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Aims: Many patients with angina, especially women, do not have obstructive coronary artery disease (CAD) yet have impaired prognosis. We investigated whether routine assessment of coronary microvascular dysfunction (CMD) is feasible and predicts adverse outcome in women with angina and no obstructive CAD., Methods and Results: After screening 7253, we included 1853 women with angina and no obstructive CAD on angiogram who were free of previous CAD, heart failure, or valvular heart disease in the prospective iPOWER (Improving Diagnosis and Treatment of Women with Angina Pectoris and Microvascular Disease) study. CMD was assessed by Doppler echocardiography in the left anterior descending artery as coronary flow velocity reserve (CFVR). Patients were followed for a composite outcome of cardiovascular death, myocardial infarction (MI), heart failure, stroke, and coronary revascularization. CFVR was obtained in 1681 patients (91%) and the median CFVR was 2.33 (quartiles 1-3: 2.00-2.74). During a median follow-up of 4.5 years, 96 events occurred. In univariate Cox regression, CFVR was associated with the composite outcome {hazard ratio (HR) 1.07 [95% confidence interval (CI) 1.03-1.11] per 0.1 unit decrease in CFVR; P < 0.001}, primarily driven by an increased risk of MI and heart failure. Results remained significant in multivariate analysis [HR 1.05 (95% CI 1.01-1.09) per 0.1 unit decrease in CFVR; P = 0.01]. In exploratory analyses, CFVR was also associated with the risk of repeated hospital admission for angina and all-cause mortality., Conclusion: Assessment of CFVR by echocardiography is feasible and predictive of adverse outcome in women with angina and no obstructive CAD. Results support a more aggressive preventive management of these patients and underline the need for trials targeting CMD., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Obesity defined by body mass index (BMI) is characterized by better prognosis and lower plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) in heart failure. We assessed whether another anthropometric measure, per cent body fat (PBF), reveals different associations with outcome and heart failure biomarkers (NT-proBNP, high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenesis-2 (sST2))., Methods: In an individual patient dataset, BMI was calculated as weight (kg)/height (m) 2 , and PBF through the Jackson-Pollock and Gallagher equations., Results: Out of 6468 patients (median 68 years, 78% men, 76% ischaemic heart failure, 90% reduced ejection fraction), 24% died over 2.2 years (1.5-2.9), 17% from cardiovascular death. Median PBF was 26.9% (22.4-33.0%) with the Jackson-Pollock equation, and 28.0% (23.8-33.5%) with the Gallagher equation, with an extremely strong correlation ( r  = 0.996, p  < 0.001). Patients in the first PBF tertile had the worst prognosis, while patients in the second and third tertile had similar survival. The risks of all-cause and cardiovascular death decreased by up to 36% and 27%, respectively, per each doubling of PBF. Furthermore, prognosis was better in the second or third PBF tertiles than in the first tertile regardless of model variables. Both BMI and PBF were inverse predictors of NT-proBNP, but not hs-TnT. In obese patients (BMI ≥ 30 kg/m 2 , third PBF tertile), hs-TnT and sST2, but not NT-proBNP, independently predicted outcome., Conclusion: In parallel with increasing BMI or PBF there is an improvement in patient prognosis and a decrease in NT-proBNP, but not hs-TnT or sST2. hs-TnT or sST2 are stronger predictors of outcome than NT-proBNP among obese patients.

Aims: To investigate whether left ventricular (LV) systolic shortening velocity (s'), diastolic lengthening velocity (e'), and non-invasively estimated LV filling pressure (E/e') during low-dose dobutamine echocardiography (LDDE) reflect invasive measures of cardiac output and pulmonary capillary wedge pressure (PCWP) in stable patients with chronic systolic heart failure., Methods and Results: Fourteen patients with heart failure (aged 65 ± 8 years, LVEF 36 ± 8%) underwent simultaneous tissue Doppler echocardiography and invasive measurements of cardiac output and PCWP by right heart catheterization at rest and during dobutamine infusion at rates of 10 and 20 µg/kg/min. Cardiac output increased from rest to peak dobutamine (4.9 ± 1.2 to 6.6 ± 2.0 L/min, P < 0.001) and correlated with the peak systolic tissue velocity (s') at rest (R = 0.61, P = 0.02) and during dobutamine stimulation (R = 0.79, P < 0.001). Increases in early diastolic mitral inflow (E, 74.9 ± 29.0-90.8 ± 29.5 cm/s) and LV lengthening (e', 6.5 ± 2.4-8.2 ± 2.8 cm/s) velocities were observed during LDDE leaving the E/e' ratio unchanged. Although a mean PCWP was also unchanged from rest to peak dobutamine (16.6 ± 8.3-14.2 ± 9.2, P = 0.25), E/e' and PCWP only correlated at rest (R = 0.64, P = 0.014)., Conclusion: The LV systolic shortening velocity is closely associated with cardiac output during LDDE in CHF patients. Dobutamine stimulation increases early diastolic mitral inflow and lengthening velocities, but the E/e' ratio does not reflect the PCWP during LDDE, which warrants some caution in converting changes in E/e' into changes in LV filling pressure. The sample size is, however, small and the observation need to be confirmed in a larger population.

Aims: To investigate the associations between glucose metabolism, left ventricular (LV) contractile reserve, and exercise capacity in patients with chronic systolic heart failure (HF)., Methods and Results: From an outpatient HF clinic, 161 patients with systolic HF were included (mean age 70 ± 10 years, 69% male, 59% had ischaemic heart disease, mean LV ejection fraction (LVEF) 37 ± 9%). Thirty-four (21%) patients had known diabetes mellitus (DM). Oral glucose tolerance testing (OGTT) classified patients without a prior DM diagnosis as normal glucose tolerance (NGT), impaired glucose tolerance or new DM. All patients completed low-dose dobutamine echocardiography (LDDE) and 154 patients a 6-min walking distance test (6MWD). Compared with patients with NGT, patients with known DM had lower resting LVEF (33.4 vs. 39.1%, P < 0.05) and higher E/e' (13.9 vs. 11.4, P < 0.05). During LDDE, an increase in LVEF could be observed in all glycemic groups (mean 8.2% absolute increase), but the contractile reserve was lower in patients with known DM (-5.4%, P = 0.001) and new DM (-3.5%, P = 0.035) compared to patients with NGT. 6MWD was lower in known DM (349 m) and new DM (379 m) compared with NGT (467 m) (P < 0.001). Differences in clinical variables, resting echocardiographic parameters or contractile reserve, did not explain the exercise intolerance related to diabetes., Conclusion: Diabetes, known or newly detected by OGTT, is independently associated with reduced LV contractile reserve and exercise intolerance in outpatients with systolic HF. These findings may offer one explanation for the excess mortality related to diabetes in HF.

Background: Parvovirus B19 infection causes severe cytopenia and can mimic a leukemic relapse or therapy-induced cytopenia in patients with hematologic malignancies. We evaluated the complications of parvovirus B19 infection, including delays in the scheduled course of chemotherapy, in children with acute lymphoblastic leukemia (ALL)., Methods: Consecutive bone marrow samples were collected from 117 children with ALL and were analyzed for parvovirus B19 DNA by polymerase chain reaction. Clinical and laboratory data were collected from the Nordic Childhood Leukemia Registry and from medical records., Results: Among the 117 children with ALL, 18 (15%) were found to be parvovirus B19 DNA positive. The infection was suspected on clinical grounds in only 1 of these 18 patients. Patients with viremia at diagnosis or during therapy for infection had lower viral loads (median viral load, 7 x 10(4) copies/mL) than did those who became viremic during maintenance therapy (median viral load, 2 x 10(8) copies/mL). The former group also had fewer clinical complications. Indeed, when parvovirus B19 DNA was present during the maintenance treatment, the number of complications (including cytopenia) increased, causing significantly longer periods without chemotherapy (median duration without chemotherapy, 59 days vs. 30 days; P < or = .05) and a higher number of blood transfusions (P = .018) in parvovirus B19 DNA-positive patients than in parvovirus B19 DNA-negative patients., Conclusions: Children with ALL who were infected with parvovirus B19 became cytopenic, leading to reduced treatment intensity and to complications during treatment. Screening for parvovirus B19 DNA by quantitative polymerase chain reaction in pediatric patients with ALL and unexplained cytopenia is suggested.

Aims: Results of previous studies on the influence of gender on prognosis in heart failure have been conflicting and most studies have been conducted in selected populations. The aim of this study was determine whether mortality risk in women and men hospitalized with congestive heart failure is different., Methods and Results: Survival analysis of 5491 consecutive patients admitted with congestive heart failure to 34 Danish hospitals between 1993-1996. Follow-up time was 5-8 years. Forty percent of the patients were female. Females were older, had less evidence of ischaemic heart disease and their left ventricular systolic function was preserved to a greater extent than in males. Men were more often treated with ACE inhibitors. During the follow-up period 1569 women (72%) and 2386 (72%) of the men died. When the age difference between men and women was adjusted for, male gender was associated with an increased risk of death (RR 1.25 (1.17-1.34)) and the increased risk was confirmed in a multivariate model containing several covariates., Conclusions: In patients hospitalized with congestive heart failure male gender is an independent predictor of mortality. Female heart failure patients may be under-treated with ACE inhibitors.

Background: We examined how prolonged antibiotic treatment affected the resistance and mutation frequency of human microflora isolated from intestine (Escherichia coli, enterococci spp.), pharynx (alpha-streptococci) and nostril (coagulase-negative staphylococci, CoNS)., Methods: Samples were collected from patients at the Center of Cystic Fibrosis (n=18) and the haematology ward (n=18) of the University Hospital, Uppsala, Sweden. The individually used amount of antibiotics for 1 year was recorded as the defined daily dose (DDD). Primary health care patients (n=30), with no antibiotic treatment for 1 year before sampling, were used as controls. Three isolates of each bacterium from each patient were examined. Antibiotic susceptibilities were determined by disc diffusion. Mutation frequencies to rifampicin resistance were measured on 30 independent cultures of each bacterial species from each individual by plating on rifampicin agar plates. For alpha-streptococci the mutation frequency to streptomycin resistance was also determined., Results: Isolates from patients with high antibiotic use showed a pronounced shift towards increased resistance and a small but significant increase in the mutation frequency compared with isolates from the controls. For E. coli, enterococci and CoNS the increase in geometric mean mutation frequency in the patient group was 3-, 1.8- and 1.5-fold, respectively (P values 0.0001, 0.016 and 0.012). For alpha-streptococci there was a significant difference in geometric mean mutation frequency between patient and control groups for streptomycin resistance (P=0.024) but not for rifampicin resistance (P=0.74)., Conclusions: High antibiotic use selected for commensals with highly increased resistance and a slight increase in mutation frequency.

Background: Antibiotic resistance typically confers a biological fitness cost on bacteria that can be manifested as a decreased growth rate in culture media and experimental animals. However, there are limited experimental data on the relative fitness of resistant and susceptible bacteria during growth in their natural environment., Objective: We have developed a human competition model to investigate the relative fitness of antibiotic-resistant and -susceptible bacteria., Materials and Methods: A non-epidemic Staphylococcus epidermidis strain was isolated from skin, and a rifampicin-resistant (RifR) clone was selected. The RifR marker was used to distinguish the inoculated strains from the resident population of coagulase-negative staphylococci. The RifR strains were further selected for resistance to ciprofloxacin (CipR) and fusidic acid (FusR). A 1:1 mix of susceptible and resistant bacteria was applied on the forearms of 12 volunteers. Competition was monitored by sampling bacteria from skin and determining their relative numbers., Results: Resistance to ciprofloxacin due to parC mutations did not decrease the growth rate in vitro, and the CipR/CipS ratio was close to 1 during day 1 and 3 in the in vivo competition experiments. In contrast, fusidic acid resistance due to fusA mutations resulted in a decrease in the growth rate in vitro and a considerable loss of fitness in the competition. The FusR/FusS ratio diminished from 1.3 to 0.023 in 3 days., Conclusions: These data show that human volunteers can be used as a simple and relevant model to study the biological cost of resistance.

Aims: The present study was performed to evaluate pre-admission history, presentation, initial treatment and long-term mortality in patients with myocardial infarction and diabetes., Methods and Results: Between 1990 and 1992, 6676 patients with acute myocardial infarction were screened for entry into the Trandolapril Cardiac Evaluation (TRACE) study. In this cohort 719 (11%) of the patients had a history of diabetes. Among the diabetic patients 19% were treated with insulin, 52% with oral hypoglycaemic agents and 29% with diet only. The diabetic patients were slightly older, more likely to be female and had a higher prevalence of known cardiovascular disease. Even though the diabetic patients had the same frequency of ST-segment elevation on the electrocardiogram and the same admission delay, treatment with thrombolysis and aspirin was less frequently prescribed to the diabetic patients than to patients without diabetes. The mortality rate was significantly increased in the diabetic patients, 7-year mortality being 79% in insulin-treated, 73% in tablet-treated and 62% in diet-treated diabetic patients compared with 46% in patients without diabetes. In a multivariate analysis only diabetic patients treated with oral hypoglycaemic agents or with insulin had an increased mortality compared with non-diabetic patients., Conclusions: Patients with diabetes mellitus and myocardial infarction are treated with thrombolysis to a lesser extent than non-diabetic patients. Diabetic patients treated with oral hypoglycaemic agents or insulin, but not those treated with diet alone, have a significantly increased mortality following acute myocardial infarction compared with non-diabetic patients., (Copyright 2000 The European Society of Cardiology.)

Hypertension has previously been suggested to be a part of a metabolic syndrome also involving hyperlipidemia, hyperinsulinemia, and decreased insulin sensitivity. In the present study, 10 untreated hypertensive subjects were challenged with a high-salt diet (20 g NaCl) for 1 week after 7 days on a low-salt diet (less than 3 g). The difference in mean blood pressure (MBP) at the end of the high-salt diet v the low-salt diet was denoted salt sensitivity. We related the salt sensitivity to indices of glucose and lipid metabolism and studied the effect of salt deprivation on these metabolic variables. Salt sensitivity was found to be significantly correlated to HDL cholesterol (r = 0.79, P less than .007), insulin sensitivity (M value at the euglycemic clamp, r = 0.68, P less than .003), and fasting serum insulin (r = 0.69, P less than .04). Salt deprivation induced an increase in fasting insulin (P less than .03), but did not significantly affect any other indices of glucose and lipid metabolism. In conclusion, our study shows that hyperinsulinemia, decreased sensitivity to insulin, and low levels of HDL cholesterol were most commonly seen in hypertensive subjects with a low sodium sensitivity. A putative mechanism might be an increased activity in pressor systems also affecting glucose and lipid metabolism.

Diet constitutes the basis of all lipid lowering therapy. The mechanisms responsible for the effects of the different dietary measures are not yet fully understood. Dietary treatment 'normalized' the lipid levels in over 50% of the mild to moderate hyperlipoproteinaemic states encountered in a middle-aged population with clinical manifestations of atherosclerotic cardiovascular disease. Triglyceride and cholesterol determinations in isolated lipoprotein fractions supplied additional information on the character and extent of the lipoprotein changes induced by diet.