Chasing Cardiac Physiology And Pathology Down The Camkii Cascade.

Calcium dynamics is central in cardiac physiology, as the key event leading to the excitation-contraction coupling (ECC) and relaxation processes. The primary function of Ca(2+) in the heart is the control of mechanical activity developed by the myofibril contractile apparatus. This key role of Ca(2+) signaling explains the subtle and critical control of important events of ECC and relaxation, such Ca(2+) influx and SR Ca(2+) release and uptake. The multifunctional Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) is a signaling molecule that regulates a diverse array of proteins involved not only in ECC and relaxation, but also in cell death, transcriptional activation of hypertrophy, inflammation and arrhythmias. CaMKII activity is triggered by an increase in intracellular Ca(2+) levels. This activity can be sustained, creating molecular memory after the decline in Ca(2+) concentration, by autophosphorylation of the enzyme, as well as by oxidation, glycosylation and nitrosylation at different sites of the regulatory domain of the kinase. CaMKII activity is enhanced in several cardiac diseases, altering the signaling pathways by which CaMKII regulates the different fundamental proteins involved in functional and transcriptional cardiac processes. Dysregulation of these pathways constitutes a central mechanism of various cardiac disease phenomena, like apoptosis and necrosis during ischemia/reperfusion injury, digitalis exposure, post-acidosis and heart failure arrhythmias, or cardiac hypertrophy. Here we summarize significant aspects of the molecular physiology of CaMKII and provide a conceptual framework for understanding the role of the CaMKII cascade on Ca(2+) regulation and dysregulation in cardiac health and disease.

Effects Of Pde Type 5 Inhibitors On Left Ventricular Diastolic Dysfunction In Resistant Hypertension.

Resistant hypertension (RHTN) is a multifactorial disease characterized by blood pressure (BP) levels above goal (140/90 mmHg) in spite of the concurrent use of three or more antihypertensive drugs of different classes. Moreover, it is well known that RHTN subjects have high prevalence of left ventricular diastolic dysfunction (LVDD), which leads to increased risk of heart failure progression. This review gathers data from studies evaluating the effects of phosphodiesterase-5 (PDE-5) inhibitors (administration of acute sildenafil and short-term tadalafil) on diastolic function, biochemical and hemodynamic parameters in patients with RHTN. Acute study with sildenafil treatment found that inhibition of PDE-5 improved hemodynamic parameters and diastolic relaxation. In addition, short-term study with the use of tadalafil demonstrated improvement of LVDD, cGMP and BNP-32 levels, regardless of BP reduction. No endothelial function changes were observed in the studies. The findings of acute and short-term studies revealed potential therapeutic effects of IPDE-5 drugs on LVDD in RHTN patients.A Hipertensão arterial resistente (HAR) é uma doença multifatorial caracterizada por níveis pressóricos acima das metas (140/90 mmHg), a despeito de tratamento farmacológico otimizado de 3 ou mais fármacos anti-hipertensivos de diferentes classes. Pacientes diagnosticados como hipertensos resistentes apresentam alta prevalência de disfunção diastólica do ventrículo esquerdo (DDVE) que proporciona risco aumentado para insuficiência cardíaca. Esta revisão reúne dados de estudos prévios avaliando os efeitos dos inibidores de fosfodiesterase-5 (PDE-5) (administração aguda de sildenafil e de curto prazo de tadalafil) na função diastólica e nos parâmetros bioquímicos e hemodinâmicos em pacientes com HAR. O estudo agudo com sildenafil demonstrou que a inibição da PDE-5 melhorou os parâmetros hemodinâmicos e de relaxamento diastólico. Além disso, o estudo curto prazo com o uso de tadalafil revelou melhora da DDVE e dos níveis de GMPc e BNP-32, independente de redução de pressão arterial. A função endotelial não apresentou alteração com ambos os tratamentos. Os resultados dos estudos agudo e de curto prazo sugerem efeitos terapêuticos potenciais dos fármacos inibidores da PDE-5 na disfunção diastólica em pacientes com HAR.

Clínica de cães com cardiomiopatia dilatada idiopática, tratados ou não com carvedilol

O tratamento convencionalmente preconizado para cães acometidos pela CMD consiste na prescrição de vasodilatadores, agentes inotrópicos positivos (digitálico), diuréticos, dieta hipossódica e, quando necessário, antiarrítmicos. O carvedilol é um β-bloqueador de 3ª geração, não seletivo, que bloqueia igualmente e competitivamente os receptores (β1, β2 e α1). Produz uma evidente vasodilatação periférica, exerce efeitos anti-oxidantes, removendo radicais livres de oxigênio e prevenindo a peroxidação lipídica nas membranas cardíacas, prevenindo a perda de miócitos e a ocorrência de arritmias e reduzindo a taxa de mortalidade em pacientes humanos. O objetivo do presente estudo foi avaliar clínica, eletrocardiográfica, radiográfica e ecocardiograficamente a evolução de cães com cardiomiopatia dilatada (CMD) tratatos com terapia convencional associada ao carvedilol. Para tal foram avaliados 49 cães com CMD divididos em: grupo NT, tratado com terapia convencional, e grupo T, tratado com terapia convencional associada ao carvedilol. Os animais foram submetidos à avaliação clínica e a exames complementares durante o período de um ano. Os resultados demonstraram que a terapia com carvedilol apresentou boa tolerabilidade na dose de 0,3mg kg-1 12-12horas, aumentou a sobrevida dos cães em 30,9%, não alterou as pressões sistólica e diastólica, reduziu a frequência cardíaca após três semanas de terapia, melhorou significantemente as frações de encurtamento e ejeção após seis meses de tratamento, não promoveu alterações radiográficas e da distância E-septo, diminuiu o índice de letalidade da doença, fato demonstrado pela melhora no escore clínico e na classe funcional dos animais, obtida após três semanas de terapia com carvedilol.

Endothelial dysfunction in cardiovascular and endocrine-metabolic diseases: an update

The endothelium plays a vital role in maintaining circulatory homeostasis by the release of relaxing and contracting factors. Any change in this balance may result in a process known as endothelial dysfunction that leads to impaired control of vascular tone and contributes to the pathogenesis of some cardiovascular and endocrine/metabolic diseases. Reduced endothelium-derived nitric oxide (NO) bioavailability and increased production of thromboxane A2, prostaglandin H2 and superoxide anion in conductance and resistance arteries are commonly associated with endothelial dysfunction in hypertensive, diabetic and obese animals, resulting in reduced endothelium-dependent vasodilatation and in increased vasoconstrictor responses. In addition, recent studies have demonstrated the role of enhanced overactivation ofβ-adrenergic receptors inducing vascular cytokine production and endothelial NO synthase (eNOS) uncoupling that seem to be the mechanisms underlying endothelial dysfunction in hypertension, heart failure and in endocrine-metabolic disorders. However, some adaptive mechanisms can occur in the initial stages of hypertension, such as increased NO production by eNOS. The present review focuses on the role of NO bioavailability, eNOS uncoupling, cyclooxygenase-derived products and pro-inflammatory factors on the endothelial dysfunction that occurs in hypertension, sympathetic hyperactivity, diabetes mellitus, and obesity. These are cardiovascular and endocrine-metabolic diseases of high incidence and mortality around the world, especially in developing countries and endothelial dysfunction contributes to triggering, maintenance and worsening of these pathological situations.

Estado nutricional e adequação da ingestão de energia e nutrientes em pacientes com insuficiência cardíaca

FUNDAMENTO: Maior conhecimento sobre o estado nutricional e a ingestão de energia e nutrientes é necessário para auxiliar no tratamento de pacientes com insuficiência cardíaca (IC). OBJETIVO: Verificar o estado nutricional e analisar a adequação da ingestão de energia, macro e micronutrientes de pacientes com IC em atendimento ambulatorial. MÉTODOS: Foram coletados dados antropométricos e de ingestão alimentar habitual de 125 pacientes (72% homens, 52,1±9,8 anos, IMC 26,9±4,4 kg/m²). As variáveis antropométricas foram comparadas entre os sexos, e analisou-se a adequação da ingestão de energia e nutrientes perante as recomendações. RESULTADOS: Depleção ou risco de depleção das reservas musculares estava presente em 38,4% dos pacientes (associação com sexo masculino; p < 0,0001). Em 69,6% dos casos, a ingestão média de energia foi menor que as necessidades energéticas (p < 0,0001). Entre os micronutrientes analisados, magnésio, zinco, ferro e tiamina apresentaram prevalências de inadequação importantes, e a maioria dos pacientes teve consumo de cálcio e potássio abaixo da ingestão adequada e consumo de sódio acima. CONCLUSÃO: Pacientes ambulatoriais com IC apresentam depleção de reservas musculares, com ingestão inadequada de energia e diversos nutrientes. Não se observou associação significante entre quantidade de energia proveniente da dieta habitual e o estado nutricional. O acompanhamento multiprofissional deve ser estimulado para avaliar melhor o estado geral desses pacientes.

Evaluation of left ventricular diastolic echocardiographic parameters in healthy dogs by pulsed-wave Doppler

Left ventricular diastolic dysfunction plays an important role on heart failure progression. In order to obtain additional reference values of left ventricular diastolic parameters and investigate influence of common variables, peak E wave (peak E), peak A wave (peak A), E/A ratio (E/A), E wave deceleration time (EDT) and isovolumic relaxation time (IRVT) were studied in 40 clinically healthy dogs, by pulsed wave Doppler. The following values were obtained: peak E = 0.747 ± 0.117 m/s, peak A = 0.487 ± 0.062 m/s, E/A = 1.533 ± 0.198, EDT = 88.7 ± 9.2 ms and IRVT = 0.080 ± 0.009 s. Some parameters were influenced by heart rate (peak E, peak A and IRVT), by age (peak A and E/A) and by body weight (TRIV). Gender influence was absent. Values obtained can be used as reference for canine specimens but its interpretation should consider on the influence of related variables.

Troponina cardíaca T para estratificação de risco na insuficiência cardíaca crônica descompensada

FUNDAMENTO: As troponinas cardíacas são marcadores altamente sensíveis e específicos de lesão miocárdica. Esses marcadores foram detectados na insuficiência cardíaca (IC) e estão associadas com mau prognóstico. OBJETIVO: Avaliar a relação da troponina T (cTnT) e suas faixas de valores com o prognóstico na IC descompensada. MÉTODOS: Estudaram-se 70 pacientes com piora da IC crônica que necessitaram de hospitalização. Na admissão, o modelo de Cox foi utilizado para avaliar as variáveis capazes de predizer o desfecho composto por morte ou re-hospitalização em razão de piora da IC durante um ano. RESULTADOS: Durante o seguimento, ocorreram 44 mortes, 36 re-hospitalizações por IC e 56 desfechos compostos. Na análise multivariada, os preditores de eventos clínicos foram: cTnT (cTnT > 0,100 ng/ml; hazard ratio (HR) 3,95 intervalo de confiança (IC) 95%: 1,64-9,49, p = 0,002), diâmetro diastólico final do ventrículo esquerdo (DDVE >70 mm; HR 1,92, IC95%: 1,06-3,47, p = 0,031) e sódio sérico (Na <135 mEq/l; HR 1,79, IC95%: 1,02-3,15, p = 0,044). Para avaliar a relação entre a elevação da cTnT e o prognóstico na IC descompensada, os pacientes foram estratificados em três grupos: cTnT-baixo (cTnT < 0,020 ng/ml, n = 22), cTnT-intermediário (cTnT > 0,020 e < 0,100 ng/ml, n = 36) e cTnT-alto (cTnT > 0,100 ng/ml, n = 12). As probabilidades de sobrevida e sobrevida livre de eventos foram: 54,2%, 31,5%, 16,7% (p = 0,020), e 36,4%, 11,5%, 8,3% (p = 0,005), respectivamente. CONCLUSÃO: A elevação da cTnT está associada com mau prognóstico na IC descompensada, e o grau dessa elevação pode facilitar a estratificação de risco

Tendência da mortalidade relacionada à doença de Chagas, Estado de São Paulo, Brasil, 1985 a 2006: estudo usando causas múltiplas de morte

OBJETIVO: Estudar a tendência da mortalidade relacionada à doença de Chagas informada em qualquer linha ou parte do atestado médico da declaração de óbito.MÉTODOS: Os dados provieram dos bancos de causas múltiplas de morte da Fundação Sistema Estadual de Análise de Dados de São Paulo (SEADE) entre 1985 e 2006. As causas de morte foram caracterizadas como básicas, associadas (não-básicas) e total de suas menções.RESULTADOS: No período de 22 anos, ocorreram 40 002 óbitos relacionados à doença de Chagas, dos quais 34 917 (87,29%) como causa básica e 5 085 (12,71%) como causa associada. Foi observado um declínio de 56,07% do coeficiente de mortalidade pela causa básica e estabilidade pela causa associada. O número de óbitos foi 44,5% maior entre os homens em relação às mulheres. O fato de 83,5% dos óbitos terem ocorrido a partir dos 45 anos de idade revela um efeito de coorte. As principais causas associadas da doença de Chagas como causa básica foram as complicações diretas do comprometimento cardíaco, como transtornos da condução, arritmias e insuficiência cardíaca. Para a doença de Chagas como causa associada, foram identificadas como causas básicas as doenças isquêmicas do coração, as doenças cerebrovasculares e as neoplasias.CONCLUSÕES: Para o total de suas menções, verificou-se uma queda do coeficiente de mortalidade de 51,34%, ao passo que a queda no número de óbitos foi de apenas 5,91%, tendo sido menor entre as mulheres, com um deslocamento das mortes para as idades mais avançadas. A metodologia das causas múltiplas de morte contribuiu para ampliar o conhecimento da história natural da doença de Chagas

Augmented muscle vasodilatory responses in obese children with Glu27 beta(2)-adrenoceptor polymorphism

This study examined forearm vasodilatation during mental challenge and exercise in 72 obese children (OC; age = 10 +/- 0.1 years) homozygous with polymorphism in the allele 27 of the beta(2)-adrenoceptors: Gln27 (n = 61) and Glu27 (n = 11). Forearm blood flow was recorded during 3 min of each using the Stroop color-word test (MS) and handgrip isometric exercise. Baseline hemodynamic and vascular measurements were similar. During the MS, peak forearm vascular conductance was significantly greater in group Glu27 (Delta = 0.35 +/- 0.4 vs. 0.12 +/- 0.1 units, respectively, p = .042). Similar results were found during exercise (Delta = 0.64 +/- 0.1 vs. 0.13 +/- 0.1 units, respectively, p = .035). Glu27 OC increased muscle vasodilatory responsiveness upon the MS and exercise.

Determination of Three-Dimensional Left Ventricle Motion to Analyze Ventricular Dyssyncrony in SPECT Images

A method to compute three-dimension (3D) left ventricle (LV) motion and its color coded visualization scheme for the qualitative analysis in SPECT images is proposed. It is used to investigate some aspects of Cardiac Resynchronization Therapy (CRT). The method was applied to 3D gated-SPECT images sets from normal subjects and patients with severe Idiopathic Heart Failure, before and after CRT. Color coded visualization maps representing the LV regional motion showed significant difference between patients and normal subjects. Moreover, they indicated a difference between the two groups. Numerical results of regional mean values representing the intensity and direction of movement in radial direction are presented. A difference of one order of magnitude in the intensity of the movement on patients in relation to the normal subjects was observed. Quantitative and qualitative parameters gave good indications of potential application of the technique to diagnosis and follow up of patients submitted to CRT.

ECG scar quantification correlates with cardiac magnetic resonance scar size and prognostic factors in Chagas' disease

Objective To test the hypothesis that 12-lead ECG QRS scoring quantifies myocardial scar and correlates with disease severity in Chagas' heart disease. Design Patients underwent 12-lead ECG for QRS scoring and cardiac magnetic resonance with late gadolinium enhancement (CMR-LGE) to assess myocardial scar. Setting University of Sao Paulo Medical School, Sao Paulo, Brazil. Patients 44 Seropositive patients with Chagas' disease without a history of myocardial infarction and at low risk for coronary artery disease. Main outcome measures Correlation between QRS score, CMR-LGE scar size and left ventricular ejection fraction. Relation between QRS score, heart failure (HF) class and history of ventricular tachycardia (VT). Results QRS score correlated directly with CMR-LGE scar size (R=0.69, p<0.0001) and inversely with left ventricular ejection fraction (R=-0.54, p=0.0002), which remained significant in the subgroup with conduction defects. Patients with class II or III HF had significantly higher QRS scores than those with class I HF (5.1 +/- 3.4 vs 2.1 +/- 3.1 QRS points (p=0.002)) and patients with a history of VT had significantly higher QRS scores than those without a history of VT (5.3 +/- 3.2% vs 2.6 +/- 3.4 QRS points (p=0.02)). A QRS score >= 2 points had particularly good sensitivity and specificity (95% and 83%, respectively) for prediction of large CMR-LGE, and a QRS score >= 7 points had particularly high specificity (92% and 89%, respectively) for predicting significant left ventricular dysfunction and history of VT. Conclusions The wide availability of 12-lead ECG makes it an attractive screening tool and may enhance clinical risk stratification of patients at risk for more severe, symptomatic Chagas' heart disease.

Selective Decrease of Components of the Creatine Kinase System and ATP Synthase Complex in Chronic Chagas Disease Cardiomyopathy

Background: Chronic Chagas disease cardiomyopathy (CCC) is an inflammatory dilated cardiomyopathy with a worse prognosis than other cardiomyopathies. CCC occurs in 30 % of individuals infected with Trypanosoma cruzi, endemic in Latin America. Heart failure is associated with impaired energy metabolism, which may be correlated to contractile dysfunction. We thus analyzed the myocardial gene and protein expression, as well as activity, of key mitochondrial enzymes related to ATP production, in myocardial samples of end-stage CCC, idiopathic dilated (IDC) and ischemic (IC) cardiomyopathies. Methodology/Principal Findings: Myocardium homogenates from CCC (N = 5), IC (N = 5) and IDC (N = 5) patients, as well as from heart donors (N = 5) were analyzed for protein and mRNA expression of mitochondrial creatine kinase (CKMit) and muscular creatine kinase (CKM) and ATP synthase subunits aplha and beta by immunoblotting and by real-time RT-PCR. Total myocardial CK activity was also assessed. Protein levels of CKM and CK activity were reduced in all three cardiomyopathy groups. However, total CK activity, as well as ATP synthase alpha chain protein levels, were significantly lower in CCC samples than IC and IDC samples. CCC myocardium displayed selective reduction of protein levels and activity of enzymes crucial for maintaining cytoplasmic ATP levels. Conclusions/Significance: The selective impairment of the CK system may be associated to the loss of inotropic reserve observed in CCC. Reduction of ATP synthase alpha levels is consistent with a decrease in myocardial ATP generation through oxidative phosphorylation. Together, these results suggest that the energetic deficit is more intense in the myocardium of CCC patients than in the other tested dilated cardiomyopathies.

Challenges and opportunities for primary, secondary, and tertiary prevention of Chagas' disease

A century after its discovery, Chagas' disease still represents a major public health challenge in Latin America. Moreover, because of growing population movements, an increasing number of cases of imported Chagas' disease have now been detected in non-endemic areas, such as North America and some European countries. This parasitic zoonosis, caused by Trypanosoma cruzi, is transmitted to humans by infected Triatominae insects, or occasionally by non-vectorial mechanisms, such as blood transfusion, mother to fetus, or oral ingestion of materials contaminated with parasites. Following the acute phase of the infection, untreated individuals enter a chronic phase that is initially asymptomatic or clinically unapparent. Usually, a few decades later, 40-50% of patients develop progressive cardiomyopathy and/or motility disturbances of the oesophagus and colon. In the last decades several interventions targeting primary, secondary and tertiary prevention of Chagas' disease have been attempted. While control of both vectorial and blood transfusion transmission of T cruzi (primary prevention) has been successful in many regions of Latin America, early detection and aetiological treatment of asymptomatic subjects with Chagas' disease (secondary prevention) have been largely underutilised. At the same time, in patients with established chronic disease, several pharmacological and non-pharmacological interventions are currently available and have been increasingly used with the intention of preventing or delaying complications of the disease (tertiary prevention). In this review we discuss in detail each of these issues.

In situ delivery of bone marrow cells and mesenchymal stem cells improves cardiovascular function in hypertensive rats submitted to myocardial infarction

This work aimed to evaluate cardiac morphology/function and histological changes induced by bone marrow cells (BMCs) and cultured mesenchymal stem cells (MSCs) injected at the myocardium of spontaneously hypertensive rats (SHR) submitted to surgical coronary occlusion. Female syngeneic adult SHR, submitted (MI) or not (C) to coronary occlusion, were treated 24 h later with in situ injections of normal medium (NM), or with MSCs (MSC) or BMCs (BM) from male rats. The animals were evaluated after 1 and 30 days by echocardiography, histology of heart sections and PCR for the Y chromosome. Improved ejection fraction and reduced left ventricle infarcted area were observed in MSC rats as compared to the other experimental groups. Treated groups had significantly reduced lesion tissue score, increased capillary density and normal (not-atrophied) myocytes, as compared to NM and C groups. The survival rate was higher in C, NM and MSC groups as compared to MI and BM groups. In situ injection of both MSCs and BMCs resulted in improved cardiac morphology, in a more physiological model of myocardial infarction represented by surgical coronary occlusion of spontaneously hypertensive rats. Only treatment with MSCs, however, ameliorated left ventricle dysfunction, suggesting a positive role of these cells in heart remodeling in infarcted hypertensive subjects.

Cardiac and peripheral adjustments induced by early exercise training intervention were associated with autonomic improvement in infarcted rats: role in functional capacity and mortality

Aims To test the effects of early exercise training (ET) on left ventricular (LV) and autonomic functions, haemodynamics, tissues blood flows (BFs), maximal oxygen consumption (VO(2) max), and mortality after myocardial infarction (MI) in rats. Methods and results Male Wistar rats were divided into: control (C), sedentary-infarcted (SI), and trained-infarcted (TI). One week after MI, TI group underwent an ET protocol (90 days, 50-70% VO2 max). Left ventricular function was evaluated noninvasively and invasively. Baroreflex sensitivity, heart rate variability, and pulse interval were measured. Cardiac output (CO) and regional BFs were determined using coloured microspheres. Infarcted area was reduced in TI (19 +/- 6%) compared with SI (34 +/- 5%) after ET. Exercise training improved the LV and autonomic functions, the CO and regional BF changes induced by MI, as well as increased SERCA2 expression and mRNA vascular endothelial growth factor levels. These changes brought about by ET resulted in mortality rate reduction in the TI (13%) group compared with the SI (54%) group. Conclusion Early aerobic ET reduced cardiac and peripheral dysfunctions and preserved cardiovascular autonomic control after MI in trained rats. Consequently, these ET-induced changes resulted in improved functional capacity and survival after MI.