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.

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.

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.

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.

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.

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.

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.

Six-minute walk distance predictors, including CT scan measures, in the COPDGene cohort.

BACKGROUND: Exercise tolerance in COPD is only moderately well predicted by airflow obstruction assessed by FEV(1). We determined whether other phenotypic characteristics, including CT scan measures, are independent predictors of 6-min walk distance (6MWD) in the COPDGene cohort. METHODS: COPDGene recruits non-Hispanic Caucasian and African American current and ex-smokers. Phenotyping measures include postbronchodilator FEV(1) % predicted and inspiratory and expiratory CT lung scans. We defined % emphysema as the percentage of lung voxels < -950 Hounsfield units on the inspiratory scan and % gas trapping as the percentage of lung voxels < -856 Hounsfield units on the expiratory scan. RESULTS: Data of the first 2,500 participants of the COPDGene cohort were analyzed. Participant age was 61 ± 9 years; 51% were men; 76% were non-Hispanic Caucasians, and 24% were African Americans. Fifty-six percent had spirometrically defined COPD, with 9.3%, 23.4%, 15.0%, and 8.3% in GOLD (Global Initiative for Chronic Obstructive Lung Disease) stages I to IV, respectively. Higher % emphysema and % gas trapping predicted lower 6MWD (P < .001). However, in a given spirometric group, after adjustment for age, sex, race, and BMI, neither % emphysema nor % gas trapping, or their interactions with FEV(1) % predicted, remained a significant 6MWD predictor. In a given spirometric group, only 16% to 27% of the variance in 6MWD could be explained by age, male sex, Caucasian race, and lower BMI as significant predictors of higher 6MWD. CONCLUSIONS: In this large cohort of smokers in a given spirometric stage, phenotypic characteristics were only modestly predictive of 6MWD. CT scan measures of emphysema and gas trapping were not predictive of 6MWD after adjustment for other phenotypic characteristics.

Testosterone and resistance training effects on muscle nitric oxide synthase isoforms in COPD men.

BACKGROUND: Skeletal muscle dysfunction contributes to exercise limitation in COPD. The role of the nitric oxide synthase (NOS) system in muscle dysfunction is ill defined. Reduced levels of endothelial NOS (eNOS) and elevated levels of inducible NOS (iNOS) in the skeletal muscle of COPD patients have been recently reported. We hypothesized that resistance exercise training (R) and/or testosterone supplementation (T) would alter the transcription and expression of the NOS isoenzymes in COPD skeletal muscle. METHODS: Vastus lateralis biopsies were obtained before and after a 10-week intervention in 40 men with severe COPD(age 67.7 ± 8.3, FEV(1) 41.4 ± 12.6% predicted): placebo + no training (P) (n = 11), placebo + resistance training (PR) (n = 8), testosterone + no training (T) (n = 11) and testosterone + resistance training (TR) (n = 10) groups. eNOS, nNOS and iNOS mRNA and protein levels were measured in each sample. mRNA and protein levels were measured using real-time PCR and enzyme-linked immunosorbant assay, respectively. RESULTS: eNOS mRNA increased in the TR group compared to P and T groups (P < 0.001). eNOS protein was increased in TR and T groups after intervention (P < 0.05) but not in the PR group. nNOS protein increased in the PR, T, and TR groups (P < 0.05). iNOS protein decreased only in the TR group (P = 0.01). CONCLUSION: Resistance training and testosterone supplementation increased eNOS and nNOS proteins and decreased iNOS protein in the skeletal muscles of men with COPD. These changes in NO system might explain some of the favorable effects of these therapies.

The effects of anesthesia method on throat pain after elective rhinoplasty.

OBJECTIVES: Throat pain is a common postoperative complaint. In this study, we aimed to determine its incidence of throat pain after rhinoplasty by general anesthesia (GA) or conscious sedation (CS). METHODS: We evaluated throat pain in postanesthesia care unit, 4, 12 and 24 hours after surgery using a numerical rating scale (NRS) in a clinical trial. A total number of 252 consecutive females aging over 18 years undergoing GA or CS for elective rhinoplasty entered the study after implementing inclusion and exclusion criteria. A logistic regression model was used to predict having throat pain. RESULTS: The incidence of throat pain after CS and GA in postanesthesia care unit, 4, 12 and 24 hours after rhinoplasty were 34.9% vs. 34.9% (P = 0.99), 27.0% vs. 33.3% (P = 0.27), 14.3% vs. 22.2% (P = 0.10), 10.3% vs. 15.9% (P = 0.19), respectively. The odds ratio for throat pain was statistically significant for nausea/vomiting in postanesthesia care unit (OR = 11.1, 95% CI: 5.7-21.8; P < 0.0001). CONCLUSIONS: Method of anesthesia had no independent role in predicting throat pain. Although larynx of subjects undergoing general anesthesia is manipulated by tracheal intubation, sedation has its specific risks for promoting throat pain after surgery. Therefore, neither CS nor GA is superior in terms of throat pain.

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.

Childhood physical abnormalities following paternal exposure to sulfur mustard gas in Iran: a case-control study.

BACKGROUND: Mustard gas, a known chemical weapon, was used during the Iran-Iraq war of 1980-1988. We aimed to determine if exposure to mustard gas among men was significantly associated with abnormalities and disorders among progenies. METHODS: Using a case-control design, we identified all progenies of Sardasht men (exposed group, n = 498), who were born at least nine months after the exposure, compared to age-matched controls in Rabat, a nearby city (non-exposed group, n = 689). We conducted a thorough medical history, physical examination, and appropriate paraclinical studies to detect any physical abnormality and/or disorder. Given the presence of correlated data, we applied Generalized Estimating Equation (GEE) multivariable models to determine associations. RESULTS: The overall frequency of detected physical abnormalities and disorders was significantly higher in the exposed group (19% vs. 11%, Odds Ratio [OR] 1.93, 95% Confidence Interval [CI], 1.37-2.72, P = 0.0002). This was consistent across sexes. Congenital anomalies (OR 3.54, 95% CI, 1.58-7.93, P = 0.002) and asthma (OR, 3.12, 95% CI, 1.43-6.80, P = 0.004) were most commonly associated with exposure. No single abnormality was associated with paternal exposure to mustard gas. CONCLUSION: Our study demonstrates a generational effect of exposure to mustard gas. The lasting effects of mustard gas exposure in parents effects fertility and may impact child health and development in the long-term.

Metabolic syndrome predicts poor health-related quality of life in women but not in men: Tehran Lipid and Glucose Study.

OBJECTIVE: To compare health-related quality of life (HRQOL) in those with and without metabolic syndrome in a general Iranian population. METHODS: This was a cross-sectional study of HRQOL conducted in a sample of individuals with and without metabolic syndrome using the data obtained from the Tehran Lipid and Glucose Study (TLGS) and information specifically collected for the present investigation. Metabolic syndrome was defined according to the adult treatment panel III (ATPIII) and HRQOL was assessed using the Short Form Health Survey (SF-36). Logistic regression analyses were performed for the whole sample and both sexes while adjusting for potential confounders in order to estimate odds ratios for predicting HRQOL in this population. RESULTS: In all, 950 participants with (n = 361) and without (n = 589) metabolic syndrome were studied. The mean age of participants was 46.5 +/- 14.4 years. In women, but not in men, metabolic syndrome had an independent role in predicting poor HRQOL. With increase in the number of metabolic syndrome components, there was a significant decreasing trend in women's physical component summary scores. CONCLUSIONS: The results indicate that metabolic syndrome is associated with poor HRQOL in women but not in men, and the association is formed mainly in relation to physical rather than mental health.

Association of serum alkaline phosphatase and bone mineral density in maintenance hemodialysis patients.

Recent studies indicate that serum alkaline phosphatase (AlkPhos), a surrogate of high turnover bone disease, is associated with coronary artery calcification and death risk in maintenance hemodialysis (MHD) patients. The association between AlkPhos and bone mineral density (BMD) is not well studied. We studied the association between AlkPhos and dual-energy X-ray absorptiometry-assessed BMD in a group of MHD patients in Southern California. In 154 MHD patients, aged 55.3 +/- 13.6 years, including 42% women, 38% Hispanics, 42% African Americans, and 55% diabetics, the mean serum AlkPhos was 121 +/- 63 U/L (median: 101, Q(25-75): 81-141); 36% had AlkPhos>/=120 U/L and 50% had a total T-score< or =-1. Whereas the total BMD did not correlate with age (r=0.01, P=0.99) or body mass index (r=0.10, P=0.22), it correlated negatively with AlkPhos (r=-0.25, P=0.002), including after multivariate adjustment (r=-0.24, P=0.003). The proportion of patients with a high coronary artery calcification score>400 was incrementally higher across worsening BMD tertiles (P trend=0.04). The BMD was significantly worse in MHD patients with serum AlkPhos> or =120 U/L compared with <120 U/L (1.01 +/- 0.016 vs. 1.08 +/- 0.013 g/cm(2), respectively, P<0.001). The multivariate adjusted odds ratio of AlkPhos> or =120 U/L for having a total T-score<-1.0 was 2.3 (1.1-4.8, P=0.037). Among routine clinical and biochemical markers, serum AlkPhos> or =120 U/L was a better predictor of total T-score< or =-1 in MHD patients. An association exists between higher serum AlkPhos and worse dual-energy X-ray absorptiometry-assessed BMD in MHD patients. Given these findings, studies are indicated to examine whether interventions that lower serum AlkPhos improve BMD in MHD patients.

Breath-by-breath quantification of progressive airflow limitation during exercise in COPD: a new method.

During heavy exercise in chronic obstructive pulmonary disease (COPD), dynamic airways compression leads to a progressive fall in intrabreath flow. This is manifested by concavity in the spontaneous expiratory flow-volume (SEFV) curve. We developed a method to quantify the SEFV curve configuration breath-by-breath during incremental exercise utilizing a computerized analysis. The flow signal was digitized at 100Hz. For each breath's SEFV curve, points of highest flow (V (max)) and end-expiration (V (EE)) were identified to define a rectangle's diagonal. Fractional area within the rectangle below the SEFV curve was defined as the "rectangular area ratio" (RAR); RAR <0.5 signifies concavity of the SEFV. To illustrate the utility of this method, time courses of RAR during incremental exercise in 12 healthy and 17 COPD individuals (FEV(1) %Pred.=39+/-12) were compared. SEFV in healthy individuals manifested progressively more convex SEFV curves throughout exercise (RAR=0.56+/-0.08 at rest and 0.61+/-0.05 at peak exercise), but became progressively more concave in COPD patients (RAR=0.52+/-0.08 at rest and 0.46+/-0.06 at peak exercise). In conclusion, breath-by-breath quantification of SEFV curve concavity describes progressive shape changes denoting expiratory flow limitation during incremental exercise in COPD patients. Further studies are warranted to establish whether this novel method can be a reliable indicator of expiratory flow limitation during exercise and to examine the relationship of RAR time course to the development of dynamic hyperinflation.