative urine output over 5 days (median 10.8 versus 8.7 L mL in placebo, group difference estimation 2.2 L [95% CI, 8.4 to 3.6]; P=0.003). Empagliflozin increased diuretic efficiency compared with placebo (14.1 mL urine per milligram furosemide equivalent [95% CI, 0.6-27.7]; P=0.041) without affecting markers of renal function (estimated glomerular filtration rate, 51±19 versus 54±17 mL/min per 1.73 m²; P=0.599) or injury (total urinary protein, 492±845 versus 503±847 mg/g creatinine; P=0.975; and urinary α1-microglobulin, 55.4±38.6 versus 31.3±33.6 mg/g creatinine; P=0.066) with more pronounced decrease in NT-proBNP in the empagliflozin group compared with placebo (-1861 versus -727.2 pg/mL after 5 days; quotient in slope, 0.89 [95% CI, 0.83-0.95]; P<0.001). There were no differences in the incidence of safety events between groups. CONCLUSIONS: Early addition of empagliflozin to standard diuretic therapy increases urine output without affecting renal function in patients with acute decompensated heart failure. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04049045.
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Insuficiência Cardíaca , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Compostos Benzidrílicos , Creatinina , Diurese , Diuréticos/efeitos adversos , Glucosídeos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , Rim , Estudos Prospectivos , Sódio/urina , Inibidores de Simportadores de Cloreto de Sódio e Potássio/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversosRESUMO
BACKGROUND: Prediction of long-term mortality in patients with severe symptomatic aortic valve stenosis undergoing transcatheter aortic valve implantation (TAVI) is still challenging but of great impact with respect to the selection of treatment strategy. Whereas most of the established scores address perioperative risk and/or short-term mortality, the aim of our current study was the integrative investigation of a multitude of patients' characteristics including novel biomarkers of cardiovascular remodeling with respect to their value for the prediction of long-term mortality. METHODS: In a first subset of patients (n = 122, identification group) a wide range of baseline characteristics were assigned to three clusters with 4 to 10 items each (classical clinical parameters; risk assessment scores; novel biomarkers of cardiovascular remodeling) and tested with respect to their predictive value for one-year mortality. Thereby, a sum-score system (Jena Mortality Score, JMS) was defined and tested in a larger collective of TAVI patients (n = 295, validation group) with respect to one- and two-year mortality prediction. RESULTS: In the identification cohort, binary logistic regression analysis, with one-year mortality as dependent variable and the items per cluster as cofounders, revealed atrial fibrillation (Afib; odds ratio [OR] 7.583, 95% confidence interval [95% CI]: 2.051-28.040, p = 0.002), clinical frailty scale (CFS; OR 2.258, 95% CI: 1.262-4.039, p = 0.006) and Tissue-Inhibitor of Metalloproeinase-1 (TIMP-1; OR 1.006, 95% CI: 1.001-1.011, p = 0.019) as independent predictors of one-year mortality. These 3 parameters were integrated into a simplified sum-score as follows: presence of Afib (no = 0, yes = 1); dichotomized CFS (1 to 4 = 0; 5 to 9 = 1); TIMP-1 range (cut-off value 187.2 ng/mL; below = 0, above = 1). The resulting sum-score (JMS) ranged from 0 to 3. By binary logistic regression analysis in the validation cohort with one- and two-year mortality as dependent variable and Society of Thoracic Surgeons (STS) score (STS), staging of extra-valvular cardiac damage (stage), presence of high gradient aortic stenosis (HGAS), EQ visual analogue scale score (EQ-VAS) and JMS as cofounders, besides STS score, only JMS could be proven to serve as independent predictor of both, one-year (OR 1.684, 95% CI: 1.094-2.592, p = 0.018) and two-year (OR 1.711, 95% CI: 1.136-2.576, p = 0.010) mortality. After dichotomization of patients into a low-risk and a high-risk group according to JMS, Kaplan-Meier survival analysis displayed a significant survival benefit for the low-risk group after one and two years (p < 0.001). CONCLUSION: JMS, including TIMP-1 as a novel biomarker of cardiac extracellular matrix accumulation and fibrosis, could serve as a novel simple tool to assess long-term mortality risk after TAVI and might thereby contribute to a more precise stratification of individual risk.
Assuntos
Estenose da Valva Aórtica , Substituição da Valva Aórtica Transcateter , Estenose da Valva Aórtica/diagnóstico por imagem , Estenose da Valva Aórtica/cirurgia , Biomarcadores , Matriz Extracelular , Fibrose , Humanos , Medição de Risco , Fatores de Risco , Substituição da Valva Aórtica Transcateter/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly used to treat cardiogenic shock. However, VA-ECMO might hamper myocardial recovery. The Impella unloads the left ventricle. This study aimed to evaluate whether left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO was associated with lower mortality. METHODS: Data from 686 consecutive patients with cardiogenic shock treated with VA-ECMO with or without left ventricular unloading using an Impella at 16 tertiary care centers in 4 countries were collected. The association between left ventricular unloading and 30-day mortality was assessed by Cox regression models in a 1:1 propensity score-matched cohort. RESULTS: Left ventricular unloading was used in 337 of the 686 patients (49%). After matching, 255 patients with left ventricular unloading were compared with 255 patients without left ventricular unloading. In the matched cohort, left ventricular unloading was associated with lower 30-day mortality (hazard ratio, 0.79 [95% CI, 0.63-0.98]; P=0.03) without differences in various subgroups. Complications occurred more frequently in patients with left ventricular unloading: severe bleeding in 98 (38.4%) versus 45 (17.9%), access site-related ischemia in 55 (21.6%) versus 31 (12.3%), abdominal compartment in 23 (9.4%) versus 9 (3.7%), and renal replacement therapy in 148 (58.5%) versus 99 (39.1%). CONCLUSIONS: In this international, multicenter cohort study, left ventricular unloading was associated with lower mortality in patients with cardiogenic shock treated with VA-ECMO, despite higher complication rates. These findings support use of left ventricular unloading in patients with cardiogenic shock treated with VA-ECMO and call for further validation, ideally in a randomized, controlled trial.
Assuntos
Oxigenação por Membrana Extracorpórea/mortalidade , Internacionalidade , Choque Cardiogênico/mortalidade , Choque Cardiogênico/terapia , Função Ventricular Esquerda/fisiologia , Adulto , Idoso , Estudos de Coortes , Oxigenação por Membrana Extracorpórea/tendências , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Choque Cardiogênico/diagnóstico , Resultado do TratamentoRESUMO
BACKGROUND: In the treatment of de-novo coronary small vessel disease, drug-coated balloons (DCBs) are non-inferior to drug-eluting stents (DESs) regarding clinical outcome up to 12 months, but data beyond 1 year is sparse. We aimed to test the long-term efficacy and safety of DCBs regarding clinical endpoints in an all-comer population undergoing percutaneous coronary intervention. METHODS: In this prespecified long-term follow-up of a multicentre, randomised, open-label, non-inferiority trial, patients from 14 clinical sites in Germany, Switzerland, and Austria with de-novo lesions in coronary vessels <3 mm and an indication for percutaneous coronary intervention were randomly assigned 1:1 to DCB or second-generation DES and followed over 3 years for major adverse cardiac events (ie, cardiac death, non-fatal myocardial infarction, and target-vessel revascularisation [TVR]), all-cause death, probable or definite stent thrombosis, and major bleeding (Bleeding Academic Research Consortium bleeding type 3-5). Analyses were performed on the full analysis set according to the modified intention-to-treat principle. Dual antiplatelet therapy was recommended for 1 month after DCB and 6 months after DES with stable symptoms, but 12 months with acute coronary syndromes. The study is registered with ClinicalTrials.gov, NCT01574534 and is ongoing. FINDINGS: Between April 10, 2012, and Feb 1, 2017, of 883 patients assessed, 758 (86%) patients were randomly assigned to the DCB group (n=382) or the DES group (n=376). The Kaplan-Meier estimate of the rate of major adverse cardiac events was 15% in both the DCB and DES groups (hazard ratio [HR] 0·99, 95% CI 0·68-1·45; p=0·95). The two groups were also very similar concerning the single components of adverse cardiac events: cardiac death (Kaplan-Meier estimate 5% vs 4%, HR 1·29, 95% CI 0·63-2·66; p=0·49), non-fatal myocardial infarction (both Kaplan-Meier estimate 6%, HR 0·82, 95% CI 0·45-1·51; p=0·52), and TVR (both Kaplan-Meier estimate 9%, HR 0·95, 95% CI 0·58-1·56; p=0·83). Rates of all-cause death were very similar in DCB versus DES patients (both Kaplan-Meier estimate 8%, HR 1·05, 95% CI 0·62-1·77; p=0·87). Rates of probable or definite stent thrombosis (Kaplan-Meier estimate 1% vs 2%; HR 0·33, 95% CI 0·07-1·64; p=0·18) and major bleeding (Kaplan-Meier estimate 2% vs 4%, HR 0·43, 95% CI 0·17-1·13; p=0·088) were numerically lower in DCB versus DES, however without reaching significance. INTERPRETATION: There is maintained efficacy and safety of DCB versus DES in the treatment of de-novo coronary small vessel disease up to 3 years. FUNDING: Swiss National Science Foundation, Basel Cardiovascular Research Foundation, and B Braun Medical.
Assuntos
Angioplastia Coronária com Balão/normas , Doença da Artéria Coronariana/terapia , Stents Farmacológicos/normas , Idoso , Angioplastia Coronária com Balão/efeitos adversos , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/mortalidade , Doença da Artéria Coronariana/mortalidade , Stents Farmacológicos/efeitos adversos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Resultado do TratamentoRESUMO
Closure of a patent foramen ovale (PFO) in patients after cryptogenic/cardioembolic stroke is recommended by current guidelines for patients who are 16-60 years of age with a high-risk PFO (class of recommendation A, level of evidence I). The use of double-disk occlusion devices followed by antiplatelet therapy is recommended. The procedure of interventional PFO closure compared with other interventions in cardiology is rather easy to learn. However, it should be performed carefully to avoid postinterventional complications. The number needed to treat (NNT) to avoid one stroke in 5 years in the RESPECT trial was 42, in the CLOSE trial even lower with 20. In the REDUCE trial, the NNT was 28â¯at 2 years. This can be reduced by longer follow-up, e.g., at 10 years the NNT is 18. While other conditions such as migraine are currently under investigation with respect to the impact of PFO closure, sufficiently powered trials are lacking so that closure in diseases other than stroke should always be individualized.
Assuntos
Forame Oval Patente , Dispositivo para Oclusão Septal , Acidente Vascular Cerebral , Forame Oval Patente/complicações , Forame Oval Patente/diagnóstico , Forame Oval Patente/cirurgia , Humanos , Inibidores da Agregação Plaquetária , Recidiva , Prevenção Secundária , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controleRESUMO
BACKGROUND: Percutaneous mechanical circulatory support devices are increasingly used in acute myocardial infarction complicated by cardiogenic shock (AMI-CS), despite limited evidence for their effectiveness. The aim of this study was to evaluate outcomes associated with use of the Impella device compared with intra-aortic balloon pump (IABP) and medical treatment in patients with AMI-CS. METHODS: Data of patients with AMI-CS treated with the Impella device at European tertiary care hospitals were collected retrospectively. All patients underwent early revascularization and received optimal medical treatment. Using IABP-SHOCK II (Intraaortic Balloon Pump in Cardiogenic Shock II) trial inclusion and exclusion criteria, 372 patients were identified and included in this analysis. These patients were matched to 600 patients from the IABP-SHOCK II trial. The following baseline criteria were used as matching parameters: age, sex, mechanical ventilation, ejection fraction, prior cardiopulmonary resuscitation, and lactate. Primary end point was 30-day all-cause mortality. RESULTS: In total, 237 patients treated with an Impella could be matched to 237 patients from the IABP-SHOCK II trial. Baseline parameters were similarly distributed after matching. There was no significant difference in 30-day all-cause mortality (48.5% versus 46.4%, P=0.64). Severe or life-threatening bleeding (8.5% versus 3.0%, P<0.01) and peripheral vascular complications (9.8% versus 3.8%, P=0.01) occurred significantly more often in the Impella group. Limiting the analysis to IABP-treated patients as a control group did not change the results. CONCLUSIONS: In this retrospective analysis of patients with AMI-CS, the use of an Impella device was not associated with lower 30-day mortality compared with matched patients from the IABP-SHOCK II trial treated with an IABP or medical therapy. To further evaluate this, a large randomized trial is warranted to determine the effect of the Impella device on outcome in patients with AMI-CS. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03313687.
Assuntos
Fármacos Cardiovasculares/uso terapêutico , Coração Auxiliar , Balão Intra-Aórtico , Infarto do Miocárdio/terapia , Revascularização Miocárdica , Choque Cardiogênico/terapia , Idoso , Fármacos Cardiovasculares/efeitos adversos , Europa (Continente) , Feminino , Coração Auxiliar/efeitos adversos , Humanos , Balão Intra-Aórtico/efeitos adversos , Balão Intra-Aórtico/mortalidade , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/complicações , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Revascularização Miocárdica/efeitos adversos , Revascularização Miocárdica/mortalidade , Desenho de Prótese , Recuperação de Função Fisiológica , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Choque Cardiogênico/etiologia , Choque Cardiogênico/mortalidade , Choque Cardiogênico/fisiopatologia , Fatores de Tempo , Resultado do TratamentoRESUMO
In patients with aortic stenosis (AS), a novel staging classification of extra-valvular left and right heart damage with prognostic relevance was introduced in 2017. The aim of the study was to evaluate the biomarkers of cardiovascular tissue remodelling in relation to this novel staging classification. Patients were categorized according to the novel staging classification into stages 0 to 4. The levels of matrix metalloproteinase 9 (MMP-9), tissue inhibitor of metalloproteinases 1 (TIMP-1), B and C domain containing tenascin-C (B+ Tn-C, C+ Tn-C), the ED-A and ED-B domain containing fibronectin (ED-A+ Fn, ED-B+ Fn), endothelin 1 (ET-1) and neutrophil gelatinase-associated lipocalin (NGAL) were determined in serum by ELISA. There were significantly decreased serum levels of MMP-9 and increased levels of B+ Tn-C and C+ Tn-C when comparing stages 0 and 1 with stage 2, with no further dynamics in stages 3 and 4. In contrast, for TIMP-1, C+ Tn-C, ED-A+ Fn, ET-1 and NGAL, significantly increased serum levels could be detected in stages 3 and 4 compared to both stages 0 and 1 and stage 2. ED-A+ Fn and ET-1 could be identified as independent predictors of the presence of stage 3 and/or 4. To the best of our knowledge, this is the first study identifying novel serum biomarkers differentially reflecting the patterns of left and right heart extra-valvular damage in patients suffering from AS. Our findings might indicate a more precise initial diagnosis and risk stratification.
Assuntos
Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/patologia , Biomarcadores/sangue , Remodelação Vascular , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/cirurgia , Estudos de Casos e Controles , Endotelina-1/sangue , Feminino , Humanos , Lipocalina-2/sangue , Masculino , Metaloproteinase 9 da Matriz/sangue , Estudos Prospectivos , Tenascina/sangue , Inibidor Tecidual de Metaloproteinase-1/sangue , Substituição da Valva Aórtica TranscateterRESUMO
BACKGROUND: Whether the benefit in quality of life (QOL) after percutaneous coronary intervention depends on the severity of the stenosis as determined by fractional flow reserve (FFR) remains unknown. This study sought to investigate the relationship between FFR values and improvement in QOL. METHODS: From the FAME 1 and 2 trials (Fractional Flow Reserve Versus Angiography for Multivessel Evaluation), we identified 706 stable patients with coronary artery disease who had at least 1 lesion with an FFR≤0.80 that was treated with percutaneous coronary intervention and 185 patients with coronary artery disease who had no lesion with an FFR≤0.80 and were treated medically who served as a reference group. QOL was assessed by the European Quality of Life-5 Dimensions index at baseline, 1 month, and 1 year. We assessed the relationship between QOL improvement (defined as the change in European Quality of Life-5 Dimensions index from baseline) and FFR as a continuous value and according to abnormal FFR tertile. RESULTS: QOL improved significantly after percutaneous coronary intervention in each abnormal FFR tertile, whereas it did not change in the reference group. The lowest abnormal FFR subgroup had the greatest improvement in QOL at 1 month ( P<0.001). In mixed-effects models for repeated measures, lower FFR ( P=0.002 for 1 month and 0.049 for 1 year), greater delta FFR ( P=0.021 for 1 month and 0.025 for 1 year), and higher angina class ( P=0.001 for 1 month and <0.001 for 1 year) were associated with the greatest magnitude of QOL improvement at both 1 month and 1 year. CONCLUSIONS: Among patients with stable coronary artery disease, FFR and angina severity predict QOL improvement after percutaneous coronary intervention. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT00267774 and NCT01132495.
Assuntos
Angina Estável/terapia , Doença da Artéria Coronariana/terapia , Reserva Fracionada de Fluxo Miocárdico , Intervenção Coronária Percutânea , Qualidade de Vida , Idoso , Angina Estável/diagnóstico , Angina Estável/fisiopatologia , Cateterismo Cardíaco , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Recuperação de Função Fisiológica , Inquéritos e Questionários , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Heart failure leads to mitochondrial dysfunction and metabolic abnormalities of the failing myocardium coupled with an energy-depleted state and cardiac remodeling. The mitochondrial deacetylase sirtuin 3 (SIRT3) plays a pivotal role in the maintenance of mitochondrial function through regulating the mitochondrial acetylome. It is interesting to note that unique cardiac and systemic microRNAs have been shown to play an important role in cardiac remodeling by modulating key signaling elements in the myocardium. METHODS: Cellular signaling was analyzed in human cardiomyocyte-like AC16 cells, and acetylation levels in rodent models of SIRT3-/-and transgenic microRNA-195 (miR-195) overexpression were compared with wild type. Luciferase assays, Western blotting, immunoprecipitation assays, and echocardiographic analysis were performed. Enzymatic activities of pyruvate dehydrogenase (PDH) and ATP synthase were measured. RESULTS: In failing human myocardium, we observed induction of miR-195 along with decreased expression of the mitochondrial deacetylase SIRT3 that was associated with increased global protein acetylation. We further investigated the role of miR-195 in SIRT3-mediated metabolic processes and its impact on regulating enzymes involved in deacetylation. Proteomic analysis of the total acetylome showed increased overall acetylation, and specific lysine acetylation of 2 central mitochondrial metabolic enzymes, PDH and ATP synthase, as well. miR-195 downregulates SIRT3 expression through direct 3'-untranslated region targeting. Treatments with either sirtuin inhibitor nicotinamide, small interfering RNA-mediated SIRT3 knockdown or miR-195 overexpression enhanced acetylation of PDH complex and ATP synthase. This effect diminished PDH and ATP synthase activity and impaired mitochondrial respiration.SIRT3-/- and miR-195 transgenic mice consistently showed enhanced global protein acetylation, including PDH complex and ATP synthase, associated with decreased enzymatic activity. CONCLUSIONS: Altogether, these data suggest that increased levels of miR-195 in failing myocardium regulate a novel pathway that involves direct SIRT3 suppression and enzymatic inhibition via increased acetylation of PDH and ATP synthase that are essential for cardiac energy metabolism.
Assuntos
Metabolismo Energético , Insuficiência Cardíaca/enzimologia , MicroRNAs/metabolismo , Mitocôndrias Cardíacas/enzimologia , Miócitos Cardíacos/enzimologia , Processamento de Proteína Pós-Traducional , Sirtuína 3/metabolismo , Acetilação , Animais , Linhagem Celular , Modelos Animais de Doenças , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Mitocôndrias Cardíacas/patologia , ATPases Mitocondriais Próton-Translocadoras/metabolismo , Miócitos Cardíacos/patologia , Complexo Piruvato Desidrogenase/metabolismo , Transdução de Sinais , Sirtuína 3/deficiência , Sirtuína 3/genéticaRESUMO
BACKGROUND: Drug-coated balloons (DCB) are a novel therapeutic strategy for small native coronary artery disease. However, their safety and efficacy is poorly defined in comparison with drug-eluting stents (DES). METHODS: BASKET-SMALL 2 was a multicentre, open-label, randomised non-inferiority trial. 758 patients with de-novo lesions (<3 mm in diameter) in coronary vessels and an indication for percutaneous coronary intervention were randomly allocated (1:1) to receive angioplasty with DCB versus implantation of a second-generation DES after successful predilatation via an interactive internet-based response system. Dual antiplatelet therapy was given according to current guidelines. The primary objective was to show non-inferiority of DCB versus DES regarding major adverse cardiac events (MACE; ie, cardiac death, non-fatal myocardial infarction, and target-vessel revascularisation) after 12 months. The non-inferiority margin was an absolute difference of 4% in MACE. This trial is registered with ClinicalTrials.gov, number NCT01574534. FINDINGS: Between April 10, 2012, and February 1, 2017, 382 patients were randomly assigned to the DCB group and 376 to DES group. Non-inferiority of DCB versus DES was shown because the 95% CI of the absolute difference in MACE in the per-protocol population was below the predefined margin (-3·83 to 3·93%, p=0·0217). After 12 months, the proportions of MACE were similar in both groups of the full-analysis population (MACE was 7·5% for the DCB group vs 7·3% for the DES group; hazard ratio [HR] 0·97 [95% CI 0·58-1·64], p=0·9180). There were five (1·3%) cardiac-related deaths in the DES group and 12 (3·1%) in the DCB group (full analysis population). Probable or definite stent thrombosis (three [0·8%] in the DCB group vs four [1·1%] in the DES group; HR 0·73 [0·16-3·26]) and major bleeding (four [1·1%] in the DCB group vs nine [2·4%] in the DES group; HR 0·45 [0·14-1·46]) were the most common adverse events. INTERPRETATION: In small native coronary artery disease, DCB was non-inferior to DES regarding MACE up to 12 months, with similar event rates for both treatment groups. FUNDING: Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Basel Cardiovascular Research Foundation, and B Braun Medical AG.
Assuntos
Angioplastia Coronária com Balão/métodos , Materiais Revestidos Biocompatíveis/uso terapêutico , Doença da Artéria Coronariana/terapia , Stents Farmacológicos , Intervenção Coronária Percutânea/métodos , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos ProspectivosRESUMO
Patients in cardiogenic shock and acute heart failure show high mortality and morbidity despite aggressive and invasive methods such as percutaneous coronary intervention and the use of mechanical support devices. Percutaneous implantation of active hemodynamic support is often the only option for hemodynamic stabilization of patients in cardiogenic shock. Therefore, current guidelines support the use of these devices. Standardized protocols and clinical algorithms for the use of these support devices decrease mortality in these patients. The aim of this review is an overview of current therapies of cardiogenic shock with special focus on mechanical support devices and the suggestion of a clinical algorithm for the differential use of current devices as well as the hemodynamic monitoring of such patients in order to reduce mortality in cardiogenic shock.
Assuntos
Insuficiência Cardíaca/terapia , Ventrículos do Coração/fisiopatologia , Coração Auxiliar , Balão Intra-Aórtico , Choque Cardiogênico/terapia , Função Ventricular Esquerda/fisiologia , Função Ventricular Direita/fisiologia , Oxigenação por Membrana Extracorpórea , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Fatores de Risco , Choque Cardiogênico/etiologiaRESUMO
BACKGROUND: A well-developed coronary collateral circulation provides a potential source of blood supply in coronary artery disease. However, the prognostic importance and functional relevance of coronary collaterals is controversial with the association between exercise training and collateral growth still unclear. METHODS AND RESULTS: This prospective, open-label study randomly assigned 60 patients with significant coronary artery disease (fractional flow reserve ≤0.75) to high-intensity exercise (group A, 20 patients) or moderate-intensity exercise (group B, 20 patients) for 4 weeks or to a control group (group C, 20 patients). The primary end point was the change of the coronary collateral flow index (CFI) after 4 weeks. Analysis was based on the intention to treat. After 4 weeks, baseline CFI increased significantly by 39.4% in group A (from 0.142±0.07 at beginning to 0.198±0.09 at 4 weeks) in comparison with 41.3% in group B (from 0.143±0.06 to 0.202±0.09), whereas CFI in the control group remained unchanged (0.7%, from 0.149±0.09 to 0.150±0.08). High-intensity exercise did not lead to a greater CFI than moderate-intensity training. After 4 weeks, exercise capacity, Vo2 peak and ischemic threshold increased significantly in group A and group B in comparison with group C with no difference between group A and group B. CONCLUSIONS: A significant improvement in CFI was demonstrated in response to moderate- and high-intensity exercise performed for 10 hours per week. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01209637.
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Circulação Colateral/fisiologia , Doença das Coronárias/terapia , Vasos Coronários/fisiopatologia , Terapia por Exercício , Adulto , Idoso , Angina Instável/etiologia , Angina Instável/terapia , Aorta/fisiopatologia , Pressão Arterial , Cateterismo Cardíaco/efeitos adversos , Pressão Venosa Central , Doença das Coronárias/fisiopatologia , Embolia Aérea/etiologia , Teste de Esforço , Terapia por Exercício/efeitos adversos , Terapia por Exercício/métodos , Tolerância ao Exercício , Feminino , Veia Femoral/fisiopatologia , Reserva Fracionada de Fluxo Miocárdico , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Estudos ProspectivosRESUMO
BACKGROUND: Drug-eluting balloons (DEB) are an alternative treatment of in-stent restenosis (ISR), but data regarding outcomes of DEB in de novo lesions are lacking. METHODSâANDâRESULTS: We investigated the effect of DEB on target lesion revascularization (TLR), procedural complications (coronary dissection/rupture, pericardial effusion, stent thrombosis, peri-interventional NSTEMI, stroke), major adverse cardiac and cerebrovascular events (all-cause mortality, myocardial infarction, TLR, stroke) in patients with ISR and de novo lesions in an all-comers setting. Between April 2009 and October 2013, 484 consecutive patients (mean age 68.4 years; 77.9% male) were enrolled in a prospective registry. TLR rate was 4.9% at 12 months and 8.7% at long-term follow-up of 2.3 years. Subgroup analysis confirmed a TLR rate of 8.9% after DEB treatment of ISR in bare-metal stents (21/235 lesions), 13.0% in drug-eluting stents (21/161 lesions) and 0% for de novo lesions (0/76 lesions). At long-term follow-up, all-cause mortality/cardiac mortality was 8.7% (42/484)/3.3% (16/484) and MACCE rate was 18.4% (89/484 patients), with no differences between DEB for ISR compared with de novo lesions. CONCLUSIONS: DEB for ISR resulted in a low rate of TLR. Our data support DEB in ISR as an effective treatment option. DEB in small coronary vessels in our limited cohort appeared to be safe. Larger, randomized trials in small coronary vessels should be undertaken to verify the long-term results of the current trial.
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Angioplastia Coronária com Balão , Oclusão de Enxerto Vascular/mortalidade , Oclusão de Enxerto Vascular/cirurgia , Paclitaxel/administração & dosagem , Sistema de Registros , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/mortalidade , Doença da Artéria Coronariana/cirurgia , Feminino , Seguimentos , Alemanha , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/cirurgia , Estudos ProspectivosRESUMO
BACKGROUND: The preferred initial treatment for patients with stable coronary artery disease is the best available medical therapy. We hypothesized that in patients with functionally significant stenoses, as determined by measurement of fractional flow reserve (FFR), percutaneous coronary intervention (PCI) plus the best available medical therapy would be superior to the best available medical therapy alone. METHODS: In patients with stable coronary artery disease for whom PCI was being considered, we assessed all stenoses by measuring FFR. Patients in whom at least one stenosis was functionally significant (FFR, ≤0.80) were randomly assigned to FFR-guided PCI plus the best available medical therapy (PCI group) or the best available medical therapy alone (medical-therapy group). Patients in whom all stenoses had an FFR of more than 0.80 were entered into a registry and received the best available medical therapy. The primary end point was a composite of death, myocardial infarction, or urgent revascularization. RESULTS: Recruitment was halted prematurely after enrollment of 1220 patients (888 who underwent randomization and 332 enrolled in the registry) because of a significant between-group difference in the percentage of patients who had a primary end-point event: 4.3% in the PCI group and 12.7% in the medical-therapy group (hazard ratio with PCI, 0.32; 95% confidence interval [CI], 0.19 to 0.53; P<0.001). The difference was driven by a lower rate of urgent revascularization in the PCI group than in the medical-therapy group (1.6% vs. 11.1%; hazard ratio, 0.13; 95% CI, 0.06 to 0.30; P<0.001); in particular, in the PCI group, fewer urgent revascularizations were triggered by a myocardial infarction or evidence of ischemia on electrocardiography (hazard ratio, 0.13; 95% CI, 0.04 to 0.43; P<0.001). Among patients in the registry, 3.0% had a primary end-point event. CONCLUSIONS: In patients with stable coronary artery disease and functionally significant stenoses, FFR-guided PCI plus the best available medical therapy, as compared with the best available medical therapy alone, decreased the need for urgent revascularization. In patients without ischemia, the outcome appeared to be favorable with the best available medical therapy alone. (Funded by St. Jude Medical; ClinicalTrials.gov number, NCT01132495.).
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Angioplastia Coronária com Balão/métodos , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/terapia , Stents Farmacológicos , Antagonistas de Receptores Adrenérgicos beta 1 , Idoso , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Aspirina/uso terapêutico , Terapia Combinada , Doença das Coronárias/mortalidade , Estenose Coronária/terapia , Quimioterapia Combinada , Feminino , Seguimentos , Reserva Fracionada de Fluxo Miocárdico , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Inibidores da Agregação Plaquetária/uso terapêutico , RetratamentoRESUMO
BACKGROUND: Transcatheter left atrial appendage (LAA) closure is an alternative therapy for stroke prevention in atrial fibrillation (AF) patients. However; real-world efficacy, safety and complications have yet to be investigated. We sought to determine the procedural outcomes and potential complications of LAA closure in routine clinical practice at a high-volume center. METHODS AND RESULTS: The study group comprised 179 patients (105 males; 72.7±9.0 years) with AF undergoing LAA closure at a single center in Germany. The rate of successful implantation was 98.9% (2 patients did not undergo implantation) and the overall procedure-related complication rate was 11.2% (major: 3.3%: tamponade 2; possibility of transient ischemic attack (TIA) 1; device dislocation 3; minor: 7.8%: pericardial effusion 2; air embolization with transient ST segment elevation 3; thrombus on device/sheath 3; puncture complications 5). At 45 days; 99.4% showed successful sealing of the LAA and 94.5% discontinued oral anticoagulation (OAC). TIA occurred in 2 patients during 6-month follow-up; but no cases of stroke were reported. There were no hemorrhagic stroke or device-related deaths. Only 1 patient was hospitalized with traumatic subdural hematoma. Minor bleeding was reported in 5 patients. CONCLUSIONS: Transcatheter LAA closure in a high-volume center is safe and feasible. Life-threatening complications are rare. Discontinuation of OAC 45 days after implantation was also safe.
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Apêndice Atrial/cirurgia , Fibrilação Atrial/cirurgia , Cateterismo Cardíaco/métodos , Acidente Vascular Cerebral/prevenção & controle , Idoso , Idoso de 80 Anos ou mais , Cateterismo Cardíaco/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologiaRESUMO
AIMS: Heart failure-related cardiogenic shock (HF-CS) accounts for a significant proportion of CS cases. Whether patients with de novo HF and those with acute-on-chronic HF in CS differ in clinical characteristics and outcome remains unclear. The aim of this study was to evaluate differences in clinical presentation and mortality between patients with de novo and acute-on-chronic HF-CS. METHODS AND RESULTS: In this international observational study, patients with HF-CS from 16 tertiary care centres in five countries were enrolled between 2010 and 2021. To investigate differences in clinical presentation and 30-day mortality, adjusted logistic/Cox regression models were fitted. Patients (n = 1030) with HF-CS were analysed, of whom 486 (47.2%) presented with de novo HF-CS and 544 (52.8%) with acute-on-chronic HF-CS. Traditional markers of CS severity (e.g. blood pressure, heart rate and lactate) as well as use of treatments were comparable between groups. However, patients with acute-on-chronic HF-CS were more likely to have a higher CS severity and also a higher mortality risk, after adjusting for relevant confounders (de novo HF 45.5%, acute-on-chronic HF 55.9%, adjusted hazard ratio 1.38, 95% confidence interval 1.10-1.72, p = 0.005). CONCLUSION: In this large HF-CS cohort, acute-on-chronic HF-CS was associated with more severe CS and higher mortality risk compared to de novo HF-CS, although traditional markers of CS severity and use of treatments were comparable. These findings highlight the vast heterogeneity of patients with HF-CS, emphasize that HF chronicity is a relevant disease modifier in CS, and indicate that future clinical trials should account for this.