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1.
BMC Nephrol ; 21(1): 179, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32410664

RESUMO

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.

2.
J Physiol ; 2020 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-32394454

RESUMO

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.

3.
J Physiol ; 598(7): 1361-1376, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30770570

RESUMO

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.

4.
J Card Surg ; 35(1): 195-199, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31609509

RESUMO

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.

5.
ESC Heart Fail ; 7(2): 692-696, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31802644

RESUMO

Cardiac sarcoidosis is a chronic inflammatory disease with a large spectrum of symptoms that can mimic diseases such as dilated, hypertrophic, or arrhythmogenic cardiomyopathies. It can be asymptomatic but can also present with ventricular arrhythmias, conduction disease, and heart failure (HF) or even sudden cardiac death (SCD). We present here the case of a patient transplanted due to end-stage arrhythmogenic right ventricular cardiomyopathy (ARVC), fulfilling the task force criteria. A few years after successful heart transplantation (HTX), the patient developed similar symptoms and morphofunctional changes of the heart, which led to critical re-evaluation of his primary diagnosis.

6.
Clin Res Cardiol ; 2019 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-31630214

RESUMO

BACKGROUND: Cardiac amyloidosis, caused by deposition of immunoglobulin light chains (AL) or transthyretin (ATTR), carries a poor prognosis. Established risk scores for amyloidosis may not predict outcomes in those patients who develop advanced heart failure and who are potential candidates for heart transplantation. Here, we aimed to identify predictive parameters for patients with severe heart failure due to amyloidosis. METHODS: Out of > 1000 patients with cardiac amyloidosis (AL or ATTR) admitted to our centre between September 1998 and January 2016, a cohort of 120 patients with a complete cardiac assessment at diagnosis, including right heart catheterization, echocardiography and biomarkers, was analysed retrospectively in this study. Primary endpoint was all-cause mortality. We performed univariate and multivariate Cox regression analysis, generated risk scores to predict outcomes in AL and ATTR amyloidosis and compared those to established risk models for amyloidosis. RESULTS: In the Cox multivariate model, high-sensitivity troponin T (hsTnT; hazard ratio (HR) 1.003; confidence interval (CI) 1.001-1.005; p = 0.009) and mean pulmonary artery pressure (HR 1.061; CI 1.024-1.100; p = 0.001) were found to significantly and independently predict outcomes for AL amyloidosis, whereas QRS duration (HR 1.021; CI 1.004-1.039; p = 0.013), hsTnT (HR 1.021; CI 1.006-1.036; p = 0.006) and N-terminal pro-brain natriuretic peptide (HR 1.0003; CI 1.0001-1.0004; p = 0.002) were the best predictors for ATTR amyloidosis. A simple risk score ("HeiRisk") including these parameters for AL and ATTR allowed a more precise risk stratification in our patient population compared to established risk models. CONCLUSIONS: Risk stratification for cardiac amyloidosis with the newly developed "HeiRisk" score may be superior to other staging systems for patients with advanced heart failure due to amyloid cardiomyopathy.

7.
J Thorac Dis ; 11(Suppl 6): S913-S920, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31183170

RESUMO

Background: Modern left ventricular assist devices (LVAD) have evolved to become standard of care in severe heart failure (HF) patients. Right HF (RHF) is a major complication responsible for early mortality. Several techniques for temporary right ventricular assist device (t-RVAD) have been described before, baring relevant disadvantages such as limited mobilization or the need for re-thoracotomy. We describe the results of an alternative technique for t-RVAD using the Tandem Heart™ with ProtekDuo™ cannula. Methods: An institutional retrospective single centre outcome analysis was performed including all permanent LVAD recipients with concomitant groin-free t-RVAD support. Results: Between October 2015 and September 2017, 11 patients (10 male, 90.9%) were included. Preoperative NYHA class was 3.8±0.75 and INTERMACS class 3.5±1.5. Four (36.4%) patients were already on mechanical circulatory support (MCS) at time of implantation with 4 (36.4%) patients already on inotropic support. All LVAD implantations were performed on-pump and 3 cases (27.3%) were re-do cases. Mean t-RVAD duration was 16.8±9.5 days. Ten patients (90.9%) could be weaned from temporary RVAD support, 1 patient deceased on support. Mean ICU stay was 23.8±16.5 days, while 30-day survival was 72.7%. Follow-up was complete with 214.7±283 days. Three patients (27.3%) died following multi-organ failure (MOF), 1 patient (9.1%) following intracranial bleed 12 days after t-RVAD explantation. No severe t-RVAD associated complications were observed. Conclusions: Our technique allows for safe groin-free t-RVAD providing all advantages of percutaneous implantation including complete mobilization and bedside explantation without any need for operation.

9.
Clin Res Cardiol ; 108(11): 1197-1207, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30879094

RESUMO

BACKGROUND: Ventricular assist devices (VAD) are increasingly used as long-term treatment for advanced heart failure. However, survival after VAD implantation is still unsatisfactory, and no specific outpatient follow-up algorithms have been formally established. Here, we evaluate the effect of an intensified follow-up protocol (IFUP) on survival rates and VAD-associated complications. METHODS AND RESULTS: This is a retrospective study of 57 patients who received a VAD at our center between February 2013 and December 2017. Inclusion criteria were discharge home after VAD implantation and follow-up in our VAD outpatient clinic. Patients implanted after October 2015 (n = 30) were monitored according to IFUP. This protocol embodied formalized, multi-disciplinary clinical visits every 4-8 weeks including a cardiologist, a cardiothoracic surgeon and a VAD-coordinator and was characterized by optimized anticoagulation and wound management as well as guideline-directed medical therapy. One-year survival in the IFUP patients was 97%, compared to 74% in the pre-IFUP era (p = 0.01). Implementation of IFUP was associated with a 90% risk-reduction for 1-year mortality (relative risk 0.099; p = 0.048). The rate of complications, e.g., device thrombosis and major bleeding, was significantly reduced, resulting in superior event-free survival in the IFUP group (p = 0.003). Furthermore, by implementation of IFUP, a more stable anticoagulation adjustment was achieved as well as an improved adherence to guideline-directed medical therapy. CONCLUSION: Implementation of an IFUP for VAD patients is associated with a significant decrease in 1-year all-cause mortality. This emphasizes the need for more vigilance in the management of VAD patients by a dedicated multi-disciplinary team.


Assuntos
Assistência Ambulatorial , Insuficiência Cardíaca/terapia , Coração Auxiliar , Adolescente , Adulto , Idoso , Protocolos Clínicos , Feminino , Seguimentos , Insuficiência Cardíaca/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Resultado do Tratamento , Adulto Jovem
10.
ESC Heart Fail ; 6(2): 271-279, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30815994

RESUMO

AIMS: Each episode of acute decompensated heart failure (HF) incrementally adds to mortality. Peritoneal dialysis (PD) offers an alternative therapeutic option in refractory HF and reduces the incidence of decompensation episodes. The objective of this study was to determine the efficacy of PD, in terms of functional status, surrogate endpoints, rate of hospitalizations, and mortality. METHODS AND RESULTS: This study is based on the registry of the German Society of Nephrology, involving 159 patients receiving PD treatment due to refractory HF between January 2010 and December 2014. Body weight was reduced by PD (82.2 ± 14.9 to 78.4 ± 14.8 kg, P < 0.001), and significant improvements in New York Heart Association functional class (3.38 ± 0.55 to 2.85 ± 0.49, P < 0.001) were found already after 3 months. Left ventricular ejection fraction did not change (31.5 ± 13.8 to 34.0 ± 15.7%, P = 0.175). C-reactive protein improved with PD treatment (33.7 ± 52.6 to 17.1 ± 26.3 mg/L, P = 0.004). Blood urea nitrogen/creatinine ratio decreased significantly (148.7 ± 68.3 to 106.7 ± 44.8 mg/dL, P < 0.001). Hospitalization rates decreased significantly (total number 2.86 ± 1.88 to 1.90 ± 1.78, P = 0.001, and 39.2 ± 30.7 to 27.1 ± 25.2 days, P = 0.004). One year mortality was 39.6% in end-stage HF patients treated with PD. CONCLUSIONS: Peritoneal dialysis offers an additional therapeutic option in end-stage HF and is associated with improved New York Heart Association classification and reduced hospitalization. Although PD treatment was associated with various benefits, further studies are necessary to identify which patients benefit the most from PD.


Assuntos
Insuficiência Cardíaca/terapia , Diálise Peritoneal/métodos , Sistema de Registros , Volume Sistólico/fisiologia , Doença Aguda , Idoso , Feminino , Seguimentos , Alemanha/epidemiologia , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Estudos Prospectivos , Taxa de Sobrevida/tendências , Fatores de Tempo , Resultado do Tratamento
11.
ESC Heart Fail ; 6(1): 217-221, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30479049

RESUMO

Severe aortic regurgitation (AR) is a rare but significant complication of ventricular assist device therapy. Experience with transcatheter aortic valve replacement (TAVR) in this setting of patients is very limited, while the scarcely reported cases exclusively refer to TAVR under continuous-flow left ventricular assist devices. Here, we present the first successful TAVR while running a pulsatile-flow biventricular assist device (PF-BiVAD). Clinical data were collected based on the patient's electronic medical records after the patient's consent was obtained. We describe the case of a 57-year-old man in whom a PF-BiVAD (EXCOR, Berlin Heart, Berlin, Germany) had been initially inserted after fulminant myocarditis with subsequent severe dilated cardiomyopathy as bridge-to-transplantation therapy. Over the following 2 years, the patient developed severe de novo AR under PF-BiVAD therapy. This, along with progressive cardiac decompensation, led to the decision for TAVR by our heart team as a minimal invasive approach for severe AR. TAVR using two Edwards SAPIEN 3 bioprostheses as a valve-in-valve procedure resulted in a significant reduction of AR from severe to mild, with trace paravalvular leakage and without significant pressure gradients. The patient underwent total orthotopic heart transplantation afterwards. This is the first report of successful TAVR in a patient with severe de novo AR while running a PF-BiVAD.


Assuntos
Insuficiência da Valva Aórtica/cirurgia , Valva Aórtica/cirurgia , Bioprótese , Cardiomiopatia Dilatada/cirurgia , Coração Auxiliar/efeitos adversos , Substituição da Valva Aórtica Transcateter/métodos , Insuficiência da Valva Aórtica/etiologia , Ecocardiografia , Falha de Equipamento , Humanos , Masculino , Pessoa de Meia-Idade , Desenho de Prótese , Fluxo Pulsátil , Índice de Gravidade de Doença
12.
Clin Res Cardiol ; 108(4): 375-387, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30191296

RESUMO

BACKGROUND: Percutaneous mitral valve repair (PMVR) via MitraClip implantation is a therapeutic option for high-risk or non-surgical candidates with severe mitral regurgitation (MR) and advanced stages of heart failure (HF). However, these patients have a high mortality despite PMVR, and predictors for outcomes are not well established. Here, we evaluated invasive hemodynamics, echocardiography parameters, and biomarkers to predict outcomes after PMVR in severe HF patients. METHODS: Patients with reduced ejection fraction (EF) and severe and moderate-to-severe MR undergoing PMVR at our centre between September 2009 and January 2016 were analysed retrospectively. Inclusion criteria were: left ventricular EF < 45%, preoperative right heart catheterization, successful MitraClip deployment ("technical success"), and follow-up for at least 1 year after the procedure. Data from preoperative right heart catheterization, echocardiography, and biomarkers were assessed. Primary endpoint was all-cause mortality at 1 year after PMVR. We performed univariate and multivariate Cox regression analyses and generated a risk score to predict outcomes. RESULTS: Of 174 patients with PMVR and severe HF, 79.9% had functional MR. Mean EF was 25% (17.2; 30.7) and advanced New York Heart Association functional class was prevalent (class II: 13%; class III: 70%; and class IV: 17%). The cumulative incidences of all-cause death were 6.9% and 17.8% at 30 days and 1 year, respectively. In the Cox multivariate model, high-sensitive troponin T [hsTnT; hazard ratio (HR) 1.01; confidence interval (CI) 1.01-1.02; p < 0.0001] and mixed venous O2-saturation (HR 0.92; CI 0.89-0.96; p < 0.0001) were found to significantly and independently predict outcomes. A simple risk score including these two parameters was sufficient to discriminate between low- and high-risk patients (HR 7.22; CI 3.4-15.5; p < 0.001). CONCLUSION: In a cohort of patients with severe HF undergoing PMVR, patients with elevated hsTnT and reduced mixed venous O2-saturation carried the worst prognosis. A simple risk score including these two parameters may improve patient selection and outcomes after PMVR.


Assuntos
Cateterismo Cardíaco/métodos , Insuficiência Cardíaca/fisiopatologia , Implante de Prótese de Valva Cardíaca/métodos , Hemodinâmica/fisiologia , Insuficiência da Valva Mitral/cirurgia , Peptídeo Natriurético Encefálico/sangue , Fragmentos de Peptídeos/sangue , Troponina T/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Ecocardiografia Transesofagiana , Feminino , Seguimentos , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Insuficiência da Valva Mitral/complicações , Insuficiência da Valva Mitral/diagnóstico , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença
13.
ESC Heart Fail ; 5(6): 1108-1117, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29984916

RESUMO

AIM: With an increasing prevalence of heart failure (HF), more patients with advanced disease have to be treated in cardiology units by sophisticated medical and interventional strategies. We therefore developed a dedicated advanced heart failure unit (AHFU) to target the specific needs of the many patients with advanced HF. We here present our concept and its impact on outcome in high-risk high-urgency (HU) heart transplant candidates. METHODS AND RESULTS: The eight-bed unit was established as an extension of the cardiologic intensive care and coronary care units in an intermediate care setting. Each bed was equipped with 24 h haemodynamic, respiratory, and arrhythmia monitoring. The unit is served 24/7 by five residents in cardiology, one staff cardiologist specializing in medical and interventional HF care, and 10 intensive care nurses. The cardiology team is supported by colleagues from cardiac surgery, sports medicine, psychosomatics, and the internal medicine departments. As an example of the intensified care on the AHFU, data from the cohorts of patients undergoing heart transplantation from HU status before (pre-AHFU 2008-11) and after establishment of the AHFU (AHFU 2012-15) were analysed. Interestingly, mortality on HU waiting list and post-heart transplant survival was comparable in both cohorts, despite significant increase in morbidity and co-morbidity as assessed by the Index for Mortality Prediction After Cardiac Transplantation model in the AHFU group. CONCLUSIONS: Our AHFU provides a unique and novel setting for the integration of modern pharmacological, interventional, surgical, and supportive HF therapy embedded in an academic heart centre. This may be a major step forward in the care of critical patients with advanced HF.


Assuntos
Cardiologia/organização & administração , Unidades de Cuidados Coronarianos/organização & administração , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Listas de Espera/mortalidade , Feminino , Alemanha/epidemiologia , Insuficiência Cardíaca/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores de Risco , Índice de Gravidade de Doença , Taxa de Sobrevida/tendências
14.
ESC Heart Fail ; 5(5): 892-901, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30058757

RESUMO

AIMS: Functional mitral regurgitation is complicating end-stage heart failure and potential heart transplantation by increasing pulmonary artery pressures. The aim of the present study was to investigate feasibility and haemodynamic effects of percutaneous mitral valve edge-to-edge repair using the MitraClip™ device in patients with end-stage heart failure awaiting heart transplantation. METHODS AND RESULTS: In this retrospective study, we identified nine patients suffering from end-stage heart failure listed for heart transplantation in whom moderate-severe or severe functional mitral regurgitation was recognized and treated with percutaneous mitral valve edge-to-edge repair. Twenty-two patients listed for heart transplantation and presenting with moderate-severe or severe functional mitral regurgitation treated in the pre-MitraClip™ era served as controls. Patients were analysed at two separate time points: MitraClip™ group: pre-procedure and post-procedure (follow-up: 215 ± 53 days) and control group: study entry with recognition of moderate-severe or severe functional mitral regurgitation (follow-up: 197 ± 47 days). Percutaneous mitral valve edge-to-edge repair with the MitraClip™ was feasible and safe in our high-risk end-stage heart failure population. The intervention resulted in significant reduction of mitral regurgitation (grade 3.0 [0.5] to 1.5 [0.5]; P = 0.009), left atrial diameter (51 mm [16] to 49 mm [4]; follow-up MitraClip™ vs. control group P = 0.0497), pulmonary artery pressures (sPA 50 mmHg [15] to 45 mmHg [10]; P = 0.02; mPA 34 mmHg [8] to 30 mmHg [10]; P = 0.02), and New York Heart Association class (3.5 [1.0] to 3.0 [0.5]; P = 0.01) and improved mixed-venous oxygen saturation (57% [11] to 55% [7]; follow-up MitraClip™ vs. control group P = 0.02). No changes in the control group were observed. CONCLUSIONS: MitraClip™ implantation as 'bridge-to-transplant' strategy in patients with end-stage heart failure and severe functional mitral regurgitation awaiting heart transplantation is feasible and appears to result in favourable haemodynamic effects.


Assuntos
Cateterismo Cardíaco/métodos , Procedimentos Cirúrgicos Cardíacos/métodos , Insuficiência Cardíaca/cirurgia , Transplante de Coração , Hemodinâmica/fisiologia , Valva Mitral/cirurgia , Listas de Espera , Ecocardiografia , Feminino , Seguimentos , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral/diagnóstico por imagem , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/etiologia , Insuficiência da Valva Mitral/cirurgia , Desenho de Prótese , Implantação de Prótese/métodos , Estudos Retrospectivos , Resultado do Tratamento
15.
Nat Med ; 24(1): 62-72, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29227474

RESUMO

The stress-responsive epigenetic repressor histone deacetylase 4 (HDAC4) regulates cardiac gene expression. Here we show that the levels of an N-terminal proteolytically derived fragment of HDAC4, termed HDAC4-NT, are lower in failing mouse hearts than in healthy control hearts. Virus-mediated transfer of the portion of the Hdac4 gene encoding HDAC4-NT into the mouse myocardium protected the heart from remodeling and failure; this was associated with decreased expression of Nr4a1, which encodes a nuclear orphan receptor, and decreased NR4A1-dependent activation of the hexosamine biosynthetic pathway (HBP). Conversely, exercise enhanced HDAC4-NT levels, and mice with a cardiomyocyte-specific deletion of Hdac4 show reduced exercise capacity, which was characterized by cardiac fatigue and increased expression of Nr4a1. Mechanistically, we found that NR4A1 negatively regulated contractile function in a manner that depended on the HBP and the calcium sensor STIM1. Our work describes a new regulatory axis in which epigenetic regulation of a metabolic pathway affects calcium handling. Activation of this axis during intermittent physiological stress promotes cardiac function, whereas its impairment in sustained pathological cardiac stress leads to heart failure.


Assuntos
Insuficiência Cardíaca/metabolismo , Hexosaminas/biossíntese , Histona Desacetilases/metabolismo , Contração Miocárdica , Animais , Epigênese Genética , Técnicas de Transferência de Genes , Insuficiência Cardíaca/genética , Histona Desacetilases/genética , Camundongos , Camundongos Knockout , Miocárdio/enzimologia , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Condicionamento Físico Animal , Proteólise , Molécula 1 de Interação Estromal/metabolismo
16.
J Heart Lung Transplant ; 37(5): 611-618, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29217108

RESUMO

BACKGROUND: Cardiac amyloidosis, caused most commonly by deposition of light chain (AL) or transthyretin (ATTR) type fibrils, has an extremely poor prognosis. In this retrospective single-center study, we evaluated temporal trends in survival after heart transplantation for cardiac amyloidosis. METHODS: We analyzed 48 patients with cardiac amyloidosis (AL, n = 32; familial ATTR, n = 16) who underwent heart transplantation from May 2002 to March 2017. Patients were analysed in 2 periods, Era 1 (2002- 2007) and Era 2 (2008- 2017), separated by altered patient selection in both, AL and ATTR amyloidosis, and changed chemotherapy regimens for AL amyloidosis. RESULTS: The modern era was characterized by a lower number of extracardiac organ involvement for AL (94% isolated cardiac amyloidosis in Era 2 vs 56% in Era 1; p = 0.0221), and more frequent treatment for AL with the proteasome inhibitor bortezomib (94% in Era 2 vs 6% in Era 1; p < 0.0001). AL patients had significantly lower survival than patients with non-amyloid cardiomyopathy after heart transplantation in Era 1, and ATTR patients had numerically lower survival. However, survival in the modern era was comparable to non-amyloid transplants in both cohorts, possibly reflecting a shift in chemotherapy strategies and patient selection, respectively. CONCLUSIONS: In the current era, use of enhanced chemotherapy regimens for isolated advanced AL cardiac amyloidosis was associated with outcomes comparable to non-amyloid cardiomyopathy. We conclude that heart transplantation in highly selected patients with isolated non-systemic advanced cardiac amyloidosis may be a feasible approach.


Assuntos
Amiloidose/mortalidade , Amiloidose/cirurgia , Cardiopatias/mortalidade , Cardiopatias/cirurgia , Transplante de Coração , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
17.
PLoS One ; 12(3): e0172070, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28282374

RESUMO

In heart failure (HF), a disturbed cardiac norepinephrine (NE) homeostasis is characterized by depleted cardiac NE stores, impairment of the cardiac NE re-uptake by the neuronal norepinephrine transporter (NET) and enhanced cardiac NE net release. Reduced cardiac NE content appears to be caused by enhanced cardiac NE net release from sympathetic neurons in HF, triggered by neurohumoral activation. However, it remains unclear whether reduced NE itself has an impact on cardiac NE re-uptake, independent of neurohumoral activation. Here, we evaluated whether depletion of cardiac NE stores alone can regulate cardiac NE re-uptake. Treatment of Wistar rats with reserpine (5 mg/kg/d) for one (1d) or five days (5d) resulted in markedly reduced cardiac NE content, comparable to NE stores in experimental HF due to pressure overload. In order to assess cardiac NE re-uptake, the specific cardiac [3H]-NE uptake via the NET in a Langendorff preparation was measured. Reserpine treatment led to decreased NE re-uptake at 1d and 5d compared to saline treatment. Expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of the NE synthesis, was elevated in left stellate ganglia after reserpine. Mechanistically, measurement of NET mRNA expression in left stellate ganglia and myocardial NET density revealed a post-transcriptional downregulation of the NET by reserpine. In summary, present data demonstrate that depletion of cardiac NE stores alone is sufficient to impair cardiac NE re-uptake via downregulation of the NET, independent of systemic neurohumoral activation. Knowledge about the regulation of the cardiac NE homeostasis may offer novel therapeutic strategies in HF.


Assuntos
Catecolaminas/metabolismo , Miocárdio/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Animais , Regulação para Baixo/efeitos dos fármacos , Ecocardiografia , Coração/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Frequência Cardíaca , Masculino , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reserpina/farmacologia , Gânglio Estrelado/metabolismo , Gânglio Estrelado/patologia , Trítio/química , Tirosina 3-Mono-Oxigenase/genética , Tirosina 3-Mono-Oxigenase/metabolismo
18.
Basic Res Cardiol ; 111(6): 65, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27683174

RESUMO

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.


Assuntos
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/fisiologia
19.
Hypertension ; 65(2): 335-44, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25489064

RESUMO

Activation of Wnt signaling results in maladaptive cardiac remodeling and cardiomyopathy. Recently, calcium/calmodulin-dependent protein kinase II (CaMKII) was reported to be a pivotal participant in myocardial remodeling. Because CaMKII was suggested as a downstream target of noncanonical Wnt signaling, we aimed to elucidate the role of CaMKII in dishevelled-1-induced cardiomyopathy and the mechanisms underlying its function. Dishevelled-1-induced cardiomyopathy was reversed by deletion of neither CaMKIIδ nor CaMKIIγ. Therefore, dishevelled-1-transgenic mice were crossed with CaMKIIδγ double-knockout mice. These mice displayed a normal cardiac phenotype without cardiac hypertrophy, fibrosis, apoptosis, or left ventricular dysfunction. Further mechanistic analyses unveiled that CaMKIIδγ couples noncanonical Wnt signaling to histone deacetylase 4 and myosin enhancer factor 2. Therefore, our findings indicate that the axis, consisting of dishevelled-1, CaMKII, histone deacetylase 4, and myosin enhancer factor 2, is an attractive therapeutic target for prevention of cardiac remodeling and its progression to left ventricular dysfunction.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/fisiologia , Insuficiência Cardíaca/enzimologia , Histona Desacetilases/fisiologia , Hipertrofia Ventricular Esquerda/enzimologia , Fosfoproteínas/fisiologia , Disfunção Ventricular Esquerda/enzimologia , Proteínas Wnt/fisiologia , Via de Sinalização Wnt/fisiologia , Animais , Apoptose , Benzilaminas/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/deficiência , Proteínas Desgrenhadas , Fibrose , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/fisiopatologia , Sistema de Sinalização das MAP Quinases , Fatores de Transcrição MEF2/fisiologia , Camundongos , Camundongos Knockout , Miocárdio/patologia , Fenótipo , Proteína Quinase C/fisiologia , Sulfonamidas/farmacologia , Ultrassonografia , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/fisiopatologia , Remodelação Ventricular , beta Catenina/fisiologia
20.
Proc Natl Acad Sci U S A ; 111(37): 13499-504, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25197047

RESUMO

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.


Assuntos
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 fármacos
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