Carolina Nazzal

Administration of growth hormone to patients with advanced cardiac heart failure: effects upon left ventricular function, exercise capacity, and neurohormonal status

Experimental and clinical studies have shown that the administration of recombinant human growth hormone can improve deteriorated left ventricular function and hemodynamics in patients with heart failure. Herein, we compared the effects of growth hormone versus placebo upon resting left ventricular ejection fraction, exercise capacity and neurohormonal status in patients with advanced heart failure. Nineteen patients with advanced cardiac heart failure (ejection fraction <30%) were studied at baseline and after 8 weeks of treatment with growth hormone (0.03 U/kg per day) or placebo. Primary end points were resting left ventricular ejection fraction, peak oxygen consumption and neurohormonal status, including plasma norepinephrine levels and insulin like growth factor-1 and its binding protein-3. Results are presented as median and interquartile ranges. Patients receiving growth hormone had a significant increase in insulin growth factor-1 plasma levels (median difference growth hormone=83 ng/ml [57-170] versus placebo=-6 ng/ml [-23-6], P<0.05) and its binding protein-3. However, no significant increase in left ventricular ejection fraction after growth hormone treatment (ejection fraction pre=16% [13-18] and post=17% [14-27]) was noticed when compared to placebo (ejection fraction pre=20% [15-24] and post=20% [15-26]). Also, no significant effect of growth hormone treatment was seen on peak oxygen consumption or norepinephrine plasma levels. Although the administration of growth hormone to patients with advanced cardiac heart failure was associated with a significant increase in insulin growth factor-1, there were no significant changes in ejection fraction, exercise capacity and/or neurohormonal status.

Bedside markers of coronary artery patency and short-term prognosis of patients with acute myocardial infarction and thrombolysis

BACKGROUND In this study we have evaluated the prognostic power of noninvasive markers of coronary artery reperfusion in patients with acute myocardial infarction who were treated with intravenous streptokinase. METHODS In 967 consecutive patients with acute myocardial infarction who were treated within 6 hours of symptoms, we analyzed the prognostic power of resolution of chest pain and ST-segment elevation >50% at 90 minutes, abrupt creatine kinase rise before 12 hours, and T-wave inversion in infarct-related electrocardiographic leads within the first 24 hours after thrombolysis. RESULTS Global in-hospital mortality rate was 12.0%. Each reperfusion marker was associated with improved outcome. Multivariate logistic regression analysis showed that 3 of the 4 markers of coronary artery reperfusion were significantly and independently associated to low in-hospital mortality rate. The presence of early T-wave inversion was associated with the lowest in-hospital mortality rate (odds ratio 0.25, confidence interval 0. 10-0.56). When all markers of coronary artery reperfusion were included in the regression model, T-wave inversion (odds ratio 0.29, confidence interval 0.11-0.68) and abrupt creatine kinase rise (odds ratio 0.36, confidence interval 0.16-0.77) continued to be significantly associated with better outcome. CONCLUSION A systemic analysis of noninvasive markers of coronary artery reperfusion can provide the clinician with an excellent tool to predict clinical outcomes when treating myocardial infarction.

Oxidative stress after reperfusion with primary coronary angioplasty: lack of effect of glucose-insulin-potassium infusion.

Objective To evaluate the oxidative stress status and the modification with glucose-insulin-potassium (GIK) therapy in patients with acute myocardial infarction undergoing primary percutaneous transluminal coronary angioplasty. Design Prospective, randomized, double-blinded, placebo-controlled study. Setting Cardiac intensive care unit at the university hospital. Patients Twenty patients were randomized to GIK solution (30% glucose in water with insulin 50 IU/L, and KCl 40 mM) vs. placebo (normal saline) at 1.5 mL/kg/hr for 24 hrs. The control group was 15 healthy volunteers with no heart disease. Interventions Eligible patients were randomized by a blinded pharmacist, patients with acute myocardial infarction were treated by primary percutaneous transluminal coronary angioplasty and randomized to GIK or placebo (saline solution). Primary angioplasty was successful in nine of ten patients (90%) and ten of ten patients (100%) in the GIK and placebo groups, respectively. Nine (100%) and six (60%) patients from GIK and placebo groups, respectively, underwent stent implantation. Measurements and Main Results We determined plasma levels of lipid peroxidation estimated by the malondialdehyde assay, superoxide dismutase, glutathione peroxidase, and catalase erythrocyte activities at admission and 0.5 and 24 hrs after angioplasty. Baseline determinations were compared with a control group (n = 15). Baseline clinical characteristics and time to treatment (4.5 ± 3.5 hrs) were similar between groups. Angioplasty success rate (Thrombolysis in Myocardial Infarction [TIMI] 3 flow with residual stenosis ≤30%) was 90% and 100% in GIK and placebo groups, respectively. Patients with acute myocardial infarction had an increase of malondialdehyde at baseline (2.9 ± 1.7 vs. 1.1 ± 0.3 &mgr;M, p < .01) and lower enzymatic activities of superoxide dismutase (0.5 ± 0.5 vs. 1.3 ± 0.4 U/mg hemoglobin, p < .01) and catalase (147 ± 73 vs. 198 ± 31 U/g hemoglobin, p < .01). These measurements did not change significantly after angioplasty and no differences were observed between GIK and placebo groups. Conclusion Patients with acute myocardial infarction had increased levels of oxidative stress associated with a reduction in enzymatic antioxidant reserve. Administration of GIK solution did not improve these abnormalities among patients undergoing primary angioplasty.

Relation between oxidative stress, catecholamines, and impaired chronotropic response to exercise in patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

O stress has been implicated in the pathogenesis of chronic heart failure (HF). Different studies have shown that reactive oxygen species are produced in the failing myocardium, causing injury in cardiac myocytes.1–3 Different factors classically associated with cardiomyocyte dysfunction and death in chronic HF, such as increased plasma catecholamine levels, are well-known stimuli for the generation of reactive oxygen species.4 In patients with advanced chronic HF at rest, the circulating norepinephrine concentrations are much higher, generally 2 to 3 times the level found in normal subjects.5,6 During comparable levels of exercise, much greater elevations in circulating norepinephrine occur in patients with chronic HF than in normal subjects. However, despite the increase in norepinephrine with exercise, patients with chronic HF had an attenuated heart rate response to exercise; this finding has been attributed to postsynaptic desensitization of the -adrenergic receptor pathway.7 A relation between cardiac exercise capacity and oxidative stress determined by malondialdehyde (MDA) plasma levels, a marker of lipid peroxidation, has been proposed.8 Experimental data also suggest that hydrogen peroxide may attenuate the -adrenoceptor– linked signal transduction in the heart by changing the functions of Gs proteins and the catalytic subunit of the adenylyl cyclase.9 In the present study we investigated the association between MDA plasma levels, catecholamines at peak exercise, and impaired heart rate response to exercise in patients with chronic HF. • • • We enrolled 27 patients with chronic HF secondary to coronary heart disease (n 15) or idiopathic dilated cardiomyopathy (n 12). They fulfilled the following criteria: (1) chronic stable HF in New York Heart Association functional classes II to IV; (2) ability to complete a symptom-limited treadmill exercise test; (3) evidence of left ventricular (LV) dilation and LV ejection fraction 40% as determined by radionuclide-gated pool scan; and (4) treatment with diuretics, digitalis, and vasodilators. We excluded patients with (1) coronary artery bypass surgery, angioplasty, or myocardial infarction in the last 6 months; (2) chronic angina; (3) uncontrolled hypertension (systolic blood pressure 160 mm Hg or diastolic blood pressure 90 mm Hg); (4) hypertensive myocardiopathy; (5) change in maintenance therapy or use of blockers in the last 2 months; (6) implanted pacemaker; (7) significant valvular disease; and (8) presence of other conditions that affect determination of oxidative stress status, such as renal insufficiency (plasma creatinine 2 mg/dl), autoimmune diseases, neoplasia, advanced liver or pulmonary disease, and acute or chronic inflammation. All patients signed an informed consent approved by our institutional review board and ethics committee. For clinical assessment we used New York Heart Association functional class and the Mahler et al10 clinical score (range 0 to 12 points), which evaluates the severity of dyspnea. The score depends on ratings for 3 different categories: functional impairment, magnitude of task, and magnitude of effort. Dyspnea is rated in 5 degrees from 0 (severe) to 4 (unimpaired) for each category. The ratings for each of the 3 categories are added to form the score. LV end-diastolic and LV end-systolic diameters were determined by Doppler 2-dimensional echocardiography, and LV ejection fraction was determined by radionuclide ventriculography. Each patient performed a 6-minute corridor walk test and a maximal exercise test with gas exchange. Plasma norepinephrine and epinephrine specimens were collected from an indwelling venous line after patients had been in the supine position in a quiet room for 30 minutes. Measurements were repeated at maximal exercise. Determination of catecholamines was performed by high-performance liquid chromatography using a commercial kit (Chromsystems Instruments & Chemicals GmbH, Munchen, Germany). The interand intra-assay coefficients were 6% and 5%, respectively. The ratio of the increment in heart rate divided by the increment in norepinephrine from From the Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile; and the Departments of Biochemistry and Molecular Biology and Chemical Pharmacology and Toxicology, Faculty of Chemical and Pharmaceutical Sciences, Faculty of Medicine and the FONDAP Center for Molecular Studies of the Cell, University of Chile, Santiago, Chile. Dr. Castro was supported in part by Grant FONDECYT 1010992, Santiago; and Dr. Lavandero was supported in part by Grant FONDAP 15010006, Santiago, Chile. Dr. Castro’s address is: Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile, Marcoleta 367, Santiago, Chile. E-mail: pcastro@med.puc.cl. Manuscript received January 23, 2003; revised manuscript received and accepted April 7, 2003.

Safety and Efficacy of the Intravenous Infusion of Umbilical Cord Mesenchymal Stem Cells in Patients With Heart Failure: A Phase 1/2 Randomized Controlled Trial (RIMECARD Trial)

Rationale: Umbilical cord–derived mesenchymal stem cells (UC-MSC) are easily accessible and expanded in vitro, possess distinct properties, and improve myocardial remodeling and function in experimental models of cardiovascular disease. Although bone marrow–derived mesenchymal stem cells have been previously assessed for their therapeutic potential in individuals with heart failure and reduced ejection fraction, no clinical trial has evaluated intravenous infusion of UC-MSCs in these patients. Objective: Evaluate the safety and efficacy of the intravenous infusion of UC-MSC in patients with chronic stable heart failure and reduced ejection fraction. Methods and Results: Patients with heart failure and reduced ejection fraction under optimal medical treatment were randomized to intravenous infusion of allogenic UC-MSCs (Cellistem, Cells for Cells S.A., Santiago, Chile; 1×106 cells/kg) or placebo (n=15 per group). UC-MSCs in vitro, compared with bone marrow–derived mesenchymal stem cells, displayed a 55-fold increase in the expression of hepatocyte growth factor, known to be involved in myogenesis, cell migration, and immunoregulation. UC-MSC–treated patients presented no adverse events related to the cell infusion, and none of the patients tested at 0, 15, and 90 days presented alloantibodies to the UC-MSCs (n=7). Only the UC-MSC–treated group exhibited significant improvements in left ventricular ejection fraction at 3, 6, and 12 months of follow-up assessed both through transthoracic echocardiography (P=0.0167 versus baseline) and cardiac MRI (P=0.025 versus baseline). Echocardiographic left ventricular ejection fraction change from baseline to month 12 differed significantly between groups (+7.07±6.22% versus +1.85±5.60%; P=0.028). In addition, at all follow-up time points, UC-MSC–treated patients displayed improvements of New York Heart Association functional class (P=0.0167 versus baseline) and Minnesota Living with Heart Failure Questionnaire (P<0.05 versus baseline). At study completion, groups did not differ in mortality, heart failure admissions, arrhythmias, or incident malignancy. Conclusions: Intravenous infusion of UC-MSC was safe in this group of patients with stable heart failure and reduced ejection fraction under optimal medical treatment. Improvements in left ventricular function, functional status, and quality of life were observed in patients treated with UC-MSCs. Clinical Trial Registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT01739777. Unique identifier: NCT01739777

Effects of glucose-insulin-potassium solution on myocardial salvage and left ventricular function after primary angioplasty.

ObjectiveTo evaluate the effects of glucose-insulin-potassium (GIK) therapy on infarct size and left ventricular function when used as an adjuvant therapy to primary angioplasty. DesignProspective, randomized, double-blind, placebo-controlled study. SettingCardiac intensive care unit at a university hospital. PatientsThirty-seven patients with acute myocardial infarction for whom primary angioplasty was indicated. InterventionsEligible patients were randomized by a blinded pharmacist to GIK solution (30% glucose in water with insulin 50 U/L, and KCl 40 mM/L) vs. placebo at 1.5 mL/kg/hr for 24 hrs. Measurements and Main ResultsTc 99m sestamibi myocardial scintigraphy was performed at admission and at 3 months. Primary end points were the changes in left ventricular ejection fraction (LVEF) and the size of salvaged myocardium. Baseline clinical characteristics were similar in both groups. At the 3-month follow-up, a significant overall decrease in infarct size (37 ± 16% vs. 12 ± 10%, p < .005) and an increase in LVEF (34 ± 13% vs. 49 ± 9%, p = .005) were observed. Patients randomized to GIK solution experienced a significant increase in their LVEF at 3 months (39 ± 12 to 51 ± 13, p = .002). Patients who received placebo had no significant differences between baseline and 3-month measurements (44 ± 13 vs. 49 ± 14, p = NS). There was a trend toward an increase in myocardial salvage in the GIK group, which did not reach statistical significance. When patients from both groups were compared directly, differences in LVEF improvement were no longer significant. ConclusionsGIK solution did not improve LVEF or decrease the infarct size among patients undergoing primary angioplasty.

Effects of early decrease in oxidative stress after medical therapy in patients with class IV congestive heart failure

I t has been reported that patients with congestive heart failure (CHF) have increased breath pentane content, conjugated diene levels, and plasma malondialdehyde (MDA) levels, an indirect marker of lipid peroxidation. Ghatak et al found that patients with chronic CHF had increased MDA and superoxide levels, which correlated with the severity of the CHF. Low glutathione levels and superoxide dismutase (SOD) activity have also been reported. There have been no studies in human refractory CHF to evaluate the impact of acute intensive medical therapy on oxidative stress status and antioxidant enzyme activity. We determined the plasma levels of MDA, SOD, catalase (CAT), and glutathione peroxidase (GSH-Px) activities before and after therapeutic intervention in patients with chronic advanced CHF and refractory symptoms (New York Heart Association functional class IV). • • • We enrolled 15 patients admitted to our Coronary Care Unit with the diagnosis of refractory CHF. All patients signed an informed consent approved by our Institutional Review Board and Ethical Committee. Inclusion criteria were: (1) persistence of pulmonary congestion, edema, or worsening of renal function despite optimal treatment with diuretics, digitalis, and vasodilators; (2) evidence of left ventricular dilation and systolic dysfunction as determined by echocardiography, with a left ventricular ejection fraction From the Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile; and the Departments of Chemical Pharmacology and Toxicology; and Biochemistry and Molecular Biology, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile. Dr. Castro was supported by grants 1990491 and 1010992 from the Fondo Nacional de Ciencia y Tecnologia, FONDECYT, Santiago, Chile, and Dr. Diaz-Araya was supported by grant PT2000-01 from the Faculty of Chemical and Pharmaceutical Science, University of Chile, Santiago, Chile. Dr. Castro’s address is: Department of Cardiovascular Diseases, Faculty of Medicine, P. Catholic University of Chile, Marcoleta 367, Santiago, Chile. E-mail: pcastro@med.puc.cl.

Incidencia y letalidad por infarto agudo del miocardio en Chile: 2001-2007

Acute myocardial infarction (AMI) causes 73.6% of coronary heart disease (CHD) deaths in Chile. Aim: To estimate the incidence and case fatality of AMI and analyze their trends between 2001-2007. Material and Methods: A time–series study analyzing all cases of AMI (according to the International Classification of Diseases (ICD)-10, I21 code), registered in the National Hospitalizations and Death databases. Annual incidence rates and case fatality by sex and age groups were calculated. The direct method was used to standardize rates by age, using the World Health Organization 2000 Population. Prais-Winsten regression models were used to evaluate trends, expressed as relative change. Results: Between 2001 and 2007, we estimated that 83,754 cases of AMI occurred. Standardized annual incidence rate was 74.4 per 100,000 inhabitants (98.0 in men and 51.0 in women). Incidence rates increased by 34% in individuals < 45 years of age and 9.2% in the group 55-64 years (p < 0.001, both). Total case fatality was 49.5% (45.4% in men and 57.2% in women; p < 0.001), and its trend analysis showed a significant annual reduction of 1.2% in men and 0.81% in women. In-hospital case fatality was 14.2% (11.3 and 20.4% in men and women, respectively; p < 0.001). There was a significant annual reduction of mortality (0.57 and 1.01% in men and women, respectively (p < 0.05). Conclusions: The incidence of AMI was stable in the whole population, but increased in younger age groups. Total and in-hospital case-fatality decreased. Despite the greater reduction of case fatality in women, they still have a higher risk of dying while in hospital

Mortalidad por cardiopatía isquémica en Chile: quiénes, cuántos y dónde

OBJETIVO: Describir las caracteristicas de la mortalidad por cardiopatia isquemica en Chile y su evolucion temporal, e identificar los factores asociados a mortalidad extrahospitalaria por esta patologia entre 1997 y 2007. METODOS. Estudio de serie temporal que utiliza las bases de defunciones del Departamento de Estadisticas e Informacion en Salud entre 1997 y 2007. De un total de 917 029 muertes notificadas, se seleccionaron aquellas cuya causa primaria fue cardiopatia isquemica (codigos I20 a I25 de la CIE-10). Se calcularon tasas crudas y ajustadas por edad y sexo para analizar la tendencia. Se analizaron las caracteristicas de la mortalidad segun el lugar de defuncion, evaluando posibles factores asociados a mortalidad extrahospitalaria (casa/habitacion u otro lugar), incluidos edad, ruralidad, estado civil, educacion y sexo, asi como el efecto de la incorporacion del infarto agudo al miocardio a la ley de garantias en salud (GES), con regresion binomial. RESULTADOS: Durante el periodo estudiado se notificaron 87 342 muertes por cardiopatia isquemica, de las cuales 57,7% eran hombres y 59,5% ocurrieron fuera del hospital. La tasa de mortalidad ajustada por edad disminuyo de 52,9 a 40,4 por 100 000 habitantes. Los factores asociados a mortalidad extrahospitalaria en hombres fueron ruralidad, riesgo relativo (RR) 1,24 (1,21-1,27); edad mayor a 70 anos, RR 1,03 (1,01-1,05); estado civil soltero, RR 1,10 (1,08-1,12), mientras que en las mujeres los valores correspondientes fueron 1,13 (1,10-1,18); 1,31 (1,27-1,36) y 1,07 (1,04-1,09). La adopcion de la GES se asocio con un aumento en el porcentaje de muertes intrahospitalarias en mujeres, RR 0,95 (0,92-0,97). CONCLUSIONES: †La mortalidad por cardiopatia isquemica en Chile ha disminuido. El mayor porcentaje de las muertes ocurren fuera de hospitales o clinicas. Los factores asociados a mortalidad extrahospitalaria en ambos sexos fueron edad avanzada, estado civil soltero y ruralidad.

Efecto del nivel educacional en la sobrevida posterior a un infarto agudo de miocardio: Registro Chileno de Infarto de Miocardio, GEMI 2009-2012

Background: Socioeconomic status is associated with cardiovascular mortality. Aim: To evaluate the effect of educational level, on the prognosis of patients with acute myocardial infarction in Chile. Material and methods: Cohort study of 3636 patients aged 63.1±13.2 years, 27% women, hospitalized in 16 centers participating in the Chilean Myocardial Infarction Registry (GEMI) between 2009 and 2012. Vital status was obtained from the National Mortality Database. Patients were divided, according to educational level, in four groups, namely none (no formal education), basic ( 12years). Crude and adjusted (age, sex, cardiovascular risk factors and treatments) hazard ratios (HR) were estimated using Cox regression models. Results: The distribution by educational level was 3.2% none, 31.8% basic, 43.0% secondary and 22.0% tertiary. During a median follow-up period of 22 months (interquartile range 11-37 years), 631 patients died (17.3%), of whom 198 died during hospitalization (5.5%). The 30 day case-fatality rate according to educational level was 3.4% in tertiary, 4.7% in secondary, 11.9% in basic, 19.1% in none (p< 0.0001). Among patients surviving the first 30 days, the case-fatality rate was 4.4%, 8.6%, 14.6% and 27.0%, respectively (p<0.0001). The increased risk of death for groups with lower education compared with individuals with tertiary education, persisted in the multivariate analysis with a hazard ratio for secondary education 1.58 ( 95% confidence intervals (CI), 1.18-2.10); for basic education 1.90 (95% CI, 1.41-2.47) and for none 3.50 (95% CI, 2.35-5.21). Conclusions: A lower educational level was associated with a worse prognosis in patients with myocardial infarction, even after controlling for potential confounding factors.