N-terminal pro-B-type natriuretic peptide for prediction of ventricular arrhythmias: Data from the SMASH study.

BACKGROUND: Elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations predict heart failure (HF) and mortality, but whether NT-proBNP predicts ventricular arrhythmias (VA) is not clear. HYPOTHESIS: We hypothesize that high NT-proBNP concentrations associate with the risk of incident VA, defined as adjudicated ventricular fibrillation or sustained ventricular tachycardia. METHODS: In a prospective, observational study of patients treated with implantable cardioverter defibrillator (ICD), we analyzed NT-proBNP concentrations at baseline and after mean 1.4 years in association to incident VA. RESULTS: We included 490 patients (age 66 ± 12 years, 83% men) out of whom 51% had a primary prevention ICD indication. The median NT-proBNP concentration was 567 (25-75 percentile 203-1480) ng/L and patients with higher concentrations were older with more HF and ICD for primary prevention. During mean 3.1 ± 0.7 years, 137 patients (28%) had ≥1 VA. Baseline NT-proBNP concentrations were associated with the risk of incident VA (hazard ratio [HR]: 1.39, 95% confidence interval [95% CI]: 1.22-1.58, p < .001), HF hospitalizations (HR: 3.11, 95% CI: 2.53-3.82, p < .001), and all-cause mortality (HR: 2.49, 95% CI: 2.04-3.03, p < .001), which persisted after adjusting for age, sex, body mass index, coronary artery disease, HF, renal function, and left ventricular ejection fraction. The association with VA was stronger in secondary versus primary prevention ICD indication: HR: 1.59 (95% CI: 1.34-1.88 C-statistics 0.71) versus HR: 1.24, 95% CI: 1.02-1.51, C-statistics 0.55), p-for-interaction = 0.06. Changes in NT-proBNP during the first 1.4 years did not associate with subsequent VA. CONCLUSIONS: NT-proBNP concentrations are associated with the risk of incident VA after adjustment for established risk factors, with the strongest association in patients with a secondary prevention ICD indication.

Rationale and design of the PRevention of cArdiac Dysfunction during Adjuvant breast cancer therapy (PRADA II) trial: a randomized, placebo-controlled, multicenter trial.

BACKGROUND: Recent advances in the treatment algorithms of early breast cancer have markedly improved overall survival. However, anthracycline- and trastuzumab-associated cardiotoxicity may lead to dose-reduction or halt in potentially life-saving adjuvant cancer therapy. Early initiated neurohormonal blockade may prevent or attenuate the cardiotoxicity-induced reduction in cardiac function, but prior studies have been inconclusive. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan has been shown to be superior to traditional treatment in heart failure with reduced ejection fraction, but its cardioprotective effects in the cardio-oncology setting remains to be tested. OBJECTIVE: To assess if sacubitril/valsartan given concomitantly with early breast cancer treatment regimens including anthracyclines, with or without trastuzumab, may prevent cardiac dysfunction. METHODS: PRADA II is a randomized, placebo-controlled, double blind, multi-center, investigator-initiated clinical trial. Breast cancer patients from four university hospitals in Norway, scheduled to receive (neo-)adjuvant chemotherapy with epirubicin independently of additional trastuzumab/pertuzumab treatment, will be randomized 1:1 to sacubitril/valsartan or placebo. The target dose is 97/103 mg b.i.d. The patients will be examined with cardiovascular magnetic resonance (CMR), echocardiography, circulating cardiovascular biomarkers and functional testing at baseline, at end of anthracycline treatment and following 18 months after enrolment. The primary outcome measure of the PRADA II trial is the change in left ventricular ejection fraction (LVEF) by CMR from baseline to 18 months. Secondary outcomes include change in LV function by global longitudinal strain by CMR and echocardiography and change in circulating cardiac troponin concentrations. RESULTS: The study is ongoing. Results will be published when the study is completed. CONCLUSION: PRADA II is the first randomized, placebo-controlled study of sacubitril/valsartan in a cardioprotective setting during (neo-)adjuvant breast cancer therapy. It may provide new insight in prevention of cardiotoxicity in patients receiving adjuvant or neo-adjuvant therapy containing anthracyclines. Furthermore, it may enable identification of patients at higher risk of developing cardiotoxicity and identification of those most likely to respond to cardioprotective therapy. TRIAL REGISTRATION: The trial is registered in the ClinicalTrials.gov registry (identifier NCT03760588 ). Registered 30 November 2018.

Pentraxin 3 in primary percutaneous coronary intervention for ST elevation myocardial infarction is associated with early irreversible myocardial damage : Kinetic profile, relationship to interleukin 6 and infarct size.

BACKGROUND: The inflammatory marker long pentraxin 3 (PTX3) has been shown to be a strong predictor of 30-day and one-year mortality after acute myocardial infarction. The aim of this study was to evaluate the kinetic profile of PTX3 and its relationship with interleukin 6 (IL-6), high-sensitive C-reactive protein (hs-CRP) and infarct size. METHODS: PTX3, IL-6 and hs-CRP were measured at predefined time points, at baseline (before percutaneous coronary intervention (PCI)), at 12 and 72 hours after PCI in 161 patients with first-time ST elevation myocardial infarction (STEMI). RESULTS: PTX3 and IL-6 levels increased in the early phase, followed by a gradual decrease between 12 and 72 hours. There were statistically significant correlations between PTX3 and IL-6 in general, for all time points and for changes over time (0-72 hours). In a linear mixed model, PTX3 predicted IL-6 (p < 0.001). PTX3 is also correlated with hs-CRP in general, and at each time point post PCI, except at baseline. PTX3, IL-6 and hs-CRP were all significantly correlated with infarct size in general, and at the peak time point for maximum troponin I. In addition, there was a modest correlation between IL-6 levels at baseline and infarct size at 72 hours after PCI (ρ = 0.23, p = 0.006). CONCLUSIONS: PTX3 had a similar kinetic profile to IL-6, with an early increase and decline, and was statistically significantly correlated with markers of infarct size in STEMI patients post primary PCI. Baseline levels of IL-6 only predicted infarct size at 72 hours post PCI.

Factors predicting the use of therapeutic hypothermia and survival in unconscious out-of-hospital cardiac arrest patients admitted to the ICU.

INTRODUCTION: Therapeutic hypothermia (TH) after out-of-hospital cardiac arrest (OHCA) was adopted early in Norway. Since 2004 the general recommendation has been to cool all unconscious OHCA patients treated in the intensive care unit (ICU), but the decision to cool individual patients was left to the responsible physician. We assessed factors that were associated with use of TH and predicted survival. METHOD: We conducted a retrospective observational study of prospectively collected cardiac arrest and ICU registry data from 2004 to 2008 at three university hospitals. RESULTS: A total of 715 unconscious patients older than 18 years of age, who suffered OHCA of both cardiac and non-cardiac causes, were included. With an overall TH use of 70%, the survival to discharge was 42%, with 90% of the survivors having a favourable cerebral outcome. Known positive prognostic factors such as witnessed arrest, bystander cardio pulmonary resuscitation (CPR), shockable rhythm and cardiac origin were all positive predictors of TH use and survival. On the other side, increasing age predicted a lower utilisation of TH: Odds Ratio (OR), 0.96 (95% CI, 0.94 to 0.97); as well as a lower survival: OR 0.96 (95% CI, 0.94 to 0.97). Female gender was also associated with a lower use of TH: OR 0.65 (95% CI, 0.43 to 0.97); and a poorer survival: OR 0.57 (95% CI, 0.36 to 0.92). After correcting for other prognostic factors, use of TH remained an independent predictor of improved survival with OR 1.91 (95% CI 1.18-3.06; P <0.001). Analysing subgroups divided after initial rhythm, these effects remained unchanged for patients with shockable rhythm, but not for patients with non-shockable rhythm where use of TH and female gender lost their predictive value. CONCLUSIONS: Although TH was used in the majority of unconscious OHCA patients admitted to the ICU, actual use varied significantly between subgroups. Increasing age predicted both a decreased utilisation of TH as well as lower survival. Further, in patients with a shockable rhythm female gender predicted both a lower use of TH and poorer survival. Our results indicate an underutilisation of TH in some subgroups. Hence, more research on factors affecting TH use and the associated outcomes in subgroups of post-resuscitation patients is needed.

Incidence of respiratory sensitisation and allergy to enzymes among employees in an enzyme producing plant and the relation to exposure and host factors.

OBJECTIVES: Belonging to the group of high molecular weight respiratory sensitisers, microbial enzymes have been reported as a well known cause of occupational allergy, typically manifesting itself as rhinitis and/or asthma. High exposure to such high molecular weight sensitisers, and possibly also peak exposures, implies a higher risk than low exposure, but the exact relation between exposure, sensitisation and clinical allergy remains to be clarified. The authors sought to estimate the risk of respiratory enzyme allergy in an enzyme producing plant and to assess the relation between exposure indices and allergy. METHODS: Retrospective follow-up study based upon data gathered from health surveillance since 1970. 1207 employees from production and laboratories were included. The level of enzyme exposure in the relevant departments was estimated retrospectively into five exposure levels based on 10-fold increments/decrements of the threshold limit value and other exposure information. The risk was estimated in an exponential regression survival model fitted with constant intensity for subperiods of time using maximum likelihood estimation. RESULTS: During the first three years of a person's employment, the enzyme sensitisation and allergy incidence rates were 0.13 and 0.03 per person-year at risk, respectively. In the fitted models, exposure class did not correlate with the outcome variables. The risk of sensitisation decreased along the three decades, whereas the risk of allergy remained unchanged. The risk of sensitisation and allergy was doubled among smokers. Pre-employment atopy was only associated with sensitisation risk. CONCLUSION: Sensitisation to enzymes decreased during the study period, possibly reflecting improvements in the working environment. A similar decrease could not be demonstrated for allergy to enzymes. Neither of the two outcomes correlated with exposure estimates, possibly because of the low precision of the estimates.

The effect of altering haemodynamics on the plasma concentrations of natriuretic peptides in heart failure.

BACKGROUND: Natriuretic peptide levels reflect haemodynamics in patients with heart failure and may serve as biochemical markers of cardiac filling pressures. The purpose of this study was to detect differences in the kinetic profile between atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and their N-terminal fragments N-ANP and N-BNP, in response to rapid and persistent vasodilatation. METHODS: Sixteen men and four women aged 63.0+/-10.4 (mean+/-S.D.) with symptomatic congestive heart failure (NYHA III) and pulmonary capillary wedge pressure (PCWP)>18 mm Hg, received a 24-h infusion of nitroglycerin (N=8) or nicorandil (N=12). A reduction of PCWP was achieved for the duration of the study. Natriuretic peptides were measured by radioimmunoassay at baseline, 1, 3, 6, 12 and 24 h. RESULTS: PCWP and right atrial pressure fell rapidly and then increased modestly. ANP and N-ANP demonstrated a similar pattern. In contrast, BNP and N-BNP levels fell steadily throughout the observation period. This was accompanied by a continuous reduction of systemic vascular resistance (SVR). PCWP was highly correlated to the levels of all the natriuretic peptides. Using a longitudinal regression model evaluating responses over time, we found separate, significant relationships between all peptides and haemodynamic variables CONCLUSION: The atrial natriuretic peptides reflect rapid changes in filling pressures while the B-type peptides respond much slower. B-type peptides are less sensitive to short-term changes in filling pressures, but should reflect changes in SVR better during vasodilator therapy.

Exercise training in congestive heart failure. A review of the current status.

Traditionally exercise training was considered contraindicated in heart failure patients. However, during the last 15 years numerous small studies have demonstrated that training is safe in stable heart failure patients and that this intervention improves quality of life in this population. The beneficial effects include improved autonomic balance, reduced neurohumoral activation and reduced inflammatory response in addition to the direct effect on exercise capacity. Pooling of the available data from small randomized studies confirms the positive effect of training on morbidity, and also suggests that this type of intervention improves survival. Large scale studies are on-going to confirm the beneficial effects of training on mortality. This paper reviews the effects of exercise training in patients with the syndrome of heart failure and discusses the different types of training protocols and the tools for assessing the training effect in this population.

Occupational exposure to airborne proteolytic enzymes and lifestyle risk factors for dental erosion--a cross-sectional study.

This study examined the hypothesis that occupational exposure to airborne proteolytic enzymes is associated with dental erosions on the facial surfaces of exposed teeth. Individuals (n = 425) working at a pharmaceutical and biotechnological enterprise (Novozymes A/S) were examined; their mean age was 35 years (range = 18-67 years) and 143 (34%) were women. Two hundred and two of these individuals were newly employed by the company. Occupational exposure was assessed from questionnaire and workplace information. For practical analytical purposes, individuals were categorized as either previously exposed to proteolytic enzymes or not. Information on relevant lifestyle factors and medical history was obtained from a questionnaire. The main effect measure was facial erosion, but lingual erosion indices and the presence of Class V restorations were also considered. The validity of these measures was shown to be very high. Adjusted for potential confounders, there was no association between history of occupational exposure to proteolytic enzymes and prevalent facial or lingual erosion. With respect to prevalence of Class V restorations, the association was significant. The present study did not support directly our primary hypothesis that occupational exposure to airborne proteolytic enzymes is associated with dental erosions on the facial surfaces of exposed teeth. However, the results indicate that exposure to proteolytic enzymes may lead to pronounced tooth substance loss, demanding treatment.

Assessing the effect of exercise training in men with heart failure; comparison of maximal, submaximal and endurance exercise protocols.

AIMS: No consensus exists regarding the most appropriate exercise testing protocol for patients with congestive heart failure. This study describes the effect of exercise training on performance using three different protocols (maximal, submaximal and endurance testing) in patients with heart failure. METHODS AND RESULTS: Thirty men (mean age 67+/-8 years) with congestive heart failure in NYHA class III (mean ejection fraction 32+/-5%) were evaluated prior to and following exercise training. A maximal exercise cycle test with gas exchange measurements, a submaximal 6 min walk test and an endurance treadmill test with blood lactate sampling were used to evaluate exercise capacity after 12 weeks of exercise training. There was a 44.6% (P<0.001) increase in work performed during the maximal cycle test, with no significant increase in peak VO(2). The distance covered by the submaximal 6 min walk test increased by 8.1% (P<0.001). Lactate measured as area under the curve during the matched work intensity treadmill endurance test was reduced by 19.5% (P<0.005). CONCLUSION: We demonstrated a significant improvement in maximal, submaximal and endurance exercise capacity following 12 weeks of exercise training in patients with congestive heart failure. Endurance tests may be more sensitive and appropriate when assessing the efficacy of intervention in this population. Specifically, demonstration of reduced lactate production at matched work intensities suggests more efficient work and decreased dependence on anaerobic metabolism following training. Although maximal cycle tests are commonly used in clinical work, submaximal and endurance testing might be preferable for evaluating new treatment regimens in this population as they are easy to perform, are reproducible, and reflect daily tasks better than the maximal cycle test in this population.

A clinical index for evaluating and monitoring dental erosion.

This study describes a new fine-scaled system for classifying initial and advanced dental erosions. The system includes the use of study casts of the teeth in an epoxy resin with an accurate surface reproduction. The severity of erosion on each tooth surface is scored according to six grades of severity. In addition, the presence of a Class V restoration and dental erosion on the same surface increases the erosion score, as it is assumed that the need for restorative treatment can be caused by the erosion. A high inter-examiner agreement was found when the present scoring system was used by two examiners on the same sample. With this prerequisite it is proposed that an index value for facial, oral, incisal/occlusal and cervical surfaces is calculated as the mean value of scores for the respective surfaces. The index values represent the severity of tooth substance loss in various locations of the oral cavity and are furthermore suitable for data analysis. The system is thereby well-suited for determining etiologic factors and monitoring the progression of erosion over time.

Comparison of the degree of hemodynamic tolerance during intravenous infusion of nitroglycerin versus nicorandil in patients with congestive heart failure.

BACKGROUND: Continuous exposure to organic nitrates is associated with substantial tachyphylaxis. This study compares the development of tolerance during continuous intravenous treatment with nitroglycerin versus nicorandil over a 24-hour period. METHODS AND RESULTS: Twenty patients with congestive heart failure and pulmonary capillary wedge pressure (PCWP) > or = 18 mm Hg were randomly assigned to nitroglycerin or nicorandil in a double-blind, crossover study. Doses were titrated to obtain a reduction of PCWP of at least 30% and then maintained. The mean pretreatment PCWP for nitroglycerin was 25.4 +/- 6.7 mm Hg, decreasing to 19.0 +/- 6.8 mm Hg at 24 hours. The values for nicorandil were 24.3 +/- 6.3 mm Hg and 15.6 +/- 4.5 mm Hg, respectively. Between-treatment difference was significant (p < 0.01). The difference between the minimal PCWP value and the 24-hour PCWP value for nitroglycerin was 5.1 mm Hg vs 1.4 mm Hg for nicorandil (p < 0.005). The mean systemic vascular resistance was 1418 +/- 355 dynes.sec.cm-5 before nitroglycerin infusion, decreasing to 1312 +/- 353 dynes.sec.cm-5 at 24 hours. Corresponding values for nicorandil were 1420 +/- 366 dynes.sec.cm-5 and 967 +/- 274 dynes.sec.cm-5. Between-treatment difference was significant (p = 0.005). Tachyphylaxis developed in 12 (60%) patients during nitroglycerin infusion versus three patients (15%) during nicorandil infusion. CONCLUSION: This study demonstrates that intravenous nicorandil administration results in significantly less hemodynamic tolerance over a 24-hour period compared with nitroglycerin. This finding may represent a clinical advantage for nicorandil in the short-term treatment of patients with congestive heart failure.

Systemic thrombin generation and activity resistant to low molecular weight heparin administered prior to streptokinase in patients with acute myocardial infarction.

One hundred patients were included in a randomized open trial to assess the systemic factor Xa (FXa) and thrombin inhibitory effect as well as the safety profile of low molecular weight heparin (LMWH) given subcutaneously in conjunction with streptokinase (SK) in patients with acute myocardial infarction (MI). The treatment was initiated prior to SK, followed by repeated injections every 12 h for 7 days, using a dose of 150 anti-Xa units per kg body weight. The control group received unfractionated heparin (UFH) 12,500 i.u. subcutaneously every 12 h for 7 days, initiated 4 h after start of SK infusion. All patients received acetylsalicylic acid (ASA) initiated prior to SK. Serial blood samples were collected prior to and during the first 24 h after initiation of SK infusion for determination of prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III (TAT) complexes, fibrinopeptide A (FPA) and cardiac enzymes. Bleeding complications and adverse events were carefully accounted for. Infarct characteristics, as judged by creatine kinase MB isoenzyme (CK-MB) and cardiac troponin T (cTnT), were similar in both groups of patients. A comparable transient increase in F1 + 2, TAT and FPA was noted irrespective of heparin regimen. Increased anti-Xa activity in patients given LMWH prior to thrombolytic treatment had no impact on indices of systemic thrombin activation. The incidence of major bleedings was significantly higher in patients receiving LMWH as compared to patients receiving UFH. However, the occurrence of bleedings was modified after reduction of the initial LMWH dose to 100 anti-Xa units per kg body weight. In conclusion, systemic FXa- and thrombin activity following SK-infusion in patients with acute MI was uninfluenced by conjunctive LMWH treatment.

[Physical exercise and heart failure. A review article]. / Fysisk trening og hjertesvikt. En oversiktsartikkel.

This review discusses the therapeutic value of physical exercise in patients with congestive heart failure. The possible circulatory, peripheral and metabolic mechanisms involved are discussed. Relevant clinical research in this field is reviewed. Physical training appears to be a safe and efficacious intervention in this large population.

[Pro-atrial natriuretic factor is predictive for the clinical status of patients with heart failure]. / Pro-atrial natriuretisk faktor i plasma er prediktiv for klinisk status hos hjertesviktpasienter.

This study was undertaken in order to evaluate the relationship between N-terminal proatrial natriuretic factor [1-98] and routinely available measures of clinical status. Odds ratio estimates demonstrated a much higher risk of presence of left ventricular dysfunction and dilatation, pulmonary hypertension, and New York Heart Association function class III or IV with increasing proANF values. Analysis is simple and can be of practical value as a supplement in the assessment of cardiac status in this heterogeneous population.

Plasma proatrial natriuretic factor is predictive of clinical status in patients with congestive heart failure.

Atrial stretch results in myocyte release of the prohormone atrial natriuretic factor (1-126). The N-terminal (1-98) fragment, proatrial natriuretic factor (proANF) is released on an equimolar basis with the C-terminal (99-126) active hormone and may be assayed simply due to in vitro stability. This study was undertaken to evaluate the relation between proANF and routinely available measures of clinical status. ProANF was sampled from 202 patients (median age 68 years [range 15 to 85], 77% men) recruited from an active outpatient heart failure clinic. Patients were subgrouped according to New York Heart Association functional class, radionuclide ejection fraction (EF), echocardiographic left ventricular (LV) end-diastolic diameter, and Doppler-determined systolic pulmonary arterial pressure. The median proANF (pmol/L) values for patients in New York Heart Association classes I, II, III, IV were 725, 1,527, 1,750, and 5,172, respectively. The proANF value for the group with EF > 40% was 1,534 versus 1,993 for EF < or = 40% (p < 0.05). The value for the group with LV diameter < 60 mm ws 838 versus 1,751 for LV diameter > or = 60 mm (p < 0.01). The value for the group with systolic pulmonary artery pressure < 45 mm Hg was 1,241 versus 2,660 for systolic pulmonary artery pressure > or = 45 mm Hg (p < 0.01). ProANF correlated better than the other variables with New York Heart Association functional class and was more closely associated with noninvasive measurements than New York Heart Association functional class.(ABSTRACT TRUNCATED AT 250 WORDS)

Cancer morbidity among employees in a Danish pharmaceutical plant.

BACKGROUND: Workers in the pharmaceutical industry may be exposed to many potential carcinogens. We investigated cancer morbidity in a Danish plant where enzymes, insulin, antibiotics and sex hormones were produced in substantial quantities. METHODS: Altogether 10,889 people ever employed (1964-1988) at the pharmaceutical plant were retrieved from the files of a compulsory pension fund, and followed-up in the nationwide Danish Cancer Registry (1964-1989). Site-specific standardized incidence ratios (SIR) were estimated, based on cancer rates for the national population. Information on risk factors for breast cancer, e.g. number of children, age at menarche and first delivery, obesity, and non-occupational use of sex hormones was obtained from samples of the female employees, and compared to equivalent variables from the general population. RESULTS: The overall SIR for women was significantly elevated (n = 5554; SIR = 1.2). Excess risk was particularly seen for breast cancer (n = 97; SIR = 1.5), especially in a subgroup who had started work at the factory aged 30-39 and had continued to work for 1-9 years (SIR = 2.8). The SIR was near unity for men (n = 5335); however, three men with breast cancer versus 0.4 expected were found. Lifestyle components explained only about one-quarter of the excess female breast cancers. Proxy measures of intensity of occupational exposure to sex hormones or insulin showed no association with the risk for breast cancer. CONCLUSIONS: It seems unlikely that either a single occupational factor or an unusual reproductive pattern can explain the elevated breast cancer risk. Therefore, the finding requires further study.

[Hazardous health effects of microwaves and radio waves]. / Sundhedsskadelige virkninger af mikrobølger og radiobølger.

About 4000 Danish employees may be significantly exposed to radiofrequency electromagnetic radiation (RF) or microwaves (MW) during work in the health sector or industrially. Exposure measurements and classifications are difficult, therefore, epidemiological as well as experimental research in the field is complicated. High exposure induces elevation of body temperature or local heating ("hot spots"). Some biological effects from RF/MW exposure seem to be mediated by heating, others are considered to be athermic. Epidemiological studies do not indicate that RF/MW should be carcinogenic, and experimental studies have not shown the radiation to be mutagenic or carcinogenic. Epidemiological studies among physiotherapists have indicated that RF may have reproductive effects. In one study, an association between ischaemic heart disease and exposure to RF is observed. The cataractogenic property of MW is supposed to be mediated by elevation in lens temperature following relatively high exposure. However, in the light of the problems in exposure classification, the epidemiological research may not be conclusive, and attempts should be made to improve the methods. In addition, Danish experience points out a number of methods of exposure reduction in the working environment.