Luis E. Rohde

Heart failure: preventing disease and death worldwide

Heart failure is a life‐threatening disease and addressing it should be considered a global health priority. At present, approximately 26 million people worldwide are living with heart failure. The outlook for such patients is poor, with survival rates worse than those for bowel, breast or prostate cancer. Furthermore, heart failure places great stresses on patients, caregivers and healthcare systems. Demands on healthcare services, in particular, are predicted to increase dramatically over the next decade as patient numbers rise owing to ageing populations, detrimental lifestyle changes and improved survival of those who go on to develop heart failure as the final stage of another disease. It is time to ease the strain on healthcare systems through clear policy initiatives that prioritize heart failure prevention and champion equity of care for all.

Echocardiography-based left ventricular mass estimation. How should we define hypertrophy?

Left ventricular hypertrophy is an important risk factor in cardiovascular disease and echocardiography has been widely used for diagnosis. Although an adequate methodologic standardization exists currently, differences in measurement and interpreting data is present in most of the older clinical studies. Variability in border limits criteria, left ventricular mass formulas, body size indexing and other adjustments affects the comparability among these studies and may influence both the clinical and epidemiologic use of echocardiography in the investigation of the left ventricular structure. We are going to review the most common measures that have been employed in left ventricular hypertrophy evaluation in the light of some recent population based echocardiographic studies, intending to show that echocardiography will remain a relatively inexpensive and accurate tool diagnostic tool.

Effects of 5′-Phosphodiesterase Four-Week Long Inhibition With Sildenafil in Patients With Chronic Heart Failure: A Double-Blind, Placebo-Controlled Clinical Trial

BACKGROUNDnThe effects of chronic inhibition of 5-phosphodiesterase with sildenafil on functional capacity, ventilatory efficiency, oxygen uptake, pulmonary hypertension, and endothelial function in chronic heart failure (CHF) are unknown.nnnMETHODSnWe conducted a randomized, double-blind, placebo-controlled trial to assess the acute (1 hour after 50 mg by mouth) and chronic (4 weeks after 50 mg 3 times per day by mouth) effects of sildenafil in outpatients with CHF. The outcomes were cardiopulmonary exercise test parameters (chronic effect), echocardiographic-derived pulmonary artery systolic pressure, and plethysmography-derived forearm blood flow (acute and chronic effects).nnnRESULTSnNineteen patients with CHF (48 +/- 12 years) with an ejection fraction of 28% +/- 6% were studied. Patients who received sildenafil (n = 11) showed improved maximal oxygen uptake, ventilatory efficiency, and oxygen uptake kinetics. Sildenafil decreased pulmonary artery systolic pressure levels at 60 minutes and at 4 weeks compared with changes after placebo (P = .004 for group and time interaction). Improvement in ventilatory efficiency was positively associated with reductions in pulmonary artery systolic pressure. Patients allocated to placebo demonstrated a trend toward decreased forearm blood flow after reactive hyperemia, whereas this remained unchanged in patients allocated to sildenafil.nnnCONCLUSIONSnSildenafil administration for 4 weeks in stable outpatients with CHF improves functional capacity, ventilatory efficiency, oxygen uptake kinetics, and pulmonary hypertension. These effects may be mediated in part by improvements in endothelial function.

IRON-HF study: A randomized trial to assess the effects of iron in heart failure patients with anemia

BACKGROUNDnAnemia in heart failure patients and has been associated with increased morbi-mortality. Previous studies have treated anemia in heart failure patients with either erythropoietin alone or combination of erythropoietin and intravenous (i.v.) iron. However, the effect of i.v. or oral (p.o.) iron supplementation alone in heart failure patients with anemia was virtually unknown.nnnAIMnTo compare, in a double-blind design, the effects of i.v. iron versus p.o. iron in anemic heart failure patients.nnnMETHODSnIRON-HF study was a multicenter, investigator initiated, randomized, double-blind, placebo controlled trial that enrolled anemic heart failure patients with preserved renal function, low transferrin saturation (TSat) and low-to-moderately elevated ferritin levels. Interventions were Iron Sucrose i.v. 200 mg, once a week, for 5 weeks, ferrous sulfate 200 mg p.o. TID, for 8 weeks, or placebo. Primary endpoint was variation of peak oxygen consumption (peak VO2) assessed by ergospirometry over 3 month follow-up.nnnRESULTSnEighteen patients had full follow-up data. There was an increment of 3.5 ml/kg/min in peak VO2 in the i.v. iron group. There was no increment in peak VO2 in the p.o. iron group. Patients ferritin and TSat increased significantly in both treated groups. Hemoglobin increased similarly in all groups.nnnCONCLUSIONnI.v. iron seems to be superior in improving functional capacity of heart failure patients. However, correction of anemia seems to be at least similar between p.o. iron and i.v. iron supplementation.

Impact of β1-Adrenergic Receptor Polymorphisms on Susceptibility to Heart Failure, Arrhythmogenesis, Prognosis, and Response to Beta-Blocker Therapy

Beta1-adrenergic receptor polymorphisms have been implicated with inconsistent results in the pathogenesis, clinical presentation, and prognosis of patients with heart failure (HF). The impact of 2 functional polymorphisms (beta1-Arg389Gly and beta1-Ser49Gly) on HF susceptibility, arrhythmogenesis, and prognosis was evaluated in Brazilian outpatients. Genotyping at codons 389 and 49 was performed using polymerase chain reaction with restriction fragment length polymorphism analysis in 201 outpatients with systolic HF and 141 apparently healthy controls. Enrolled patients were followed up at the HF clinic, and vital status was evaluated using electronic hospital records, telephone contact, and a local death certificate database. Allele frequencies were similar between patients with HF and controls, with neither polymorphism related to HF susceptibility. The beta1-389Gly homozygotes had significantly less nonsustained ventricular tachycardia on Holter monitoring (17% vs 48% for Arg/Arg patients; p = 0.015) and improved HF-related survival, with no events after a median follow-up of 40 months (log-rank statistics = 0.025). The negative impact of beta1-389Arg allele on HF-related survival was substantially reduced using high-dose beta-blocker therapy (80% survival for high-dose vs 42% for low-dose beta blockers or nonusers; log-rank statistics = 0.0003). The beta1-Ser49Gly polymorphism was not associated with nonsustained ventricular tachycardia or HF prognosis. In conclusion, beta1-Arg389Gly and beta1-Ser49Gly polymorphisms had no influence on HF susceptibility. However, the Gly389 allele was associated with a lower prevalence of ventricular arrhythmias and better HF-related survival. A pharmacogenetic interaction is suggested because beta blockers were more effective in beta1-389Arg allele carriers.

Improved Oral Anticoagulation After a Dietary Vitamin K–Guided Strategy. A Randomized Controlled Trial

Background— Dietary vitamin K is thought to be an important factor that interferes with anticoagulation stability, but the clinical applicability of this interaction has not been evaluated adequately in prospective studies. Methods and Results— In a randomized controlled trial that enrolled outpatients with a recent international normalized ratio (INR) outside the therapeutic target, we compared 2 strategies to optimize long-term oral anticoagulation: (1) a conventional approach based on changes in anticoagulant prescription and (2) a dietary vitamin K–guided strategy based on simple modifications of the amount of vitamin K–rich foods ingested per week. The primary efficacy end point was the percentage of patients who achieved a prespecified INR target at 90 days after randomization. Study population (n=132) predominantly included men with mechanical heart prostheses (58%) or atrial fibrillation (35%). Over time, patients allocated to the vitamin K–guided strategy reached the prespecified INR more frequently so that after 90 days of follow-up, 74% were on target compared with 58% of patients managed conventionally (P=0.04). Patients allocated to the dietary vitamin K–guided strategy had the same magnitude and direction of INR variation as those observed with the conventional approach in the short term (15 days) for both underanticaogulated and overanticoagulated patients. Minor bleeding or use of parenteral vitamin K were also marginally less frequent in patients managed according to the dietary intervention (1 [1.5%] versus 7 [11%]; P=0.06). Conclusions— A vitamin K–guided management strategy to adjust long-term oral anticoagulation is feasible and safe and may result in an increased chance of reaching target levels of INR.

Influence of genetic, biological and pharmacological factors on warfarin dose in a Southern Brazilian population of European ancestry.

AIMSnTo investigate the influence of polymorphisms in CYP2C9, VKORC1, CYP4F2 and F2 genes on warfarin dose-response and develop a model including genetic and non-genetic factors for warfarin dose prediction needed for each patient.nnnMETHODSnA total of 279 patients of European ancestry on warfarin medication were investigated. Genotypes for -1639G>A, 1173C>T, and 3730G>A SNPs in the VKORC1 gene, CYP2C9*2 and CYP2C9*3, 1347C>T in the CYP4F2 gene and 494C>T in the F2 gene were determined by allelic discrimination with Taqman 5-nuclease assays.nnnRESULTSnThe CYP2C9*2 and CYP2C9*3 polymorphisms in the CYP2C9 gene, -1639G>A and 1173C>T in the VKORC1 gene and 494C>T in the F2 gene are responsible for lower anticoagulant doses. In contrast, 1347C>T in the CYP4F2 gene and 3730G>A in the VKORC1 gene are responsible for higher doses of warfarin. An algorithm including genetic, biological and pharmacological factors that explains 63.3% of warfarin dose variation was developed.nnnCONCLUSIONnThe model suggested has one of the highest coefficients of determination among those described in the literature.

Bone marrow derived cells decrease inflammation but not oxidative stress in an experimental model of acute myocardial infarction

AIMSnBone marrow cell (BMC) therapy is thought to exert beneficial effects on the infarcted heart. We assessed cardiac function and its correlation with redox status and inflammation in cardiac tissue early post-AMI in rats treated with BMC.nnnMAIN METHODSnMale Wistar rats (8-week-old) were randomized into four groups: Sham-operated (S); AMI; S+treatment (ST) and AMI+treatment (AMIT). Therapy with BMC was carried out immediately post-experimental left anterior coronary artery ligation induced-AMI, and assessments made 48h later. Cardiac function and morphometrics were evaluated by echocardiographyc parameters in vivo. Cardiac tissue tumor necrosis factor (TNF)-α and interleukin (IL)-6 were measured by Western Blot. Oxidative stress parameters including reduced (GSH) and oxidized (GSSG) glutathione ratio, hydrogen peroxide level, lipid and protein oxidation, superoxide dismutase, catalase and glutathione peroxidase activities were measured spectrophotometrically.nnnKEY FINDINGSnEjection fraction was lower in infarcted groups and did not improve in BMC-treated animals: AMI (51±5%) vs. S (74±7%) and AMIT (56±10%) vs. ST groups (73±3%). Both TNF-α and IL-6 myocardial expression increased post-AMI and were reduced following BMC therapy. Nonetheless, there was a decrease in GSH/GSSG ratio in infarcted groups which was greater in BMC-treated groups: AMI (8.21±3.8) vs. S (14.61±3.4) and AMIT (2.1±0.7) vs. ST (4.7±1.5).nnnSIGNIFICANCEnThe data suggest that BMC promoted a redox status favorable to the oxidation of the pro-inflammatory cytokines in the myocardium, exerting an anti-inflammatory-like effect.

Endothelial Dysfunction Is Related to Poor Glycemic Control in Adolescents with Type 1 Diabetes under 5 Years of Disease: Evidence of Metabolic Memory

CONTEXTnThe relation between endothelial dysfunction (ED), glycemic control, and early type I diabetes mellitus (T1DM) is unclear.nnnOBJECTIVEnThe objective of the study was to evaluate the association of ED, glycemic control, and the duration of diabetes in T1DM.nnnDESIGNnThis was a cross-sectional study.nnnSETTINGnThe study was conducted at a public outpatient clinic.nnnPATIENTSnFifty-seven T1DM adolescents and 10 healthy age-matched controls participated in the study.nnnINTERVENTIONnThere were no interventions.nnnMETHODS AND OUTCOME MEASURESnEndothelial function (ED) was evaluated by flow-mediated dilation (FMD) in the brachial artery after reactive hyperemia. Biochemical data, including HbA1c (glycohemoglobin), high-sensitivity C-reactive protein, lipids, and urinary albumin excretion were collected. Means of four HbA1c values collected at 3-month intervals in the first and second year before FMD analyses were obtained.nnnRESULTSnMean FMD was decreased in T1DM compared with controls (P = 0.023), independent of age, smoking, hypertension, or dyslipidemia. Twenty-eight of 57 T1DM patients enrolled (49%) had ED. FMD was decreased in microalbuminuric (4.1%) compared with normoalbuminuric patients (10.1%, P = 0.01) and controls (14.6%, P < 0.001). FMD correlated inversely with mean second-year HbA1c (r = -0.426, P = 0.02), particularly in patients with less than 5 yr of T1DM (r = -0.61, P = 0.004). In these patients, high-sensitivity C-reactive protein was strongly correlated with mean first-year HbA1c (r = -0.66, P = 0.0003). In patients with more than 5 yr of T1DM, we found no significant correlations between ED and glycemic control.nnnCONCLUSIONSnEndothelial dysfunction is common in T1DM adolescents with less than 5 yr of disease. It is associated with duration of disease, microalbuminuria, and mean second-year HbA1c but not with mean first-year HbA1c. These data support the metabolic memory hypothesis.

Transcoronary gradient of plasma microRNA 423-5p in heart failure: evidence of altered myocardial expression

Abstract Context: Elevated plasmatic microRNAs (miRs) are observed in heart failure (HF). However, the cardiac origin of these miRs remains unclear. Objective: We calculated transcoronary gradients of miR-29b, miR-133a and miR-423-5p in 17 outpatients with stable systolic HF and in controls without structural cardiac disease. Materials and methods: MicroRNAs were measured by quantitative real-time polymerase chain reaction. Results: Positive transcoronary miR gradients were observed in patients with HF but not in controls (pu2009=u20090.03). B-type natriuretic peptide (BNP) moderately correlated with the transcoronary gradients of miR-133a and miR-423-5p. Discussion and conclusions: The difference in transcoronary gradients between HF outpatients and controls suggests that miR-423-5p has a cardiac origin. The positive correlation between miR-423-5p and BNP transcoronary gradients supports this hypothesis.