RESUMO
NEW FINDINGS: What is the central question of this study? In Zucker Diabetic Fatty rats, does cardiomyocyte myofilament function change through the time course of diabetes and what are the mechanisms behind alterations in calcium sensitivity? What is the main finding and its importance? Zucker Diabetic Fatty rats had increased myofilament calcium sensitivity and reduced phosphorylation at cardiac troponin I without differential O-GlcNAcylation. ABSTRACT: The diabetic heart has impaired systolic and diastolic function independent of other comorbidities. The availability of calcium is altered, but does not fully explain the cardiac dysfunction seen in the diabetic heart. Thus, we explored if myofilament calcium regulation of contraction is altered while also categorizing the levels of phosphorylation and O-GlcNAcylation in the myofilaments. Calcium sensitivity (pCa50 ) was measured in Zucker Diabetic Fatty (ZDF) rat hearts at the initial stage of diabetes (12 weeks old) and after 8 weeks of uncontrolled hyperglycaemia (20 weeks old) and in non-diabetic (nDM) littermates. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+ ]). Fluorescent gel stain (ProQ Diamond) was used to measure total protein phosphorylation. Specific phospho-sites on cardiac troponin I (cTnI) and total cTnI O-GlcNAcylation were quantified using immunoblot. pCa50 was greater in both 12- and 20-week-old diabetic (DM) rats compared to nDM littermates (P = 0.0001). Total cTnI and cTnI serine 23/24 phosphorylation were lower in DM rats (P = 0.003 and P = 0.01, respectively), but cTnI O-GlcNAc protein expression was not different. pCa50 is greater in DM rats and corresponds with an overall reduction in cTnI phosphorylation. These findings indicate that myofilament calcium sensitivity is increased and cTnI phosphorylation is reduced in ZDF DM rats and suggests an important role for cTnI phosphorylation in the DM heart.
Assuntos
Diabetes Mellitus , Miofibrilas , Animais , Cálcio/metabolismo , Diabetes Mellitus/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Fosforilação/fisiologia , Ratos , Ratos Zucker , Troponina I/metabolismoRESUMO
BACKGROUND: Attenuated increases in ventricular stroke volume during exercise are common in type 2 diabetes and contribute to reduced aerobic capacity. The purpose of this study was to determine whether impaired ventricular filling or reduced systolic ejection were responsible for the attenuated stroke volume reserve in people with uncomplicated type 2 diabetes. METHODS: Peak aerobic capacity and total blood volume were measured in 17 people with diabetes and 16 non-diabetic controls with no evidence of cardiovascular disease. Left ventricular volumes and other systolic and diastolic functional parameters were measured with echocardiography at rest and during semi-recumbent cycle ergometry at 40 and 60% of maximal aerobic power and compared between groups. RESULTS: People with diabetes had reduced peak aerobic capacity and heart rate reserve, and worked at lower workloads than non-diabetic controls. Cardiac output, stroke volume and ejection fraction were not different at rest, but increased less in people with diabetes during exercise. Left ventricular end systolic volume was not different between groups in any condition but end diastolic volume, although not different at rest, was smaller in people with diabetes during exercise. Total blood volume was not different between the groups, and was only moderately associated with left ventricular volumes. CONCLUSIONS: People with type 2 diabetes exhibit an attenuated increase in stroke volume during exercise attributed to an inability to maintain/increase left ventricular filling volumes at higher heart rates. This study is the first to determine the role of filling in the blunted cardiac reserve in adults with type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/complicações , Cardiomiopatias Diabéticas/etiologia , Tolerância ao Exercício , Volume Sistólico , Disfunção Ventricular Esquerda/etiologia , Função Ventricular Esquerda , Adulto , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/fisiopatologia , Ecocardiografia Doppler , Teste de Esforço , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Patients undergoing cardiopulmonary bypass procedures require inotropic support to improve hemodynamic function and cardiac output. Current inotropes such as dobutamine, can promote arrhythmias, prompting a demand for improved inotropes with little effect on intracellular Ca2+ flux. Low-dose carbon monoxide (CO) induces inotropic effects in perfused hearts. Using the CO-releasing pro-drug, oCOm-21, we investigated if this inotropic effect results from an increase in myofilament Ca2+ sensitivity. Male Sprague Dawley rat left ventricular cardiomyocytes were permeabilized, and myofilament force was measured as a function of -log [Ca2+ ] (pCa) in the range of 9.0-4.5 under five conditions: vehicle, oCOm-21, the oCOm-21 control BP-21, and levosimendan, (9 cells/group). Ca2+ sensitivity was assessed by the Ca2+ concentration at which 50% of maximal force is produced (pCa50 ). oCOm-21, but not BP-21 significantly increased pCa50 compared to vehicle, respectively (pCa50 5.52 vs. 5.47 vs. 5.44; p < 0.05). No change in myofilament phosphorylation was seen after oCOm-21 treatment. Pretreatment of cardiomyocytes with the heme scavenger hemopexin, abolished the Ca2+ sensitizing effect of oCOm-21. These results support the hypothesis that oCOm-21-derived CO increases myofilament Ca2+ sensitivity through a heme-dependent mechanism but not by phosphorylation. Further analyses will confirm if this Ca2+ sensitizing effect occurs in an intact heart.
Assuntos
Monóxido de Carbono , Miofibrilas , Ratos , Animais , Humanos , Masculino , Monóxido de Carbono/farmacologia , Contração Miocárdica , Ratos Sprague-Dawley , Miócitos Cardíacos , Heme , CálcioRESUMO
OBJECTIVES: This study sought to evaluate the safety and feasibility of all operators at a single center changing from predominantly femoral to radial access for coronary percutaneous procedures. BACKGROUND: The radial artery is currently regarded as a useful vascular access site for coronary angiography and percutaneous coronary intervention (PCI). The reduction in local vascular access complications is thought to be a major advantage of the radial route. Despite this, the technique is used less frequently possibly reflecting concerns by cardiologists about the feasibility of using radial access as a preferred option. METHODS: A retrospective study of 1004 consecutive patients who underwent coronary angiography with or without PCI was analyzed. Procedure details and clinical outcomes were assessed according to the radial or femoral approaches. RESULTS: The success rate for cardiac catheterization via the radial approach was 97.4% (815/837) and the femoral approach was 98.8% (165/167). The procedural failure rate for radial access was not different from the femoral route [2.6% vs. 1.2%; odds ratio (OR), 2.26; 95% confidence interval (CI), 0.53-9.71; P = 0.41]. Major access site complications occurred in 0.25% patients in the radial group compared with 4.8% patients in the femoral group [OR, 0.05 (95% CI, 0.01-0.23); P < 0.0001]. CONCLUSIONS: The radial approach has a high rate of success and is associated with fewer major local vascular access site complications than the femoral route. These results can be achieved early in the operator learning curve of low to medium volume operators.
Assuntos
Angioplastia Coronária com Balão/métodos , Cateterismo Cardíaco/métodos , Angiografia Coronária/métodos , Artéria Femoral , Hemorragia/prevenção & controle , Artéria Radial , Idoso , Angioplastia Coronária com Balão/efeitos adversos , Cateterismo Cardíaco/efeitos adversos , Competência Clínica , Angiografia Coronária/efeitos adversos , Estudos de Viabilidade , Feminino , Hemorragia/etiologia , Humanos , Curva de Aprendizado , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Razão de Chances , Punções , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Systolic and diastolic dysfunction in diabetes have frequently been associated with abnormal calcium (Ca2+) regulation. However, there is emerging evidence that Ca2+ mishandling alone is insufficient to fully explain diabetic heart dysfunction, with focus shifting to the properties of the myofilament proteins. Our aim was to examine the effects of diabetes on myofilament Ca2+ sensitivity and Ca2+ handling in left ventricular tissues isolated from the same type 2 diabetic rat hearts. We measured the force-pCa relationship in skinned left ventricular cardiomyocytes isolated from 20-week-old type 2 diabetic and non-diabetic rats. Myofilament Ca2+ sensitivity was greater in the diabetic relative to non-diabetic cardiomyocytes, and this corresponded with lower phosphorylation of cardiac troponin I (cTnI) at ser23/24 in the diabetic left ventricular tissues. Protein expression of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), phosphorylation of phospholamban (PLB) at Ser16, and SERCA/PLB ratio were lower in the diabetic left ventricular tissues. However, the maximum SERCA Ca2+ uptake rate was not different between the diabetic and non-diabetic myocardium. Our data suggest that impaired contractility in the diabetic heart is not caused by SERCA Ca2+ mishandling. This study highlights the important role of the cardiac myofilament and provides new insight on the pathophysiology of diabetic heart dysfunction.
Assuntos
Cardiomiopatias , Diabetes Mellitus Tipo 2 , Animais , Cálcio/metabolismo , Cálcio da Dieta/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatias/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Retículo Endoplasmático/metabolismo , Contração Miocárdica , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , Ratos , Ratos Zucker , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Troponina I/metabolismoRESUMO
The cardiovascular benefits of regular exercise are unequivocal, yet patients with type 2 diabetes respond poorly to exercise due to a reduced cardiac reserve. The contractile response of diabetic cardiomyocytes to ß-adrenergic stimulation is attenuated, which may result in altered myofilament calcium sensitivity and posttranslational modifications of cardiac troponin I (cTnI). Treadmill running increases myofilament calcium sensitivity in nondiabetic rats, and thus we hypothesized that endurance training would increase calcium sensitivity of diabetic cardiomyocytes and alter site-specific phosphorylation of cTnI. Calcium sensitivity, or pCa50, was measured in Zucker diabetic fatty (ZDF), nondiabetic (nDM), and diabetic (DM) rat hearts after 8 wk of either a sedentary (SED) or progressive treadmill running (TR) intervention. Skinned cardiomyocytes were connected to a capacitance-gauge transducer and a torque motor to measure force as a function of pCa (-log[Ca2+]). Specific phospho-sites on cTnI and O-GlcNAcylation were quantified by immunoblot and total protein phosphorylation by fluorescent gel staining (ProQ Diamond). The novel finding in this study was that training increased pCa50 in both DM and nDM cardiomyocytes (P = 0.009). Phosphorylation of cTnI amino acid residues Ser23/24, a crucial protein kinase A site, and Threonine (Thr)144 was lower in DM hearts, but there was no effect of training on site-specific phosphorylation. In addition, total phosphorylation and O-GlcNAcylation levels were not different between SED and TR groups. These findings suggest that regular exercise may benefit the diabetic heart by specifically targeting myofilament contractile function.NEW & NOTEWORTHY We examined the effects of training on the myofilament calcium in diabetic rat hearts. After 8 wk of treadmill running, both nondiabetic and diabetic cardiomyocytes had increased myofilament calcium sensitivity compared with their sedentary counterparts, but there was no effect of training on the phosphorylation or O-GlcNAcylation status of myofilament proteins measured in this study. These data highlight one potential mechanism capable of reversing, in part, reduced cardiac reserve in the diabetic heart.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Corrida , Animais , Cálcio/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Contração Miocárdica/fisiologia , Miocárdio/metabolismo , Miofibrilas/metabolismo , Fosforilação , Ratos , Ratos Zucker , Troponina I/metabolismoRESUMO
The coronavirus 2019 (COVID-19) pandemic requires significant changes to standard operating procedures for non-COVID-19 related illnesses. Balancing the benefit from standard evidence-based treatments with the risks posed by COVID-19 to patients, healthcare workers and to the population at large is difficult due to incomplete and rapidly changing information. In this article, we use management of acute coronary syndromes as a case study to show how these competing risks and benefits can be resolved, albeit incompletely. While the risks due to COVID-19 in patients with acute coronary syndromes is unclear, the benefits of standard management are well established in this condition. As an aid to decision making, we recommend systematic estimation of the risks and benefits for management of any condition where there is likely to be an increase in non-COVID-19 related mortality and morbidity due to changes in routine care.
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Síndrome Coronariana Aguda/terapia , Infecções por Coronavirus/epidemiologia , Gerenciamento Clínico , Intervenção Coronária Percutânea , Pneumonia Viral/epidemiologia , COVID-19 , Tomada de Decisões , Humanos , Nova Zelândia/epidemiologia , Pandemias , Resultado do TratamentoRESUMO
Hypertension plays an important role in the development and progression of chronic kidney disease. Studies to date, with mineralocorticoid receptor antagonists (MRA), have demonstrated varying degrees of results in modifying the development of renal fibrosis. This study aimed to investigate whether treatment with a MRA commenced following the establishment of hypertension, a situation more accurately representing the clinical setting, modified the progression of renal fibrosis. Using male Cyp1a1Ren2 rats (n = 28), hypertension was established by addition of 0.167% indole-3-carbinol (w/w) to the rat chow, for 2 weeks prior to treatment. Rats were then divided into normotensive, hypertensive (H), or hypertensive with daily oral spironolactone treatment (H + SP) (human equivalent dose 50 mg/day). Physiological data and tissue were collected after 4 and 12 weeks for analysis. After 4 weeks, spironolactone had no demonstrable effect on systolic blood pressure (SBP), proteinuria, or macrophage infiltration in the renal cortex. However, glomerulosclerosis and renal cortical fibrosis were significantly decreased. Following 12 weeks of spironolactone treatment, SBP was lowered (not back to normotensive levels), proteinuria was reduced, and the progression of glomerulosclerosis and renal cortical fibrosis was significantly blunted. This was associated with a significant reduction in macrophage and myofibroblast infiltration, as well as CTGF and pSMAD2 expression. In summary, in a model of established hypertension, spironolactone significantly blunted the progression of renal fibrosis and glomerulosclerosis, and downregulated the renal inflammatory response, which was associated with reduced proteinuria, despite only a partial reduction in systolic blood pressure. This suggests a blood pressure independent effect of MRA on renal fibrosis.
Assuntos
Fibrose/prevenção & controle , Nefropatias/prevenção & controle , Espironolactona/farmacologia , Aldosterona/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Fibrose/etiologia , Fibrose/genética , Fibrose/patologia , Hipertensão/genética , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Ratos , Ratos TransgênicosRESUMO
PURPOSE: Increasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as ß-blockers. ß-blocker efficacy is heterogenous, with second generation ß-blocker metoprolol selectively inhibiting ß1 -AR, while third generation ß-blocker carvedilol has α1 -AR inhibition, antioxidant, and anti-apoptotic actions alongside nonselective ß-AR inhibition. These additional properties have led to the hypothesis that carvedilol may improve cardiac contractility in the diabetic heart to a greater extent than metoprolol. The present study aimed to compare the efficacy of metoprolol and carvedilol on myocardial function in animal models and cardiac tissue from patients with type 2 diabetes and preserved ejection fraction. METHODS: Echocardiographic examination of cardiac function and assessment of myocardial function in isolated trabeculae was carried out in patients with and without diabetes undergoing coronary artery bypass grafting (CABG) who were prescribed metoprolol or carvedilol. Equivalent measures were undertaken in Zucker Diabetic Fatty (ZDF) rats following 4 weeks treatment with metoprolol or carvedilol. RESULTS: Patients receiving carvedilol compared to metoprolol had no difference in cardiac function, and no difference was apparent in myocardial function between ß-blockers. Both ß-blockers similarly improved myocardial function in diabetic ZDF rats treated for 4 weeks, without significantly affecting in vivo cardiac function. CONCLUSIONS: Metoprolol and carvedilol were found to have no effect on cardiac function in type 2 diabetes with preserved ejection fraction, and were similarly effective in preventing myocardial dysfunction in ZDF rats.
Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Carvedilol/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Coração/efeitos dos fármacos , Metoprolol/uso terapêutico , Idoso , Animais , Carvedilol/administração & dosagem , Ponte de Artéria Coronária/métodos , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Feminino , Coração/fisiopatologia , Humanos , Masculino , Metoprolol/administração & dosagem , Pessoa de Meia-Idade , Ratos Zucker , Resultado do TratamentoRESUMO
Type 2 diabetes is associated with reduced left ventricular reserve. It is unclear whether exercise training improves left ventricular function in people with type 2 diabetes. PURPOSE: This study aimed to determine whether 3 months of high-intensity interval training (HIIT) improves left ventricular function during exercise in adults with type 2 diabetes. METHODS: Participants performed a VËO2peak test and received a DXA scan and total blood volume measurement at baseline. Left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and left ventricular stroke volume (LVSV) were then measured at rest and during low- and moderate-intensity semirecumbent exercise in adults with type 2 diabetes before and after 3 months of HIIT (n = 11) or no training (control) (n = 5). The effects of HIIT were determined using repeated-measures ANOVA. RESULTS: HIIT increased VËO2peak by approximately 15% (P < 0.002) but did not change body composition or total blood volume. LVESV decreased and LVEDV and LVSV increased from rest to moderate-intensity exercise in both groups at baseline (all P < 0.01). Three months of HIIT increased LVEDV (P = 0.008) and LVSV (P = 0.02) at all conditions, but there was no difference in controls (all P > 0.05). HIIT augmented the reduction in LVESV from rest to moderate-intensity exercise (P < 0.04), but LVESV was unchanged in controls. Increased LVEDV explained 51% of the change in LVSV after HIIT intervention. Mitral inflow parameters and mitral annular velocities were unaffected by HIIT (all P > 0.05). CONCLUSIONS: HIIT training increased the LVSV response to exercise in adults with type 2 diabetes. These data suggest that HIIT can improve LV filling and emptying during exercise and reverse early cardiac consequences of type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Treinamento Intervalado de Alta Intensidade , Função Ventricular Esquerda/fisiologia , Adulto , Volume Sanguíneo/fisiologia , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Ecocardiografia , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio , Cooperação do Paciente , Volume Sistólico/fisiologiaRESUMO
Hypertension is a leading risk factor for cardiovascular and chronic kidney disease. A new rodent model (transgenic male Cyp1a1-Ren2 rats) provides reversible induction of hypertension through the addition of indole-3-carbinol (I3C) to the diet, without the need for surgical intervention, thus giving researchers control over both the onset of hypertension and its magnitude (I3C dose-dependency). We here report the breeding performance and productivity of Cyp1a1-Ren2 rats. Despite being transgenic, these animals proved to be efficient breeders. In addition to confirming inducible and reversible dose-dependent hypertension (by using I3C doses of 0.125%, 0.167%, and 0.25% [w/w] in the diet for 14 d, followed by normal chow for 4 d), we demonstrated that hypertension can be sustained chronically (14 wk) by continuous dosing with I3C (0.167% [w/w]) in the diet. In chronically dosed male rats, systolic blood pressure continued to rise, from 173 ± 11 mm Hg after 1 mo to 196 ± 19 mm Hg after 3 mo, with no adverse phenotypic features observed. In conclusion, Cyp1a1-Ren2 rats are a useful animal model to investigate hypertension-induced end-organ damage and potential new therapeutic targets to manage hypertension.
Assuntos
Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Ratos , Animais , Cruzamento , Citocromo P-450 CYP1A1/genética , Feminino , Indóis , Masculino , Ratos Transgênicos , Renina/genéticaRESUMO
Type 2 diabetes (T2D) is associated with reduced cardiac reserve and aerobic capacity. Altered myocardial autonomic nervous regulation has been demonstrated in humans with diabetes (indirectly) and animal models (directly). PURPOSE: This study aimed to determine the chronotopic and inotropic response of the type 2 diabetic heart to ß-adrenergic stimulation. METHODS: Eight people with uncomplicated T2D and seven matched controls performed a dual-energy x-ray absorptiometry scan and VËO2peak test. Plasma catecholamines were determined at rest and during peak exercise. On a second visit, HR and left ventricular contractility were assessed using echocardiography during supine rest, parasympathetic blockade (atropine), and during incremental ß-adrenergic stimulation (dobutamine). RESULTS: VËO2peak and HR reserve were lower in T2D (P < 0.05) as expected. Both groups increased norepinephrine comparably (P = 0.23) during peak exercise; however, epinephrine increased less in the T2D group (P < 0.05). The dobutamine dose required to achieve 85% of age-predicted maximal HR was 36% higher in CON (P < 0.05). Resting HR was higher (P < 0.01) and stroke volume indexed to fat free mass was smaller (P < 0.05) in T2D. During dobutamine infusion the response (% change) in HR, end-diastolic volumeFFM, stroke volume, ejection fraction, and cardiac output were not different between the groups. However, HR was higher (P < 0.01) and end-diastolic volume indexed to fat free mass (P < 0.01), stroke volumeFFM (P < 0.01), ejection fraction (P < 0.05), and stroke work (P < 0.01) were lower in T2D. CONCLUSIONS: Although the type 2 diabetic heart worked at smaller volumes, the HR and contractile response to ß-adrenergic stimulation were unaffected by diabetes. The reduced cardiac reserve observed in uncomplicated T2D was not explained by impaired myocardial sympathetic responsiveness but may reflect changes in the loading conditions or function of the diabetic left ventricle.
Assuntos
Agonistas de Receptores Adrenérgicos beta 1/farmacologia , Diabetes Mellitus Tipo 2/fisiopatologia , Dobutamina/farmacologia , Coração/efeitos dos fármacos , Coração/inervação , Sistema Nervoso Simpático/fisiopatologia , Adulto , Atropina/farmacologia , Catecolaminas/sangue , Ecocardiografia , Teste de Esforço , Feminino , Coração/diagnóstico por imagem , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Contração Miocárdica/efeitos dos fármacos , Contração Miocárdica/fisiologia , Consumo de Oxigênio/fisiologia , Parassimpatolíticos/farmacologiaRESUMO
BACKGROUND AND AIMS: Catheter-based renal denervation for the treatment of drug-resistant hypertension has been intensively investigated in recent years. To date, only limited data have been published using multi-electrode radiofrequency ablation systems that can deliver lesions with a pre-determined pattern. This study was designed to evaluate the safety and performance of the second generation EnligHTN™ Renal Denervation System. METHODS: This first-in-human, prospective, multi-center, non-randomized study included 39 patients (62% male, mean age 63 years, and mean baseline office blood pressure 174/93 mmHg) with drug-resistant hypertension. The primary safety and performance objectives were to characterize, from baseline to 6 months post procedure, the rate of serious procedural and device related adverse events, as adjudicated by an independent Clinical Events Committee, and the reduction of office systolic blood pressure. RESULTS: Renal artery denervation, using the second generation EnligHTN multi-electrode system significantly reduced office blood pressure from baseline to 1, 3, 6, 12, 18 and 24 months by 19/7, 26/9, 25/7, 23/7, 25/8 and 27/9 mmHg, respectively (p ≤ 0.0005). No serious device or procedure related adverse events affecting the renal arteries or renal function occurred through 24 months of follow-up. CONCLUSIONS: Renal sympathetic denervation using the second generation EnligHTN Renal Denervation System resulted in safe, rapid, and significant mean office blood pressure reduction that was sustained through 24 months. Future studies will need to address the utility of this system against an appropriate sham based comparator.
Assuntos
Pressão Sanguínea , Ablação por Cateter/instrumentação , Hipertensão/cirurgia , Rim/irrigação sanguínea , Artéria Renal/inervação , Simpatectomia/instrumentação , Sistema Nervoso Simpático/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anti-Hipertensivos/uso terapêutico , Austrália , Pressão Sanguínea/efeitos dos fármacos , Ablação por Cateter/efeitos adversos , Ablação por Cateter/métodos , Resistência a Medicamentos , Feminino , Humanos , Hipertensão/diagnóstico , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Estudos Prospectivos , Simpatectomia/efeitos adversos , Simpatectomia/métodos , Sistema Nervoso Simpático/fisiopatologia , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Sympathetic neural activation is markedly increased in end-stage kidney disease (ESKD). Catheter-based renal denervation (RDN) reduces sympathetic overactivity and blood pressure in resistant hypertension. We investigated the effect of RDN on sympathetic neural activation and left ventricular mass in patients with ESKD. METHODS: Nine ESKD (6 hemodialysis and 3 peritoneal dialysis) patients with dialysis vintage of ≥11 months were treated with RDN (EnligHTN system). Data were obtained on a nondialysis day; at baseline, 1, 3, and 12 months post-RDN. RESULTS: At baseline sympathetic neural activation measured by muscle sympathetic nervous activity (MSNA) and plasma norepinephrine concentrations were markedly elevated. Left ventricular hypertrophy (LVH) was evident in 8 of the 9 patients. At 12 months post-RDN, blind analysis revealed that MSNAfrequency (-12.2 bursts/min1, 95% CI [-13.6, -10.7]) and LV mass (-27 g/m2, 95% CI [-47, -8]) were reduced. Mean ambulatory BP (systolic: -24 mm Hg, 95% CI [-42, -5] and diastolic: -13 mm Hg, 95% CI [-22, -4]) was also reduced at 12 months. Office BP was reduced as early as 1 month (systolic: -25 mm Hg, 95% CI [-45, -5] and diastolic: -13 mm Hg, 95% CI [-24, -1]). Both ambulatory and office BP had clinically significant reductions in at least 50% of patients out to 12 months. DISCUSSION: Catheter-based RDN significantly reduced MSNA and LV mass as well as systemic BP in this group of patients with ESKD.
RESUMO
People with type 1 diabetes (T1D) have lower exercise capacity (VÌO2max) than their age-matched nondiabetic counterparts (CON), which might be related to cardiac autonomic dysfunction. We examined whether Heart Rate Variability (HRV; indicator of cardiac autonomic modulation) was associated with exercise capacity in those with and without T1D. Twenty-three participants with uncomplicated T1D and 17 matched CON were recruited. Heart rate (HR; ECG), blood pressure (BP; finger photo-plethysmography), and respiratory rate (respiratory belt) were measured during baseline, paced-breathing and clinical autonomic reflex tests (CARTs); deep breathing, lying-to-stand, and Valsalva maneuver. Baseline and paced-breathing ECG were analyzed for HRV (frequency-domain). Exercise capacity was determined during an incremental cycle ergometer test while VÌO2, 12-lead ECG, and BP were measured. In uncomplicated T1D, resting HR was elevated and resting HRV metrics were reduced, indicative of altered cardiac parasympathetic modulation; this was generally undetected by the CARTs. However, BP and plasma catecholamines were not different between groups. In T1D, VÌO2max tended to be lower (P = 0.07) and HR reserve was lower (P < 0.01). Resting Total Power (TP) had stronger positive associations with VÌO2max (R2 ≥ 0.3) than all other traditional indicators such as age, resting HR, and self-reported exercise (R2 = 0.042-0.3) in both T1D and CON Alterations in cardiac autonomic modulation are an early manifestation of uncomplicated T1D. Total Power was associated with reduced exercise capacity regardless of group, and these associations were generally stronger than traditional indicators.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Exercício Físico , Frequência Cardíaca , Adulto , Pressão Sanguínea , Estudos de Casos e Controles , Catecolaminas/sangue , Feminino , Humanos , Masculino , Consumo de Oxigênio , RespiraçãoRESUMO
The metabolic and microvascular benefits of regular exercise for people with diabetes are unequivocal. However, cardiovascular disease, which disproportionately affects people with diabetes, is not reduced by regular exercise, and heart disease remains the leading cause of death for people with type 2 diabetes. 'Subclinical' changes in the function of the diabetic left ventricle are common and reduce cardiac reserve and exercise capacity. This review describes the changes in resting and exercising left ventricular function, and the possible causes of these changes, and introduces the possibility that more vigorous exercise may be needed to improve left ventricular function and reduce rates of cardiovascular disease in people with type 2 diabetes.
Assuntos
Complicações do Diabetes , Diabetes Mellitus Tipo 2/fisiopatologia , Terapia por Exercício/métodos , Tolerância ao Exercício , Exercício Físico , Coração/fisiologia , Função Ventricular Esquerda/fisiologia , Diabetes Mellitus Tipo 2/complicações , Teste de Esforço , HumanosRESUMO
OBJECTIVES: We sought to demonstrate the safety and performance of the actinomycin D-coated Multilink-Tetra stent(Guidant Corp., Santa Clara, California) in the treatment of patients with single de novo native coronary lesions. BACKGROUND: Drug-eluting stents (DES) releasing sirolimus or paclitaxel dramatically reduce restenosis. The anti-proliferative drug, actinomycin D, which is highly effective in reducing neointimal proliferation in preclinical studies, was selected for clinical evaluation. METHODS: The multi-center, single-blind, three-arm ACTinomycin-eluting stent Improves Outcomes by reducing Neointimal hyperplasia (ACTION) trial randomized 360 patients to receive a DES (2.5 or 10 microg/cm(2) of actinomycin D) or metallic stent (MS). The primary end points were major adverse cardiac events (MACE) at 30 days, diameter stenosis by angiography, tissue effects, and neointimal volume by intravascular ultrasound (IVUS) at six months. When early monitoring revealed an increased rate of repeat revascularization, the protocol was amended to allow for additional follow-up for DES patients. Angiographic control of MS patients was no longer mandatory. RESULTS: The biased selection of DES patients undergoing IVUS follow-up invalidated the interpretation of the IVUS findings. The in-stent late lumen loss and that at the proximal and distal edges were higher in both DES groups than in the MS group and resulted in higher six-month and one-year MACE (34.8% and 43.1% vs. 13.5%), driven exclusively by target vessel revascularization without excess death or myocardial infarction. CONCLUSIONS: The results of the ACTION trial indicate that all anti-proliferative drugs will not uniformly show a drug class effect in the prevention of restenosis.
Assuntos
Doença da Artéria Coronariana/terapia , Reestenose Coronária/prevenção & controle , Vasos Coronários/efeitos dos fármacos , Dactinomicina/uso terapêutico , Revascularização Miocárdica/métodos , Stents , Idoso , Angiografia Coronária , Doença da Artéria Coronariana/tratamento farmacológico , Reestenose Coronária/complicações , Reestenose Coronária/diagnóstico por imagem , Reestenose Coronária/patologia , Dactinomicina/administração & dosagem , Dactinomicina/farmacologia , Morte Súbita Cardíaca/prevenção & controle , Esquema de Medicação , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/prevenção & controle , Estudos Prospectivos , Viés de Seleção , Método Simples-Cego , Stents/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Túnica Íntima/efeitos dos fármacos , Ultrassonografia de IntervençãoRESUMO
STUDY OBJECTIVES: To evaluate the frequency of sleep-disordered breathing (SDB) in patients presenting with acute cardiovascular events. DESIGN: Repeat observational study. SETTING: Coronary care unit of a university hospital. PATIENTS: A total of 26 patients presenting with unstable angina, myocardial infarction, or left ventricular failure. MEASUREMENTS: Level 3 portable sleep study performed at the time of acute presentation (study 1; 26 patients) and again > or = 6 weeks later (study 2; 18 patients). RESULTS: SDB (apnea-hypopnea index > or = 15) was identified in 13 of 26 patients (50%) during study 1. One patient had central sleep apnea. Of the 18 who completed the two studies, SDB was confirmed in 10 of 18 patients (56%) during study 1 but in only 5 of 18 patients (28%) during study 2. All five of those patients had obstructive sleep apnea (OSA). Six patients were deemed to have false-positive results for SDB at follow-up, and one patient was deemed to have a false-negative result. Detailed analysis suggested that supine posture during study 1 may have contributed to the high false-positive rate, even though only three of six patients fulfilled the criteria for positional OSA. CONCLUSIONS: SDB occurs commonly in patients presenting with an acute cardiovascular event. Consideration of the diagnosis of SDB is an important strategy for secondary prevention. However, our findings indicate that SDB abnormalities may be transient. Sleep studies to investigate SDB as a potential risk factor for cardiovascular morbidity should be carried out when the patient is clinically stable.
Assuntos
Angina Instável/epidemiologia , Doença das Coronárias/epidemiologia , Insuficiência Cardíaca/epidemiologia , Infarto do Miocárdio/epidemiologia , Polissonografia/métodos , Síndromes da Apneia do Sono/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Unidades de Cuidados Coronarianos , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Endovascular renal denervation (sympathectomy) is a novel procedure developed for the treatment of resistant hypertension. Evidence suggests that it reduces both afferent and efferent sympathetic nerve activity, which may offer clinical benefit over and above any blood pressure-lowering effect. Studies have shown objective improvements in left ventricular mass, ventricular function, central arterial stiffness, central haemodynamics, baroreflex sensitivity and arrhythmia frequency. Benefits have also been seen in insulin resistance, microalbuminuria and glomerular filtration rate. In chronic kidney disease, elevated sympathetic activity has been causally linked to disease progression and cardiovascular sequelae. Effecting a marked reduction in sympathetic hyperactivity may herald a significant step in the management of this and other conditions. In this in-depth review, the pathophysiology and clinical significance of the sympatholytic effects of endovascular renal denervation are discussed.