Pharmacological heart rate lowering in patients with a preserved ejection fraction-review of a failing concept.

Epidemiological studies have demonstrated that high resting heart rates are associated with increased mortality. Clinical studies in patients with heart failure and reduced ejection fraction have shown that heart rate lowering with beta-blockers and ivabradine improves survival. It is therefore often assumed that heart rate lowering is beneficial in other patients as well. Here, we critically appraise the effects of pharmacological heart rate lowering in patients with both normal and reduced ejection fraction with an emphasis on the effects of pharmacological heart rate lowering in hypertension and heart failure. Emerging evidence from recent clinical trials and meta-analyses suggest that pharmacological heart rate lowering is not beneficial in patients with a normal or preserved ejection fraction. This has just begun to be reflected in some but not all guideline recommendations. The detrimental effects of pharmacological heart rate lowering are due to an increase in central blood pressures, higher left ventricular systolic and diastolic pressures, and increased ventricular wall stress. Therefore, we propose that heart rate lowering per se reproduces the hemodynamic effects of diastolic dysfunction and imposes an increased arterial load on the left ventricle, which combine to increase the risk of heart failure and atrial fibrillation. Pharmacologic heart rate lowering is clearly beneficial in patients with a dilated cardiomyopathy but not in patients with normal chamber dimensions and normal systolic function. These conflicting effects can be explained based on a model that considers the hemodynamic and ventricular structural effects of heart rate changes.

Oxygen Uptake and Lactate Kinetics in Patients with Chronic Obstructive Pulmonary Disease during Heavy Intensity Exercise: Role of Pedaling Cadence.

Oxygen uptake slow component ([Formula: see text]sc) is associated with lactate accumulation, likely a contribution of poorly oxidative muscle fibers. We aimed to test the hypothesis that higher muscle tension during slow pedaling rates would yield more prominent [Formula: see text]sc in healthy subjects, but not in COPD patients. Eight severe COPD patients and 8 age-matched healthy individuals performed 4 rest-heavy exercise transitions at 40 and 80 RPM. Work rates at the two cadences were balanced. Venous blood was sampled for measurement of lactate concentration at rest and every 2 minutes until the end of exercise. [Formula: see text] kinetics were analyzed utilizing nonlinear regression. [Formula: see text] phase II amplitudes at the two cadences were similar in both groups. In healthy individuals, [Formula: see text]sc was steeper at 40 than 80 RPM (46.6 ± 12.0 vs. 29.5 ± 11.7 mL/min2, p = 0.002) but not in COPD patients (16.2 ± 14.7 vs. 13.3 ± 7.6 mL/min2). End-exercise lactate concentration did not differ between cadences in either group. In healthy individuals, greater slow-cadence [Formula: see text]sc seems likely related to oxidative muscle fiber recruitment at higher muscular tension. COPD patients, known to have fast-twitch fiber predominance, might be unable to recruit oxidative fibers at high muscle tension, blunting [Formula: see text]sc response.

Brugada phenocopy in concomitant ethanol and heroin overdose.

Brugada phenocopy describes conditions with Brugada-like ECG pattern but without true congenital Brugada syndrome. We report a case of 44-year-old man with no known medical history who presented with loss of consciousness. Toxicology screening was positive for opiates and high serum alcohol level. His initial ECG showed Brugada type 1 pattern which resolved after several hours of observation and treatment with continuous naloxone infusion. Patient regained his consciousness and disclosed heroin abuse and drinking alcohol. This case highlights the heroin overdose as a possible cause of Brugada phenocopy.

Sinusoidal high-intensity exercise does not elicit ventilatory limitation in chronic obstructive pulmonary disease.

During exercise at critical power (CP) in chronic obstructive pulmonary disease (COPD) patients, ventilation approaches its maximum. As a result of the slow ventilatory dynamics in COPD, ventilatory limitation during supramaximal exercise might be escaped using rapid sinusoidal forcing. Nine COPD patients [age, 60.2 ± 6.9 years; forced expiratory volume in the first second (FEV(1)), 42 ± 17% of predicted; and FEV(1)/FVC, 39 ± 12%] underwent an incremental cycle ergometer test and then four constant work rate cycle ergometer tests; tolerable duration (t(lim)) was recorded. Critical power was determined from constant work rate testing by linear regression of work rate versus 1/t(lim). Patients then completed fast (FS; 60 s period) and slow (SS; 360 s period) sinusoidally fluctuating exercise tests with mean work rate at CP and peak at 120% of peak incremental test work rate, and one additional test at CP; each for a 20 min target. The value of t(lim) did not differ between CP (19.8 ± 0.6 min) and FS (19.0 ± 2.5 min), but was shorter in SS (13.2 ± 4.2 min; P < 0.05). The sinusoidal ventilatory amplitude was minimal (37.4 ± 34.9 ml min(-1) W(-1)) during FS but much larger during SS (189.6 ± 120.4 ml min(-1) W(-1)). The total ventilatory response in SS reached 110 ± 8.0% of the incremental test peak, suggesting ventilatory limitation. Slow components in ventilation during constant work rate and FS exercises were detected in most subjects and contributed appreciably to the total response asymptote. The SS exercise was associated with higher mid-exercise lactate concentrations (5.2 ± 1.7, 7.6 ± 1.7 and 4.5 ± 1.3 mmol l(-1) in FS, SS and CP). Large-amplitude, rapid sinusoidal fluctuation in work rate yields little fluctuation in ventilation despite reaching 120% of the incremental test peak work rate. This high-intensity exercise strategy might be suitable for programmes of rehabilitative exercise training in COPD.

Dietary sodium and clinical outcome in hemodialysis: where do we stand and what is next?

The association of dietary sodium and outcome is widely studied in the general population, but less is known in hemodialysis patients. The evidence supporting daily dietary sodium intake of 2 g on hemodialysis is not strong. Mc Causland et al. found that higher dietary sodium intake was marginally associated with a higher ultrafiltration requirement and mortality, but not with blood pressure. Well-designed clinical trials are needed to examine the association of dietary sodium modification and outcomes in hemodialysis patients.

Conceptualization of category-oriented likelihood ratio: a useful tool for clinical diagnostic reasoning.

BACKGROUND: In the diagnostic reasoning process medical students and novice physicians need to be made aware of the diagnostic values of the clinical findings (including history, signs, and symptoms) to make an appropriate diagnostic decision. Diagnostic reasoning has been understood in light of two paradigms on clinical reasoning: problem solving and decision making. They advocate the reasoning strategies used by expert physicians and the statistical models of reasoning, respectively. Evidence-based medicine (EBM) applies decision theory to the clinical diagnosis, which can be a challenging topic in medical education.This theoretical article tries to compare evidence-based diagnosis with expert-based strategies in clinical diagnosis and also defines a novel concept of category-oriented likelihood ratio (LR) to propose a new model combining both aforementioned methods. DISCUSSION: Evidence-based medicine advocates the use of quantitative evidence to estimate the probability of diseases more accurately and objectively; however, the published evidence for a given diagnosis cannot practically be utilized in primary care, especially if the patient is complaining of a nonspecific problem such as abdominal pain that could have a long list of differential diagnoses. In this case, expert physicians examine the key clinical findings that could differentiate between broader categories of diseases such as organic and non-organic disease categories to shorten the list of differential diagnoses. To approach nonspecific problems, not only do the experts revise the probability estimate of specific diseases, but also they revise the probability estimate of the categories of diseases by using the available clinical findings. SUMMARY: To make this approach analytical and objective, we need to know how much more likely it is for a key clinical finding to be present in patients with one of the diseases of a specific category versus those with a disease not included in that category. In this paper, we call this value category-oriented LR.

Heart Rate-Induced Myocardial Ca2+ Retention and Left Ventricular Volume Loss in Patients With Heart Failure With Preserved Ejection Fraction.

Background Increases in heart rate are thought to result in incomplete left ventricular (LV) relaxation and elevated filling pressures in patients with heart failure with preserved ejection fraction (HFpEF). Experimental studies in isolated human myocardium have suggested that incomplete relaxation is a result of cellular Ca2+ overload caused by increased myocardial Na+ levels. We tested these heart rate paradigms in patients with HFpEF and referent controls without hypertension. Methods and Results In 22 fully sedated and instrumented patients (12 controls and 10 patients with HFpEF) in sinus rhythm with a preserved ejection fraction (≥50%) we assessed left-sided filling pressures and volumes in sinus rhythm and with atrial pacing (95 beats per minute and 125 beats per minute) before atrial fibrillation ablation. Coronary sinus blood samples and flow measurements were also obtained. Seven women and 15 men were studied (aged 59±10 years, ejection fraction 61%±4%). Patients with HFpEF had a history of hypertension, dyspnea on exertion, concentric LV remodeling and a dilated left atrium, whereas controls did not. Pacing at 125 beats per minute lowered the mean LV end-diastolic pressure in both groups (controls -4.3±4.1 mm Hg versus patients with HFpEF -8.5±6.0 mm Hg, P=0.08). Pacing also reduced LV end-diastolic volumes. The volume loss was about twice as much in the HFpEF group (controls -15%±14% versus patients with HFpEF -32%±11%, P=0.009). Coronary venous [Ca2+] increased after pacing at 125 beats per minute in patients with HFpEF but not in controls. [Na+] did not change. Conclusions Higher resting heart rates are associated with lower filling pressures in patients with and without HFpEF. Incomplete relaxation and LV filling at high heart rates lead to a reduction in LV volumes that is more pronounced in patients with HFpEF and may be associated with myocardial Ca2+ retention.

Association of soluble endotoxin receptor CD14 and mortality among patients undergoing hemodialysis.

BACKGROUND: CD14 is a key molecule in innate immunity that mediates cell activation and signaling in response to endotoxin and other bacterial wall-derived components. CD14 protein exists in soluble (sCD14) and membrane-bound forms. The correlates of sCD14 in persons undergoing long-term hemodialysis (HD) therapy are not known. We hypothesized that increased sCD14 levels in HD patients are associated with proinflammatory cytokine activation and increased mortality. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 310 long-term HD patients who participated in the Nutritional and Inflammatory Evaluation in Dialysis (NIED) Study, a cohort derived from a pool of more than 3,000 HD outpatients during 5 years in 8 DaVita maintenance dialysis facilities in the South Bay Los Angeles, CA, area. PREDICTORS: sCD14 levels in serum. OUTCOMES: 33-month mortality. RESULTS: Mean sCD14 level was 7.24 +/- 2.45 microg/mL. Tumor necrosis factor alpha level was the strongest correlate of sCD14 level (r = +0.24; P < 0.001), followed by interleukin 6 level (r = +0.18; P = 0.002), serum ferritin level (r = +0.21; P < 0.001), total iron-binding capacity (r = -0.19; P < 0.001), body mass index (r = -0.15; P = 0.008), vintage (r = +0.14; P = 0.01), low-density lipoprotein cholesterol level (r = +0.13; P = 0.03), and body fat (r = -0.11; P = 0.06). During the 33-month follow-up, 71 (23%) patients died. Multivariable Cox proportional analysis adjusted for case-mix and other nutritional and inflammatory confounders, including serum tumor necrosis factor alpha, C-reactive protein, and interleukin 6 levels, showed that compared with the lowest sCD14 tertile, sCD14 levels in the third tertile (>7.8 microg/mL) were associated with greater death risk (hazard ratio, 1.94; 95% confidence interval, 1.01 to 3.75; P = 0.04). LIMITATIONS: Survivor bias in combined incident/prevalent studies. CONCLUSIONS: Increased sCD14 level is related positively to markers of inflammation and negatively to nutritional status and is an independent predictor of mortality in long-term HD patients. Additional studies are needed to examine the usefulness of sCD14 level in risk stratification and the clinical decision-making process in HD patients.

Association of Malnutrition-Inflammation Score with quality of life and mortality in hemodialysis patients: a 5-year prospective cohort study.

BACKGROUND: The Malnutrition-Inflammation Score (MIS), an inexpensive and easy-to-assess score of 0 to 30 to examine protein-energy wasting (PEW) and inflammation, includes 7 components of the Subjective Global Assessment, body mass index, and serum albumin and transferrin concentrations. We hypothesized that MIS risk stratification of hemodialysis (HD) patients in predicting outcomes is better than its components or laboratory markers of inflammation. STUDY DESIGN: 5-Year cohort study. SETTING & PARTICIPANTS: We examined 809 stable HD outpatients and followed them for up to 5 years (October 2001 to December 2006). PREDICTORS: MIS and other nutritional and inflammatory markers. OUTCOMES & MEASUREMENTS: Prospective all-cause mortality, health-related quality of life using the 36-Item Short Form Health Survey (SF-36), and tests of body composition. RESULTS: The MIS correlated with logarithm of serum interleukin 6 level (r = +0.26; P < 0.001), logarithm of C-reactive protein level (r = +0.16; P < 0.001), and several measures of nutritional status. Patients with a higher MIS had lower SF-36 scores. After multivariate adjustment for case-mix and other measures of PEW, HD patients in the second (3 to 4), third (5 to 7), and fourth (>or=8) quartiles of MIS had worse survival rates than those in the first (0 to 2) quartile (P < 0.001). Each 2-unit increase in MIS was associated with a 2-fold greater death risk, ie, adjusted death hazard ratio of 2.03 (95% confidence interval, 1.76 to 2.33; P < 0.001). Cubic spline survival models confirmed linear trends. Adding MIS to the constellation of age, sex, race/ethnicity, and vintage significantly improved the area under the receiver operating characteristic curve developed for predicting mortality (0.71 versus 0.67; P < 0.001). LIMITATIONS: Selection bias and unknown confounders. CONCLUSIONS: In HD patients, the MIS is associated with inflammation, nutritional status, quality of life, and 5-year prospective mortality. The mortality predictability of the MIS appears equal to serum interleukin 6 and somewhat greater than C-reactive protein levels. Controlled trials are warranted to examine whether interventions to improve the MIS can also improve clinical outcomes in HD patients.

Association of serum total iron-binding capacity and its changes over time with nutritional and clinical outcomes in hemodialysis patients.

Serum transferrin, estimated by total iron-binding capacity (TIBC), may be a marker of protein-energy wasting (PEW) in maintenance hemodialysis (MHD) patients. We hypothesized that low TIBC or its fall over time is associated with poor clinical outcomes. In 807 MHD patients in a prospective 5-year cohort, associations of TIBC and its changes over time with outcomes were examined after adjustment for case-mix and markers of iron stores and malnutrition-inflammation including serum interleukin-6, iron and ferritin. Patients with serum TIBC >or=250 mg/dl had higher body mass index, triceps and biceps skinfolds and mid-arm muscle circumference and higher serum levels of iron but lower ferritin and inflammatory markers. Some SF-36 quality of life (QoL) components were worse in the lowest and/or highest TIBC groups. Mortality was incrementally higher in lower TIBC levels (p-trend <0.001). Adjusted death hazard ratio was 1.75 (95% CI: 1.00-3.05, p = 0.05) for TIBC <150 compared to TIBC of 200-250 mg/dl. A fall in TIBC >20 mg/dl over 6 months was associated with a death hazard ratio of 1.57 (95% CI: 1.04-2.36, p = 0.03) compared to the stable TIBC group. Hence, low baseline serum TIBC is associated with iron deficiency, PEW, inflammation, poor QoL and mortality, and its decline over time is independently associated with increased death risk.

Serum alkaline phosphatase predicts mortality among maintenance hemodialysis patients.

Several observational studies have demonstrated that serum levels of minerals and parathyroid hormone (PTH) have U- or J-shaped associations with mortality in maintenance hemodialysis patients, but the relationship between serum alkaline phosphatase (AlkPhos) and risk for all-cause or cardiovascular death is unknown. In this study, a 3-yr cohort of 73,960 hemodialysis patients in DaVita outpatient dialysis were studied, and the hazard ratios for all-cause and cardiovascular death were higher across 20-U/L increments of AlkPhos, including within the various strata of intact PTH and serum aspartate aminotransferase. In the fully adjusted model, which accounted for demographics, comorbidity, surrogates of malnutrition and inflammation, minerals, PTH, and aspartate aminotransferase, AlkPhos > or =120 U/L was associated with a hazard ratio for death of 1.25 (95% confidence interval 1.21 to 1.29; P < 0.001). This association remained among diverse subgroups of hemodialysis patients, including those positive for hepatitis C antibody. A rise in AlkPhos by 10 U/L during the first 6 mo was incrementally associated with increased risk for death during the subsequent 2.5 yr. In summary, high levels of serum AlkPhos, especially >120 U/L, are associated with mortality among hemodialysis patients. Prospective controlled trials will be necessary to test whether serum AlkPhos measurements could be used to improve the management of renal osteodystrophy.

Malnutrition-Inflammation Score for risk stratification of patients with CKD: is it the promised gold standard?

Traditional cardiovascular disease risk factors including hyperlipidemia and obesity are paradoxically associated with improved survival in individuals with advanced chronic kidney disease. Such paradoxes underscore the important role of malnutrition-inflammation-cachexia syndrome in chronic kidney disease mortality and highlight the urgent need for comprehensive but practical nutritional assessment tools. In this Practice Point commentary, Rambod and colleagues discuss a recent paper by Yamada et al. that used the Malnutrition-Inflammation Score (MIS) as the 'reference standard' to validate five simplified nutritional screening tools in 422 Japanese patients on hemodialysis. The study found the Geriatric Nutritional Risk Index to be the most accurate of the simplified tools for identifying those patients on dialysis who are at nutritional risk. The commentary authors discuss Yamada et al.'s study and conclude that although the MIS has been widely used in patients undergoing maintenance dialysis, its wide utility does not automatically make it the ultimate reference standard for assessing other nutritional scoring tools.

Pattern of injury in Shiraz.

OBJECTIVE: Injury is a major neglected health problem in developing countries. The first step in dealing with injury problem is to identify the injury patterns and characteristics. Therefore, we aimed to demonstrate the current status of trauma admissions to hospitals in Shiraz, as a major city of Iran. METHODS: A hospital-based study was conducted in 2002. All injured patients admitted during 6 months in emergency departments of two general hospitals of Shiraz, Nemazi and Chamran were included. RESULTS: A total of 1,765 injured patients were registered during the study period, with mean age of 33 years. Manual workers were the most vulnerable group among occupational categories. Inner-city roads were the most common place of injury and traffic accident was the major cause of injury. Overally, falling injury was the second common cause of injury in males and the first cause in females (especially at the age of over 60). CONCLUSION: As other studies conducted in our society, traffic accidents are the major cause of morbidity and mortality and this can emphasize on the obligation to take legislative action in the field of driving and road safety, directing resources and educating the public and raising the awareness of the community in prevention of this iceberg-like problem.

Population attributable risk for diabetes associated with excess weight in Tehranian adults: a population-based cohort study.

BACKGROUND: Little evidence exists regarding the magnitude of contribution of excess weight to diabetes in the Middle East countries. This study aimed at quantification of the impact of overweight and obesity on the incidence of type 2 diabetes mellitus (T2DM) at a population level in Tehran, Iran. METHODS: Using data of a population-based short-term cohort study in Iran, which began in 1997 with 3.6-year follow-up, we calculated the adjusted odds ratios (OR) and population attributable risks (PAR) of developing T2DM, i.e. the proportion of diabetes that could have been avoided had overweight and/or obesity not been present in the population. RESULTS: Of the 4728 subjects studied, aged > or = 20 years, during the 3.6-year follow-up period, 3.8% (n = 182) developed T2DM. This proportion was 1.4%, 3.6%, and 7.8% for the normal, overweight, and obese subjects, respectively. When compared to normal BMI, the adjusted ORs for incident diabetes were 1.76 [95% confidence interval (CI) 1.07 to 2.89] for overweight and 3.54 (95% CI 2.16 to 5.79) for obesity. The PARs adjusted for family history of diabetes, age, triglycerides, systolic blood pressure was 23.3% for overweight and 37.1% for obesity. These figures were 7.8% and 26.6% for men and 35.3% and 48.3% for women, respectively. CONCLUSION: Incident T2DM is mainly attributable to excess weight, significantly more so in Tehranian women than men. Nonetheless, the contribution of excess weight in developing T2DM was lower in our short-term study than that reported in long-term periods. This probably reflects the significant role of other risk factors of T2DM in a short-term follow-up. Hence, prevention of excess weight probably should be considered as a major strategy for reducing incidence of T2DM; the contribution of other risk factors in developing T2DM in short-term period deserve to be studied and be taken into account.

Effect of Megestrol Acetate and Testosterone on Body Composition and Hormonal Responses in COPD Cachexia.

Background: Underweight chronic obstructive pulmonary disease (COPD) patients with involuntary weight loss have a poor prognosis; no effective therapy is currently available. We conducted the first clinical trial seeking to determine whether combination therapy with an appetite stimulant and an anabolic steroid would have beneficial effects on body composition for patients with COPD cachexia. Methods: We conducted a 12-week pilot study in which 4 men and 5 women (age 64±10 y, forced expiratory volume in 1 second [FEV1] 31±9 %pred., body mass index [BMI] 18±3 kg/m2) with low-normal testosterone levels (average 532±45ng/dl in men and 12.4±5.3ng/dl in women) and weight loss ≥10 lbs over the previous year were treated with oral megestrol acetate 800mg/day plus weekly testosterone enanthate injections, initially 125 mg in men and 40 mg in women, with doses subsequently adjusted targeting circulating nadir testosterone levels of 850 and 300 ng/dl, respectively. Results: On treatment, nadir testosterone level increases averaged 160±250 ng/dl (NS) in men and 322±49 (p<0.001) ng/dl in women. Body weight increased in all individuals, with average end-intervention weight gain of 3.1±2.2 kg (p<0.005). Two women and 2 men had COPD exacerbations and did not complete the 12-week study. In the 5 individuals who completed, dual energy x ray absorptiometry (DEXA) scans revealed an average 2.0±1.5 kg lean mass and 2.3±1.7 kg fat mass increase (each p<0.05). No adverse effects of treatment were detected. Conclusions: Combination therapy reversed the trajectory of involuntary weight loss and increased lean mass in cachectic COPD patients. Though the interventions were apparently well tolerated, participant drop-out rate was high. Larger randomized placebo-controlled long-term studies with functional outcomes are needed.

Association of vascular endothelial factors with cardiovascular outcome and mortality in chronic kidney disease patients: a 4-year cohort study.

BACKGROUND: Angiogenic cytokines fms-like tyrosine kinase-1(sFlt-1) and placental growth factor (PlGF) are associated with increased risk for cardiovascular disease (CVD) in the general population. In this study we examine the association between these vascular endothelial factors and atherosclerosis, cardiovascular outcome, and mortality in chronic kidney disease (CKD) patients. METHODS: Serum level of PlGF and sFlt-1 were measured in 301 patients with CKD, who were followed for up to 4 years. Primary outcomes were CV events and all-cause mortality. Carotid-intima media thickness (CIMT) was used as marker of atherosclerosis. Kaplan-Meier survival curves and the Cox proportional hazard model were used to assess the association of biomarkers and clinical outcomes. RESULTS: Mean (SD) PlGF and sFlt-1 were 5.45 ng/ml (3.76) and 68.6 (28.0) pg/ml, respectively. During the follow up time, 60 patients (19.9%) experienced CV events and 22 patients (7.3%) died. Compared with low PlGF, patients with PlGF above median level had higher CV events (12.7% vs. 27.2%, p = 0.002) and mortality (2.0% vs. 12.6%, p < 0.001). The associations of PlGF and sFlt-1 with CV events were not statistically significant in the fully adjusted model. Higher PlGF was associated with greater death risk (HR = 5.22, 95% CI: 1.49-18.33, p = 0.01), which was robust to adjustment for sFlt-1 and other risk factors. Elevated sFlt-1 level was also an independent predictor of mortality (HR 3.41, 95% CI: 1.49-9.51, p = 0.019). CONCLUSION: In CKD patients not yet on dialysis, higher serum level of PlGF and sFlt-1 are associated with increased mortality, but not CV events.