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BACKGROUND: Due to its high impact on quality of life and mental health, close monitoring and often psychotherapy is recommended for patients with a ventricular assist device (VAD). This study investigates the psychological comorbidity and the corresponding psychotherapeutic treatment situation of VAD patients. Special attention is also given to the professional perspective VAD team (assistant and senior cardiologists and specialized nurses). METHODS: We conducted a cross-sectional observational study. Data from 50 VAD patients (mean age = 53.52, standard deviation = 13.82 years, 84.0% male) and their VAD team were analyzed. The presence of a psychological disorder was evaluated by structured clinical interviews for DSM-IV (SCID-I-Interviews). Patients answered a questionnaire regarding their current psychotherapeutic treatment status and their attitude towards psychotherapy. The VAD team answered a questionnaire about the patients' needs for psychotherapy and indicated whether they addressed this topic with the patient. Data were analyzed descriptively, by analysis of variance and t-test. RESULTS: A total of 58% of VAD patients suffered from at least one significant psychological disorder, 79.3% of those were not in psychotherapy. The VAD team could not identify the patients who suffered from a psychological disorder (F = 1.90; p = 0.18). They perceived more need for psychotherapy than they addressed with their patients (T = 3.39; p < 0.001). CONCLUSIONS: While there is a high psychological morbidity among VAD patients, only few receive psychotherapy. Psychological comorbidity is not easily detected by the VAD team. Standardized psychosocial care could be implemented by regular psychological assessments and further information of patients and their VAD teams.
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OBJECTIVE: Psychosocial parameters play a pivotal role in organ recipient evaluation before wait-listing for transplantation because of their impact on organ and patient outcome. Patients in need of heart (HTx), liver (LTx), or kidney transplantation (KTx) face distinct physical and psychological challenges. This study compares the psychosocial characteristics and preferences for additional therapy for patients undergoing assessment for these three types of organ transplantation to optimize patient-tailored psychological, social, and other supportive interventions. METHODS: We conducted a cross-sectional, observational study with 1110 potential transplantation candidates (LTx, n = 544; KTx, n = 330; HTx, n = 236), psychosocial status was determined for depressive symptoms (Patient Health Questionnaire Depression Scale), anxiety symptoms (seven-item Generalized Anxiety Disorder Screener), health-related quality of life (36-Item Short Form Health Survey), perceived social support (Perceived Social Support Questionnaire), sense of coherence (SoC; short form of the Sense of Coherence Scale), self-efficacy (General Self-Efficacy Short Scale), and body image (German Body Image Questionnaire-20). Preferences for additional supportive therapy were assessed dichotomously. Data were analyzed using multivariate analysis of covariance and χ2 tests. RESULTS: Patient groups differed significantly regarding depression ( F (2,1107) = 35.283, p < .001, partial η2 = 0.01), anxiety ( F (2,1107) = 15.027, p < .001, partial η2 = 0.03), health-related quality of life (physical: F (2,1107) = 96.772, p < .001, partial η2 = 0.15; mental: F (2,1107) = 11.442, p < .001, partial η2 = 0.02), perceived social support ( F (2,1107) = 20.813, p < .001, partial η2 = 0.04), SoC ( F (2,1107) = 12.920, p < .001, partial η2 = 0.02), self-efficacy ( F (2,1107) = 17.308, p < .001, partial η2 = 0.03), and body image (rejecting body evaluation: F (2,1107) = 5.006, p = .007, partial η2 = 0.01; vital body dynamics: F (2,1107) = 40.216, p < .001, partial η2 = 0.07). Patients evaluated for HTx showed the highest psychosocial impairment and the highest inclination regarding additional supportive therapy. CONCLUSIONS: Patients evaluated for HTx, LTx, and KTx have distinct psychosocial characteristics and treatment preferences. HTx patients display the highest psychosocial impairment. We suggest psychocardiological treatment structures for optimal outcome.
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Transplante de Coração , Transplante de Rim , Transplante de Fígado , Humanos , Estudos Transversais , Transplante de Coração/psicologia , Rim , Fígado , Qualidade de Vida/psicologia , Transplante de Rim/psicologia , Transplante de Fígado/psicologia , Depressão , Ansiedade , Apoio Social , Imagem Corporal , AutoeficáciaRESUMO
Histone deacetylase 4 (HDAC4) is a member of class IIa histone deacetylases (class IIa HDACs) and is believed to possess a low intrinsic deacetylase activity. However, HDAC4 sufficiently represses distinct transcription factors (TFs) such as the myocyte enhancer factor 2 (MEF2). Transcriptional repression by HDAC4 has been suggested to be mediated by the recruitment of other chromatin-modifying enzymes, such as methyltransferases or class I histone deacetylases. However, this concept has not been investigated by an unbiased approach. Therefore, we studied the histone modifications H3K4me3, H3K9ac, H3K27ac, H3K9me2 and H3K27me3 in a genome-wide approach using HDAC4-deficient cardiomyocytes. We identified a general epigenetic shift from a 'repressive' to an 'active' status, characterized by an increase of H3K4me3, H3K9ac and H3K27ac and a decrease of H3K9me2 and H3K27me3. In HDAC4-deficient cardiomyocytes, MEF2 binding sites were considerably overrepresented in upregulated promoter regions of H3K9ac and H3K4me3. For example, we identified the promoter of Adprhl1 as a new genomic target of HDAC4 and MEF2. Overexpression of HDAC4 in cardiomyocytes was able to repress the transcription of the Adprhl1 promoter in the presence of the methyltransferase SUV39H1. On a genome-wide level, the decrease of H3K9 methylation did not change baseline expression but was associated with exercise-induced gene expression. We conclude that HDAC4, on the one hand, associates with activating histone modifications, such as H3K4me3 and H3K9ac. A functional consequence, on the other hand, requires an indirect regulation of H3K9me2. H3K9 hypomethylation in HDAC4 target genes ('first hit') plus a 'second hit' (e.g., exercise) determines the transcriptional response.
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Repressão Epigenética , Histona Desacetilases , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Metilação , Processamento de Proteína Pós-TraducionalRESUMO
Heart transplantation across preformed donor-specific HLA-antibody barriers is associated with impaired short- and long-term survival. Therefore, in recipients with preformed anti-HLA antibodies, waiting for crossmatch-negative donors is standard practice. As an alternative strategy, recipients with preformed anti-HLA donor specific antibodies have been managed at our institutions with a perioperative desensitization regimen. A retrospective analysis was performed comparing heart transplant recipients with preformed donor-specific HLA-antibodies to recipients without donor-specific antibodies. Recipients with a positive virtual crossmatch received a perioperative desensitization protocol including tocilizumab intraoperatively, plasma exchange and rituximab followed by a six-month course of IgGAM. Among the 117 heart-transplanted patients, 19 (16%) patients underwent perioperative desensitization, and the remaining 98 (84%) patients did not. Cold ischemic time, posttransplant extracorporeal life support for primary graft dysfunction, and intensive care unit stay time did not differ between groups. At 1-year follow-up, freedom from pulsed steroid therapy for presumed rejection and biopsy-confirmed acute cellular or humoral rejection did not differ between groups. One-year survival amounted to 94.7% in the treated patients and 81.4% in the control group. Therefore, heart transplantation in sensitized recipients undergoing a perioperative desensitization appears safe with comparable postoperative outcomes as patients with a negative crossmatch.
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Transplante de Coração , Transplante de Rim , Anticorpos , Soro Antilinfocitário , Dessensibilização Imunológica/métodos , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Antígenos HLA , Teste de Histocompatibilidade/métodos , Humanos , Transplante de Rim/efeitos adversos , Estudos RetrospectivosRESUMO
BACKGROUND: Atrial septal defects (ASD) following endovascular mitral valve clipping are potentially hemodynamically relevant complications. Immediate closure with an occluder can represent a safe and effective treatment. An 81-year-old female patient suffering from severe dyspnea due to previously known severe mitral valve regurgitation was scheduled for elective mitral valve clipping. The clip was successfully implanted. Removal of the transseptal cannula resulted in a sudden drop in oxygen saturation and systolic blood pressure as well as an immediate increase in central venous pressure. An iatrogenic left-right shunt was observed at the atrial level with a relevant shunt volume. Immediate closure using an atrial septal occluder successfully restored the oxygen saturation and hemodynamic parameters. CONCLUSION: An increase in central venous pressure, reduction of systolic blood pressure or oxygen saturation after withdrawal of the transseptal cannula during mitral valve clipping should always be further investigated regarding a possible ASD.
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Insuficiência da Valva Mitral , Valva Mitral , Idoso de 80 Anos ou mais , Pressão Sanguínea , Cateterismo Cardíaco , Pressão Venosa Central , Feminino , Humanos , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/cirurgia , Saturação de OxigênioRESUMO
BACKGROUND: Percutaneous mitral valve repair (PMVR) is a therapeutic option for severe mitral regurgitation (MR) in patients with heart failure due to differential aetiologies. However, only little is known about the safety and efficacy of this procedure in patients with amyloid cardiomyopathy. METHODS: Five patients with cardiac amyloidosis and moderate to severe or severe MR undergoing PMVR were analysed retrospectively and compared to seven patients with cardiac amyloidosis and severe MR without intervention. Clinical and functional data, renal function and cardiac biomarkers as well as established risk scores for cardiac amyloidosis were assessed. Primary endpoint was the reduction in MR one year after PMVR. Secondary endpoints were safety, overall mortality after 12 months compared with the control group, as well as changes in clinical and functional parameters. RESULTS: Amyloidosis risk assessment documented amyloid cardiomyopathy at an advanced stage in all patients. Procedural, technical and device success of PMVR were all 100% and residual MR remained mild to moderate at 12 months follow-up (P = .038 vs before PMVR). Differences in survival compared with the control (no PMVR) group pointed to a possible survival benefit in the PMVR group (P = .02). CONCLUSION: PMVR is a feasible and safe procedure in patients with cardiac amyloidosis and might carry a possible survival benefit in this patient group.
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Amiloidose/fisiopatologia , Cateterismo Cardíaco/métodos , Cardiomiopatias/fisiopatologia , Anuloplastia da Valva Mitral/métodos , Insuficiência da Valva Mitral/cirurgia , Idoso , Idoso de 80 Anos ou mais , Amiloidose/complicações , Cardiomiopatias/complicações , Feminino , Humanos , Masculino , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/fisiopatologia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Patients with reduced left ventricular (LV) function undergoing coronary artery bypass graft surgery or/and aortic valve replacement occasionally show severe mitral valve (MV) regurgitation and thus also undergo surgical mitral annuloplasty. Over time, further deterioration of LV function and additional ischemic events cause recurrence of severe MV regurgitation due to the Carpentier IIIb morphology of the MV that is not adequately addressed by the previously implanted annuloplasty ring. METHODS: Seven patients (Society of Thoracic Surgeons score: 7.5⯱ 1.5%) with Carpentier type-IIIb recurrent severe MV regurgitation, having undergone prior cardiothoracic surgery (median: 40 months) including mitral annuloplasty, were treated with the MitraClip device. RESULTS: MitraClip implantation resulted in significantly reduced MV regurgitation and improved New York Heart Association functional state, translating into an increased exercise capability and improved cardiac biomarkers. The morphology of the MV was adequately addressed without causing relevant MV stenosis, while the MV annulus area remained unaltered. The procedure was safe with a 30-day mortality rate of 0%. CONCLUSION: MitraClip-in-the-ring is feasible and in principle safe for treating Carpentier type IIIb severe MV regurgitation after surgical MV repair using mitral annuloplasty. MitraClip-in-the-ring resulted in immediate amelioration of clinical symptoms and increased physical exercise capacity.
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Implante de Prótese de Valva Cardíaca , Próteses Valvulares Cardíacas , Anuloplastia da Valva Mitral , Insuficiência da Valva Mitral , Humanos , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/cirurgia , Resultado do TratamentoRESUMO
KEY POINTS: Mitochondrial Ca2+ uptake stimulates the Krebs cycle to regenerate the reduced forms of pyridine nucleotides (NADH, NADPH and FADH2 ) required for ATP production and reactive oxygen species (ROS) elimination. Ca2+ /calmodulin-dependent protein kinase II (CaMKII) has been proposed to regulate mitochondrial Ca2+ uptake via mitochondrial Ca2+ uniporter phosphorylation. We used two mouse models with either global deletion of CaMKIIδ (CaMKIIδ knockout) or cardiomyocyte-specific deletion of CaMKIIδ and γ (CaMKIIδ/γ double knockout) to interrogate whether CaMKII controls mitochondrial Ca2+ uptake in isolated mitochondria and during ß-adrenergic stimulation in cardiac myocytes. CaMKIIδ/γ did not control Ca2+ uptake, respiration or ROS emission in isolated cardiac mitochondria, nor in isolated cardiac myocytes, during ß-adrenergic stimulation and pacing. The results of the present study do not support a relevant role of CaMKII for mitochondrial Ca2+ uptake in cardiac myocytes under physiological conditions. ABSTRACT: Mitochondria are the main source of ATP and reactive oxygen species (ROS) in cardiac myocytes. Furthermore, activation of the mitochondrial permeability transition pore (mPTP) induces programmed cell death. These processes are essentially controlled by Ca2+ , which is taken up into mitochondria via the mitochondrial Ca2+ uniporter (MCU). It was recently proposed that Ca2+ /calmodulin-dependent protein kinase II (CaMKII) regulates Ca2+ uptake by interacting with the MCU, thereby affecting mPTP activation and programmed cell death. In the present study, we investigated the role of CaMKII under physiological conditions in which mitochondrial Ca2+ uptake matches energy supply to the demand of cardiac myocytes. Accordingly, we measured mitochondrial Ca2+ uptake in isolated mitochondria and cardiac myocytes harvested from cardiomyocyte-specific CaMKII δ and γ double knockout (KO) (CaMKIIδ/γ DKO) and global CaMKIIδ KO mice. To simulate a physiological workload increase, cardiac myocytes were subjected to ß-adrenergic stimulation (by isoproterenol superfusion) and an increase in stimulation frequency (from 0.5 to 5 Hz). No differences in mitochondrial Ca2+ accumulation were detected in isolated mitochondria or cardiac myocytes from both CaMKII KO models compared to wild-type littermates. Mitochondrial redox state and ROS production were unchanged in CaMKIIδ/γ DKO, whereas we observed a mild oxidation of mitochondrial redox state and an increase in H2 O2 emission from CaMKIIδ KO cardiac myocytes exposed to an increase in workload. In conclusion, the results obtained in the present study do not support the regulation of mitochondrial Ca2+ uptake via the MCU or mPTP activation by CaMKII in cardiac myocytes under physiological conditions.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Miócitos Cardíacos , Animais , Cálcio , Camundongos , Espécies Reativas de Oxigênio , Retículo SarcoplasmáticoRESUMO
KEY POINTS: The Anrep effect represents the alteration of left ventricular (LV) contractility to acutely enhanced afterload in a few seconds, thereby preserving stroke volume (SV) at constant preload. As a result of the missing preload stretch in our model, the Anrep effect differs from the slow force response and has a different mechanism. The Anrep effect demonstrated two different phases. First, the sudden increased afterload was momentary equilibrated by the enhanced LV contractility as a result of higher power strokes of strongly-bound myosin cross-bridges. Second, the slightly delayed recovery of SV is perhaps dependent on Ca2+ /calmodulin-dependent protein kinase II activation caused by oxidation and myofilament phosphorylation (cardiac myosin-binding protein-C, myosin light chain 2), maximizing the recruitment of available strongly-bound myosin cross-bridges. Short-lived oxidative stress might present a new facet of subcellular signalling with respect to cardiovascular regulation. Relevance for human physiology was demonstrated by echocardiography disclosing the Anrep effect in humans during handgrip exercise. ABSTRACT: The present study investigated whether oxidative stress and Ca2+ /calmodulin-dependent protein kinase II (CaMKII) activity are involved in triggering the Anrep effect. LV pressure-volume (PV) analyses of isolated, preload controlled working hearts were performed at two afterload levels (60 and 100 mmHg) in C57BL/6N wild-type (WT) and CaMKII-double knockout mice (DKOCaMKII ). In snap-frozen WT hearts, force-pCa relationship, H2 O2 generation, CaMKII oxidation and phosphorylation of myofilament and Ca2+ handling proteins were assessed. Acutely raised afterload showed significantly increased wall stress, H2 O2 generation and LV contractility in the PV diagram with an initial decrease and recovery of stroke volume, whereas end-diastolic pressure and volume, as well as heart rate, remained constant. Afterload induced increase in LV contractility was blunted in DKOCaMKII -hearts. Force development of single WT cardiomyocytes was greater with elevated afterload at submaximal Ca2+ concentration and associated with increases in CaMKII oxidation and phosphorylation of cardiac-myosin binding protein-C, myosin light chain and Ca2+ handling proteins. CaMKII activity is involved in the regulation of the Anrep effect and associates with stimulation of oxidative stress, presumably starting a cascade of CaMKII oxidation with downstream phosphorylation of myofilament and Ca2+ handling proteins. These mechanisms improve LV inotropy and preserve stroke volume within few seconds.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina , Contração Miocárdica , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Força da Mão , Homeostase , Camundongos , Camundongos Endogâmicos C57BL , FosforilaçãoRESUMO
BACKGROUND: Peritoneal ultrafiltration (pUF) in refractory heart failure (HF) reduces the incidence of decompensation episodes, which is of particular significance as each episode incrementally adds to mortality. Nevertheless, there are insufficient data about which patient cohort benefits the most. The objective of this study was to compare pUF in HFrEF and HFpEF, focusing on functional status, hospitalizations, surrogate endpoints and mortality. METHODS: This study involves 143 patients, who could be classified as either HFpEF (n = 37, 25.9%) or HFrEF (n = 106, 74.1%) and who received pUF due to refractory HF. RESULTS: Baseline eGFR was similar in HFrEF (23.1 ± 10.6 mg/dl) and HFpEF (27.8 ± 13.2 mg/dl). Significant improvements in NYHA class were found in HFpEF (3.19 ± 0.61 to 2.72 ± 0.58, P < 0.001) and HFrEF (3.45 ± 0.52 to 2.71 ± 0.72, P < 0.001). CRP decreased in HFrEF (19.4 ± 17.6 mg/l to 13.7 ± 21.4 mg/l, P = 0.018) and HFpEF (33.7 ± 52.6 mg/l to 17.1 ± 26.3 mg/l, P = 0.004). Body weight was significantly reduced in HFrEF (81.1 ± 14.6 kg to 77.2 ± 15.6 kg, P = 0.003) and HFpEF (86.9 ± 15.8 kg to 83.1 ± 15.9 kg, P = 0.005). LVEF improved only in HFrEF (25.9 ± 6.82% to 30.4 ± 12.2%, P = 0.046). BCR decreased significantly in HFrEF and HFpEF (55.7 ± 21.9 to 34.3 ± 17.9 P > 0.001 and 50.5 ± 68.9 to 37.6 ± 21.9, P = 0.006). Number of hospitalization episodes as well as number of hospitalization days decreased significantly only in HFpEF (total number 2.88 ± 1.62 to 1.25 ± 1.45, P < 0.001, days 40.4 ± 31.7 to 18.3 ± 22.5 days, P = 0.005). CONCLUSIONS: pUF offers various benefits in HFpEF and HFrEF, but there are also substantial differences. In particular, hospitalization rates were found to be significantly reduced in HFpEF patients, indicating a greater medical and economical advantage. However, LVEF was only found to be improved in HFrEF patients. While pUF can now be regarded as an option to supplement classical HF therapy, further studies are desirable to obtain specifications about pUF in HFpEF, HFmEF and HFrEF patients.
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Insuficiência Cardíaca/terapia , Hemofiltração/métodos , Hospitalização/estatística & dados numéricos , Diálise Peritoneal/métodos , Volume Sistólico , Desequilíbrio Hidroeletrolítico/terapia , Diuréticos/uso terapêutico , Feminino , Insuficiência Cardíaca/fisiopatologia , Hemodiafiltração/métodos , Humanos , Masculino , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Diálise Peritoneal Ambulatorial Contínua/métodos , Resultado do Tratamento , Desequilíbrio Hidroeletrolítico/fisiopatologiaRESUMO
BACKGROUND: Cardiogenic shock (CS) from biventricular heart failure that requires acute mechanical circulatory support (MCS) is associated with high mortality. Different MCS methods and techniques have emerged as a standard of care in CS. Nevertheless, the routine MCS approach carries multiple limitations such as limb ischemia, missing of left ventricular unloading and immobilization. We describe a method to establish a groin-free full support MCS in patients with CS without the need for thoracotomy. This is the first report of the ECPELLA 2.0 concept, a peripheral groin-free biventricular MCS in patients with acute CS. METHODS AND RESULTS: We discuss two patients in acute CS (INTERMACS I) treated with two peripheral MCS devices (Impella 5.0 or 5.5 surgically via an axillary artery and ProtekDuo cannula percutaneously via a right internal jugular vein) as a bridge before the implantation of a durable left ventricular assist device (LVAD). Biventricular assist device (BIVAD)-support duration was 9 and 15 days and both of the patients were successfully bridged to a durable LVAD. As our BIVAD-concept is groin-free, the patients started full mobilization as early as they were weaned from the respirator 2 days after the BIVAD-implantation. ECPELLA 2.0 provides a high cardiac output, right and left ventricular unloading with end-organ recovery and a possibility of administration of a membrane oxygenator. There were no device-related complications. CONCLUSION: The ECPELLA 2.0 biventricular support concept for patients suffering from an acute CS. Allows for rapid extubation, mobilization, and physical exercise while on full support. Additional application of a membrane oxygenator is easily feasible if required.
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Cânula , Coração Auxiliar , Choque Cardiogênico/terapia , Doença Aguda , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
BACKGROUND: Survival rates following cardiac transplantation continue to improve. Due to the scarcity of available organs, extended donor criteria have become more prevalent in clinical practice. In this context, the risk of developing cardiac pathology requiring surgical correction is increasing. METHODS: Between January 1991 and October 2010, a total of 479 patients received cardiac transplantations at the University Hospital Heidelberg. Of those, 18 (3.8%) patients required subsequent cardiac surgery until 2018. Short- and long-term analyses were performed. RESULTS: Indications for cardiac surgery included valvular disease (n = 16) with the majority of cases affecting the tricuspid valve (n = 10), while 6 patients received mitral valve surgery, of whom 3 patients underwent concomitant valve surgery. Other indications included CABG (n = 1) and re-transplantation (n = 1) for allograft dysfunction. Mean follow-up time was 6.5 years, while mean interval to surgery was 6.0 years. Early mortality was 11.1% (n = 2), while overall survival at 1, 5, and 10 years were, 88.1%, 81.4%, and 52.2%, respectively. Compared to an overall survival of that transplant cohort at 1, 5, and 10 years of 76.7%, 66.7%, and 52.4% percent, respectively (P = .271). CONCLUSION: According to our data, redo cardiac surgery can be performed with acceptable mortality and morbidity. Atrioventricular valve pathology plays a chief role in these patients.
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Procedimentos Cirúrgicos Cardíacos/mortalidade , Cardiopatias/mortalidade , Transplante de Coração/mortalidade , Reoperação/mortalidade , Transplantados/estatística & dados numéricos , Idoso , Feminino , Seguimentos , Cardiopatias/patologia , Cardiopatias/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Resultado do TratamentoRESUMO
In preclinical studies, endothelin receptor A (ETA) antagonists (ETAi) attenuated the progression of heart failure (HF). However, clinical HF trials failed to demonstrate beneficial effects of ETAi. These conflicting data may be explained by the possibility that established HF drugs such as adrenergic receptor blockers interfered with the mechanism of ETAi action in clinical trials. Here we report that mice lacking ETA only in sympathetic neurons (SN-KO) showed less adverse structural remodeling and cardiac dysfunction in response to pathological pressure overload induced by transverse aortic constriction (TAC). In contrast, mice lacking ETA only in cardiomyocytes (CM-KO) were not protected. TAC led to a disturbed sympathetic nerve function as measured by cardiac norepinephrine (NE) tissue levels and [(124)I]-metaiodobenzylguanidine-PET, which was prevented in SN-KO. In a rat model of HF, ETAi improved cardiac and sympathetic nerve function. In cocultures of cardiomyocytes (CMs) and sympathetic neurons (SNs), endothelin-1 (ET1) led to a massive NE release and exaggerated CM hypertrophy compared with CM monocultures. ETA-deficient CMs gained a hypertrophic response through wild-type SNs, but ETA-deficient SNs failed to mediate exaggerated CM hypertrophy. Furthermore, ET1 mediated its effects indirectly via NE in CM-SN cocultures through adrenergic receptors and histone deacetylases, resulting in activation of the prohypertrophic transcription factor myocyte enhancer factor 2. In conclusion, sympathetic ETA amplifies ET1 effects on CMs through adrenergic signaling pathways. Thus, antiadrenergic therapies may blunt potentially beneficial effects of ETAi. Taken together, this may indicate that patients with ß blocker intolerance or disturbed sympathetic nerve function could be evaluated for a potential benefit from ETAi.
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Miócitos Cardíacos/metabolismo , Receptor de Endotelina A/metabolismo , Sistema Nervoso Simpático/metabolismo , Remodelação Ventricular , Animais , Aorta/patologia , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Constrição Patológica , Modelos Animais de Doenças , Antagonistas do Receptor de Endotelina A/farmacologia , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Histona Desacetilases/metabolismo , Técnicas In Vitro , Fatores de Transcrição MEF2/metabolismo , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Neurônios/metabolismo , Ratos Sprague-Dawley , Receptores Adrenérgicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
CaM kinase II (CaMKII) has been suggested to drive pathological cardiac remodeling and heart failure. However, the evidence provided so far is based on inhibitory strategies using chemical compounds and peptides that also exert off-target effects and followed exclusively preventive strategies. Therefore, the aim of this study was to investigate whether specific CaMKII inhibition after the onset of cardiac stress delays or reverses maladaptive cardiac remodeling and dysfunction. Combined genetic deletion of the two redundant CaMKII genes δ and γ was induced after the onset of overt heart failure as the result of pathological pressure overload induced by transverse aortic constriction (TAC). We used two different strategies to engineer an inducible cardiomyocyte-specific CaMKIIδ/CaMKIIγ double knockout mouse model (DKO): one model bases on tamoxifen-inducible mER/Cre/mER expression under control of the cardiac-specific αMHC promoter; the other strategy bases on overexpression of Cre recombinase via cardiac-specific gene transfer through adeno-associated virus (AAV9) under control of the cardiac-specific myosin light chain promoter. Both models led to a substantial deletion of CaMKII in failing hearts. To approximate the clinical situation, CaMKII deletion was induced 3 weeks after TAC surgery. In both models of DKO, the progression of cardiac dysfunction and interstitial fibrosis could be slowed down as compared to control animals. Taken together, we show for the first time that "therapeutic" CaMKII deletion after cardiac damage is sufficient to attenuate maladaptive cardiac remodeling and to reverse signs of heart failure. These data suggest that CaMKII inhibition is a promising therapeutic approach to combat heart failure.
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Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/patologia , Miócitos Cardíacos/enzimologia , Animais , Western Blotting , Modelos Animais de Doenças , Camundongos , Camundongos Knockout , Remodelação Ventricular/fisiologiaRESUMO
AIM OF THE STUDY: Capillary/myocyte mismatch is a hallmark of maladaptive myocardial hypertrophy, but the exact mechanisms of this phenomenon remain unknown. We therefore aimed to evaluate the role of calcineurin A in the regulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) in a calcineurin overexpressing mouse model of myocardial hypertrophy. METHODS AND RESULTS: Mice overexpressing calcineurin A (CnATg) showed persistent upregulation of HIF-1 alpha protein without evidence of a reduction in capillary density despite progressive myocardial hypertrophy. Likewise, overexpression of calcineurin A in isolated cardiomyocytes induced upregulation of HIF-1 alpha protein. In contrast, NFAT-overexpression had no such effect, implying that NFAT-independent mechanisms were responsible for increased HIF-1 alpha levels. In addition, inhibition of HSP90 via the HSP90-inhibitor 17-AAG or siRNA abolished calcineurin A-induced upregulation of HIF-1 alpha. Consequently, upregulation of HIF-1 alpha target genes like VEGF-A, BNIP-3 or PGK-1 was also inhibited by either 17-AAG or siRNA directed against HSP90. Finally, when CnATg mice were treated with 17-AAG, they demonstrated reduced left ventricular function and capillary density. CONCLUSIONS: We describe here for the first time that overexpression of the phosphatase calcineurin A prevents the development of a capillary/myocyte mismatch despite progressive myocardial hypertrophy. This effect was mediated by HSP-90 induced stabilization of HIF-1 alpha. Further work is needed to understand this unexpected cardioprotective effect of calcineurin A.
Assuntos
Calcineurina/metabolismo , Cardiomegalia/metabolismo , Proteínas de Choque Térmico HSP90/fisiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Animais , Núcleo Celular/metabolismo , Células Cultivadas , Vasos Coronários/patologia , Regulação para Baixo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microvasos/patologia , Fatores de Transcrição NFATC/metabolismo , Estabilidade Proteica , Ratos Wistar , Transcrição GênicaRESUMO
BACKGROUND: Ca(2+)-dependent signaling through CaM Kinase II (CaMKII) and calcineurin was suggested to contribute to adverse cardiac remodeling. However, the relative importance of CaMKII versus calcineurin for adverse cardiac remodeling remained unclear. METHODS AND RESULTS: We generated double-knockout mice (DKO) lacking the 2 cardiac CaMKII genes δ and γ specifically in cardiomyocytes. We show that both CaMKII isoforms contribute redundantly to phosphorylation not only of phospholamban, ryanodine receptor 2, and histone deacetylase 4, but also calcineurin. Under baseline conditions, DKO mice are viable and display neither abnormal Ca(2+) handling nor functional and structural changes. On pathological pressure overload and ß-adrenergic stimulation, DKO mice are protected against cardiac dysfunction and interstitial fibrosis. But surprisingly and paradoxically, DKO mice develop cardiac hypertrophy driven by excessive activation of endogenous calcineurin, which is associated with a lack of phosphorylation at the auto-inhibitory calcineurin A site Ser411. Likewise, calcineurin inhibition prevents cardiac hypertrophy in DKO. On exercise performance, DKO mice show an exaggeration of cardiac hypertrophy with increased expression of the calcineurin target gene RCAN1-4 but no signs of adverse cardiac remodeling. CONCLUSIONS: We established a mouse model in which CaMKII's activity is specifically and completely abolished. By the use of this model we show that CaMKII induces maladaptive cardiac remodeling while it inhibits calcineurin-dependent hypertrophy. These data suggest inhibition of CaMKII but not calcineurin as a promising approach to attenuate the progression of heart failure.
Assuntos
Calcineurina/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Cardiomegalia/metabolismo , Cardiomegalia/prevenção & controle , Miocárdio/enzimologia , Remodelação Ventricular/genética , Animais , Sinalização do Cálcio/genética , Sinalização do Cálcio/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/deficiência , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cardiomegalia/fisiopatologia , Modelos Animais de Doenças , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fatores de Transcrição NFATC/metabolismo , Condicionamento Físico Animal/fisiologia , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Remodelação Ventricular/fisiologiaRESUMO
RATIONALE: Myocardial diastolic stiffness and cardiomyocyte passive force (F(passive)) depend in part on titin isoform composition and phosphorylation. Ca(2+)/calmodulin-dependent protein kinase-II (CaMKII) phosphorylates ion channels, Ca(2+)-handling proteins, and chromatin-modifying enzymes in the heart, but has not been known to target titin. OBJECTIVE: To elucidate whether CaMKII phosphorylates titin and modulates F(passive) in normal and failing myocardium. METHODS AND RESULTS: Titin phosphorylation was assessed in CaMKIIδ/γ double-knockout (DKO) mouse, transgenic CaMKIIδC-overexpressing mouse, and human hearts, by Pro-Q-Diamond/Sypro-Ruby staining, autoradiography, and immunoblotting using phosphoserine-specific titin-antibodies. CaMKII-dependent site-specific titin phosphorylation was quantified in vivo by mass spectrometry using stable isotope labeling by amino acids in cell culture mouse heart mixed with wild-type (WT) or DKO heart. F(passive) of single permeabilized cardiomyocytes was recorded before and after CaMKII-administration. All-titin phosphorylation was reduced by >50% in DKO but increased by up to ≈100% in transgenic versus WT hearts. Conserved CaMKII-dependent phosphosites were identified within the PEVK-domain of titin by quantitative mass spectrometry and confirmed in recombinant human PEVK-fragments. CaMKII also phosphorylated the cardiac titin N2B-unique sequence. Phosphorylation at specific PEVK/titin N2B-unique sequence sites was decreased in DKO and amplified in transgenic versus WT hearts. F(passive) was elevated in DKO and reduced in transgenic compared with WT cardiomyocytes. CaMKII-administration lowered F(passive) of WT and DKO cardiomyocytes, an effect blunted by titin antibody pretreatment. Human end-stage failing hearts revealed higher CaMKII expression/activity and phosphorylation at PEVK/titin N2B-unique sequence sites than nonfailing donor hearts. CONCLUSIONS: CaMKII phosphorylates the titin springs at conserved serines/threonines, thereby lowering F(passive). Deranged CaMKII-dependent titin phosphorylation occurs in heart failure and contributes to altered diastolic stress.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Insuficiência Cardíaca/enzimologia , Proteínas Musculares/metabolismo , Proteínas Quinases/metabolismo , Sequência de Aminoácidos , Animais , Fenômenos Biomecânicos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/deficiência , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Células Cultivadas/efeitos dos fármacos , Células Cultivadas/metabolismo , Complacência (Medida de Distensibilidade) , Conectina , Diástole/fisiologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Dados de Sequência Molecular , Miócitos Cardíacos/enzimologia , Miócitos Cardíacos/fisiologia , Fosforilação , Fosfosserina/metabolismo , Fosfotreonina/metabolismo , Processamento de Proteína Pós-Traducional , Estrutura Terciária de Proteína , Ratos , Proteínas Recombinantes de Fusão/fisiologiaRESUMO
Impairment of the cardiac norepinephrine (NE) reuptake by the neuronal NE transporter contributes to enhanced cardiac NE net release in congestive heart failure. Elevated plasma levels of aldosterone (AL) promote sympathetic overstimulation in failing hearts by unclear mechanisms. Our aim was to evaluate if elevated AL and/or alterations in Na(+) intake regulate cardiac NE reuptake. To test the effects of AL and Na(+) on cardiac NE reuptake, Wistar rats were fed a normal-salt (NS) diet (0.2% NaCl), a low-salt (LS) diet (0.015% NaCl), or a high-salt (HS) diet (8% NaCl). Another group of animals received AL infusion alone (0.75 µg/h) or AL infusion plus HS diet. Specific cardiac [(3)H]NE uptake via the NE transporter in a Langendorff preparation and AL plasma levels were measured at different time points between 5 and 42 days of treatment. To compare these findings from healthy animals with a disease model, Dahl salt-sensitive rats were investigated as a model of congestive heart failure with endogenously elevated AL. In summary, neither exogenous nor endogenous elevations of AL alone were sufficient to reduce cardiac NE reuptake. Only the HS diet induced a reduction of NE reuptake by 26%; additional infusion of AL augmented this effect to a further reduction of NE reuptake by 36%. In concordance, Dahl salt-sensitive rats treated with a HS diet displayed elevated AL and a marked reduction of NE reuptake. We conclude that exogenous or endogenous AL elevations alone do not reduce cardiac NE reuptake, but AL serves as an additional factor that negatively regulates cardiac NE reuptake in concert with HS intake.
Assuntos
Aldosterona/sangue , Miocárdio/metabolismo , Norepinefrina/metabolismo , Cloreto de Sódio na Dieta/metabolismo , Animais , Transporte Biológico , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/metabolismo , Masculino , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Ratos Endogâmicos Dahl , Ratos Wistar , Cloreto de Sódio na Dieta/efeitos adversosRESUMO
BACKGROUND: When advanced heart failure occurs in cardiac amyloidosis, prognosis is poor. In this setting heart transplantation (HTX) is a treatment option for selected patients. We here present the results of post-transplantation outcomes in cardiac amyloidosis within the Eurotransplant area, investigating possible predictors of survival. METHODS: Of 115 patients undergoing HTX due to cardiac amyloidosis in the Eurotransplant region between November 1987 and May 2020, detailed assessment prior to transplantation was available in 85 patients. The present study was conducted in a retrospective approach. Primary endpoint was mortality after HTX. Baseline variables were entered in a Cox proportional hazards model with the primary endpoint as a dependent variable. RESULTS: Median overall survival following HTX was 6.3 years in the overall collective and the subgroup. Univariate Cox proportional hazards model revealed a significant relationship between overall survival and the transplantation period (2008 to 2020 vs 1987 to 2007; median survival 9.7 years vs 1.8 years, hazard ratio 0.45, p = 0.01). Further predictors were albumin concentration (hazard ratio 0.92, p < 0.001), and systolic blood pressure (hazard ratio 0.96, p < 0.001). The transplant period as well as albumin concentration remained significant independent predictors in the AL sub cohort in a multivariate Cox proportional hazards model. CONCLUSIONS: HTX is a viable treatment option for patients at an advanced stage of cardiac amyloidosis as overall survival after transplantation has improved in the modern age. Patients at a very advanced stage of the disease, indicated by low serum albumin and blood pressure, show worse outcomes following HTX. Optimal timing and careful patient selection may therefore be particularly important to further improve post-HTX survival in amyloidosis patients.
Assuntos
Amiloidose , Insuficiência Cardíaca , Transplante de Coração , Humanos , Estudos Retrospectivos , Transplante de Coração/efeitos adversos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/cirurgia , Amiloidose/complicações , Amiloidose/cirurgia , AlbuminasRESUMO
Acute and chronic injuries to the heart result in perturbation of intracellular calcium signaling, which leads to pathological cardiac hypertrophy and remodeling. Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transduction of calcium signals in the heart, but the specific isoforms of CaMKII that mediate pathological cardiac signaling have not been fully defined. To investigate the potential involvement in heart disease of CaMKIIdelta, the major CaMKII isoform expressed in the heart, we generated CaMKIIdelta-null mice. These mice are viable and display no overt abnormalities in cardiac structure or function in the absence of stress. However, pathological cardiac hypertrophy and remodeling are attenuated in response to pressure overload in these animals. Cardiac extracts from CaMKIIdelta-null mice showed diminished kinase activity toward histone deacetylase 4 (HDAC4), a substrate of stress-responsive protein kinases and suppressor of stress-dependent cardiac remodeling. In contrast, phosphorylation of the closely related HDAC5 was unaffected in hearts of CaMKIIdelta-null mice, underscoring the specificity of the CaMKIIdelta signaling pathway for HDAC4 phosphorylation. We conclude that CaMKIIdelta functions as an important transducer of stress stimuli involved in pathological cardiac remodeling in vivo, which is mediated, at least in part, by the phosphorylation of HDAC4. These findings point to CaMKIIdelta as a potential therapeutic target for the maintenance of cardiac function in the setting of pressure overload.