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1.
Circulation ; 130(15): 1262-73, 2014 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-25124496

RESUMO

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/fisiologia
2.
J Invasive Cardiol ; 32(1): E1-E8, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31893503

RESUMO

BACKGROUND: Optimal timing for percutaneous mitral regurgitation (MR) treatment using MitraClip (Abbott Vascular) remains unclear. We evaluated the outcome after MitraClip in patients with moderate resting MR, progressing to severe exercise- induced MR (MR2+) compared to patients with severe resting MR (MR3). METHODS: We retrospectively investigated 221 patients undergoing MitraClip. All-cause deaths and heart failure (HF) hospitalizations were assessed as the combined primary endpoint. RESULTS: We identified 55 MR2+ and 166 MR3 patients. At baseline, MR3 patients showed higher STS scores (6.7 ± 7.3 vs 4.4 ± 5.5; P<.01), more HF hospitalizations in the 2 years prior to the procedure (51% vs 29%; P<.01), worse left ventricular ejection fraction (44.9 ± 16.5% vs 52.5 ± 14.3%; P<.01), larger left ventricular end-diastolic diameter (LVEDd; 57.0 ± 9.3 mm vs 51.7 ± 8.2 mm; P<.001), and larger left atrial volumes (118.3 ± 55.8 mL vs 98.6 ± 35.2 mL; P=.02). Long-term outcome according to the combined endpoint was significantly worse in MR3 patients (P=.01). HF hospitalizations significantly declined in both groups 2 years after MitraClip (P<.001 in MR3 patients, P=.03 in MR2+ patients). Multivariate Cox regression analysis revealed LVEDd (hazard ratio, 1.035; 95% confidence interval, 1.005-1.066; P=.02) and previous HF hospitalizations (hazard ratio, 1.813; 95% confidence interval, 1.016-3.234; P=.04) as strong outcome predictors. CONCLUSIONS: Symptomatic patients with moderate resting and severe exercise-induced MR during handgrip echocardiography may represent an MR cohort at an earlier disease stage with improved treatment response following MitraClip implantation compared to individuals with severe resting MR. Larger left ventricular diameters and preprocedural HF hospitalizations were identified as independent adverse outcome predictors.


Assuntos
Implante de Prótese de Valva Cardíaca , Efeitos Adversos de Longa Duração , Anuloplastia da Valva Mitral , Insuficiência da Valva Mitral , Valva Mitral , Cateterismo Cardíaco/métodos , Ecocardiografia/métodos , Feminino , Implante de Prótese de Valva Cardíaca/efeitos adversos , Implante de Prótese de Valva Cardíaca/métodos , Humanos , Estimativa de Kaplan-Meier , Efeitos Adversos de Longa Duração/diagnóstico , Efeitos Adversos de Longa Duração/mortalidade , Masculino , Pessoa de Meia-Idade , Valva Mitral/diagnóstico por imagem , Valva Mitral/cirurgia , Anuloplastia da Valva Mitral/efeitos adversos , Anuloplastia da Valva Mitral/métodos , Insuficiência da Valva Mitral/diagnóstico , Insuficiência da Valva Mitral/fisiopatologia , Insuficiência da Valva Mitral/cirurgia , Avaliação de Processos e Resultados em Cuidados de Saúde , Resistência Física , Índice de Gravidade de Doença , Volume Sistólico , Instrumentos Cirúrgicos , Avaliação de Sintomas/métodos , Avaliação de Sintomas/estatística & dados numéricos
3.
Biomed Eng Lett ; 9(4): 425-434, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31799012

RESUMO

Heart rate variability (HRV) is governed by the autonomic nervous system (ANS) and is routinely used to estimate the state of body and mind. At the same time, recorded HRV features can vary substantially between people. A model for HRV that (1) correctly simulates observed HRV, (2) reliably functions for multiple scenarios, and (3) can be personalised using a manageable set of parameters, would be a significant step forward toward understanding individual responses to external influences, such as physical and physiological stress. Current HRV models attempt to reproduce HRV characteristics by mimicking the statistical properties of measured HRV signals. The model presented here for the simulation of HRV follows a radically different approach, as it is based on an approximation of the physiology behind the triggering of a heart beat and the biophysics mechanisms of how the triggering process-and thereby the HRV-is governed by the ANS. The model takes into account the metabolisation rates of neurotransmitters and the change in membrane potential depending on transmitter and ion concentrations. It produces an HRV time series that not only exhibits the features observed in real data, but also explains a reduction of low frequency band-power for physically or psychologically high intensity scenarios. Furthermore, the proposed model enables the personalisation of input parameters to the physiology of different people, a unique feature not present in existing methods. All these aspects are crucial for the understanding and application of future wearable health.

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