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Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Supported by Swedish Heart and Lung foundation and Stockholm County Council. Background/Introduction Cardiac resynchronization therapy (CRT) is a valuable treatment in selected patients with heart failure (HF) but is still underutilized. Aim We compared three informative data sources, which enrolled patients with HF at different organization setting and identified clinical, organizational, and level of care factors linked to CRT implantation in these cohorts. Methods Data from three large cohorts of patients with HF were compared. Patients with HF with reduced ejection fraction (HFrEF) in an ESC HF-Long Term Registry (ESC-HF-LT, n=25,621), a National HF Registry - Swede HF (n=156,621) and in the ESC-CRT Survey II (n=11088, all receiving CRT across 42 ESC countries), contributed data to the analysis. The ESC Survey II recruited patients at implanting centers, ESC-HF-LT at HF centers, whereas SwedeHF enrolled HF patients at different levels of care. Firstly, we compared patient characteristics, socio-economic and organizational factors between cohorts as well as between overlapping countries participating both in CRT Survey II and ESC HF LT. Secondly, we identified independent predictors of CRT use in the two registries using multivariable logistic regressions. Results Of the 1031 patients in ESC-HF-LT and the 5008 patients in Swede-HF, CRT was not used in 53-75 % of guideline- indicated patients. Women constituted 22% and median age ranged between 68-72 years. Guideline Directed Medical Therapy (GDMT), atrial fibrillation, previous myocardial infarction (SwedeHF) and HF hospitalization (ESC-HF-LT) was associated with more CRT use as was enrollment at university hospital and follow-up at HF center/Hospital. In Swede-HF above median income and higher education level were also independently associated with use of CRT. In the ESC-CRT Survey II (n=11.088) all patients received CRT with differences in the clinical indications between countries. Conclusion(s) CRT is an important treatment option for eligible patients with HF, which is still largely underused. The findings reported demonstrate that awareness of CRT indications as well as demographics, organizational and economic factors play an important role in CRT utilization.

Introduction Bilirubin is a recognized predictor of adverse outcomes in patients with heart failure and reduced ejection fraction (HFrEF), possibly because it is a marker of congestion. Alkaline phosphatase (ALP) is an enzyme produced in many tissues including the biliary ducts and elevated levels are also associated with congestion. Purpose To examine the prognostic value of ALP alone and in combination with bilirubin in patients with HFrEF. Methods The study population was ambulatory patients with HFrEF enrolled in 2 recent clinical trials with similar inclusion and exclusion criteria: ATMOSPHERE (derivation cohort) and PARADIGM-HF (validation). Cut points to define elevated bilirubin and alkaline phosphatase were >17mg/dL and >120 U/L respectively. The composite of cardiovascular death or HF hospitalization, its components, and all-cause death related to elevation of one, other or both of bilirubin and ALP was examined using Cox regression. Univariable and multivariable models with adjustment for other recognized prognostic variables including NT-proBNP were analyzed. Results Of 7016 patients with HFrEF enrolled in ATMOSPHERE, 6870 had a measurement of both bilirubin and ALP at baseline: mean age 63 years, 22% women, mean LVEF 28% and proportion NYHA class III/IV 37%. Bilirubin and ALP were both normal in 4810 (70.0%) patients, bilirubin was elevated in 1393 (20.3%), ALP was elevated in 360 (5.2%) and both were elevated in 307 (4.5%) patients. Patients with elevation of both ALP and bilirubin were older, had lower systolic blood pressure, higher heart rate, higher NT-pro BNP, more clinical features of congestion, more atrial fibrillation and a greater proportion were treated with diuretics and digoxin. The primary endpoint rates (per 100 person-years) were 10.4 (95% CI 9.9–11.0) when both markers were normal, 15.1 (13.9–16.4) when bilirubin was elevated, 12.4 (10.4–14.9) when alkaline phosphatase was elevated, and 25.6 (22.0–29.9) when both markers were elevated (Figure 1). The adjusted hazard ratios (95% CI) were (both biomarkers normal = reference): elevated bilirubin 1.19 (1.07–1.31), P=0.001; elevated ALP 1.03 (0.84–1.26), P=0.81; both elevated 1.45 (1.21–1.73), P Conclusions Elevation of ALP in combination with elevated bilirubin identifies a small group of patients at very high risk of adverse outcomes. This may reflect more significant congestion. ALP and bilirubin, inexpensive and routinely measured biochemical tests, are useful prognostic markers in patients with HFrEF. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship.

Background: Muscle wasting and unintentional weight loss (cachexia) have been associated with worse outcomes in heart failure (HF), but timely identification of these adverse phenomena is difficult. Spot urinary creatinine may be an easily accessible marker to assess muscle loss and cachexia. This study investigated the association of urinary creatinine with body composition changes and outcomes in patients with new-onset or worsening HF (WHF). Methods: In BIOSTAT-CHF, baseline spot urinary creatinine measurements were available in 2315 patients with new-onset or WHF in an international cohort (index cohort) and a validation cohort of 1431 similar patients from Scotland. Results: Median spot urinary creatinine concentrations were 5.2 [2.7–9.6] mmol/L in the index cohort. Median age was 69 ± 12 years and 73% were men. Lower spot urinary creatinine was associated with older age, lower height and weight, worse renal function, more severe HF, and a higher risk of >5% weight loss from baseline to 9 months (odds ratio = 1.23, 95% CI = 1.09–1.39 per log decrease; P = 0.001). Spot urinary creatinine was associated with Evans criteria of cachexia (OR = 1.26 per log decrease, 95% CI = 1.04–1.49; P = 0.016) and clustered with markers of heart failure severity in hierarchical cluster analyses. Lower urinary creatinine was associated with poorer exercise capacity and quality of life (both P

Background: Loop diuretics are frequently prescribed to patients with heart failure and reduced ejection fraction (HFrEF) for the treatment of congestion; however, they might hamper uptitration of inhibitors of the renin–angiotensin system. Methods: Loop diuretic dose at baseline was recorded in 2338 patients with HFrEF enrolled in BIOSTAT-CHF, an international study of HF patients on loop diuretic therapy who were eligible for uptitration of angiotensin-converting enzyme inhibitors (ACEi)/mineralocorticoid receptor antagonists (MRA). The association between loop diuretic dose and uptitration of ACEi/MRA to percentage of target dose was adjusted for a previously published model for likelihood of uptitration and a propensity score. Results: Baseline median loop diuretic dose was 40 [40–100] mg of furosemide or equivalent. Higher doses of loop diuretics were associated with higher NYHA class and higher levels of NT-proBNP, more severe signs and symptoms of congestion, more frequent MRA use, and lower doses of ACEi reached at 3 and 9 months (all P < 0.01). After propensity adjustment, higher doses of loop diuretics remained significantly associated with poorer uptitration of ACEi (Beta per log doubling of loop diuretic dose: − 1.66, P = 0.021), but not with uptitration of MRAs (P = 0.758). Higher doses of loop diuretics were independently associated with an increased risk of all-cause mortality or HF hospitalization [HR per doubling of loop diuretic dose: 1.06 (1.01–1.12), P = 0.021]. Conclusions: Higher doses of loop diuretics limited uptitration of ACEi in patients with HFrEF and were associated with a higher risk of death and/or HF hospitalization, independent of their lower likelihood of uptitration and higher baseline risk. Graphic abstract: This figure was created with images adapted from Servier Medical Art licensed under a Creative Commons Attribution 3.0[Figure not available: see fulltext.]. © 2020, The Author(s).

Cardiac resynchronization therapy (CRT) is an important treatment modality for patients with heart failure with a reduced ejection fraction and interventricular conduction delay which is supported by current guidelines from major medical societies. One of the largest international clinical practice surveys regarding the CRT - CRT Survey II was conducted from October 2015 to December 2016 in 42 ESC member countries. We compared the outcome data of the CRT Survey II with the Georgian cohort, where 24 patients were enrolled from 2 participating medical centers of Georgia. Despite CRT II Survey analysis did show us some similarities, there were also multiple, notable differencies between Georgian population and all other European countries' data, which can be explained by a number of socio-economic or healthcare-related factors.

The effects of topical timolol vs betaxolol on cardiopulmonary exercise performance were studied in a randomised double-masked fashion in 12 healthy male volunteers. Cardiopulmonary parameters were evaluated at the anaerobic threshold and at peak exercise. Intraocular pressure was determined before and after treatment by applanation tonometry. No differences were found in aerobic or peak exercise capacity. Maximal heart rate was slightly lower (P less than 0.05) following treatment with timolol compared with betaxolol. However, a correspondingly higher oxygen pulse (oxygen uptake/heart rate) compensated for this reduction and resulted in no difference in peak performance. At physiological work levels, it was not possible to demonstrate any influence of topical, selective or non-selective, beta-adrenergic blockade on cardiopulmonary exercise performance in these healthy volunteers.

To assess the relationship between interleukin (IL)-1-related molecules, infarct size and left ventricular (LV) remodelling following acute myocardial infarction (MI).Forty-two patients with first-time diagnosis of ST segment elevation MI (STEMI), with a single occluded vessel successfully revascularized by primary percutaneous coronary intervention (PCI), were recruited to this observational study conducted at a university teaching hospital and followed for 1 year.Plasma levels of IL-1β, IL-1 receptor antagonist (IL-1Ra), IL-18 and caspase-1 were analysed before and 2 days, 1 week and 2 months after PCI. Serial cardiac magnetic resonance imaging (CMR) was used for the assessment of infarct size and LV remodelling. CMR findings at 1 year was the primary outcome variable.Univariate analysis showed that IL-1-related mediators were strongly (IL-1 β), moderately (caspase-1) and weakly (IL-1Ra) associated with impaired myocardial function and noninfarct mass, but not infarct size, 1 year after reperfused STEMI. In multivariate analyses, troponin T predicted LV ejection fraction (LVEF), infarct size and LV end-diastolic (LVEDVi) and end-systolic volume index (LVESVi). However, significant additional variance was explained by IL-1β, IL-18 and caspase-1. IL-1β levels at 2 months, IL-18 at 2 days and pre-PCI caspase-1 were predictors of LVEF. Caspase-1 and in particular IL-1β at 2 days were the only predictors of noninfarct mass. IL-1β and IL-18 at 2 days were predictors of LVEDVi, whilst pre-PCI levels of IL-1β contributed to prediction of LVESVi. By contrast, pro-B-type natriuretic peptide, C-reactive protein, IL-6 and transforming growth factor-β1 (TGF-β1) had no or only a weak (TGF-β1) association with these CMR parameters in multivariate analyses.IL-1β levels after STEMI were strongly associated with impaired myocardial function and noninfarct LV mass after 1 year, suggesting a potential role for IL-1β as a predictor of maladaptive myocardial remodelling following reperfused MI.

This parallel, double-blind trial was designed to evaluate the efficacy of three dose levels of moexipril versus placebo as add-on therapy to hydrochlorothiazide (HCTZ) in patients with uncomplicated moderate to severe hypertension. Two hundred patients (aged 25-74 years) with sitting diastolic blood pressure (DBP) between 95 and 114 mm Hg after 4 week treatment with HCTZ 25 mg once daily were randomized to placebo, or moexipril 3.75, 7.5 mg, or 15 mg. BP was measured at 22-26 h postdose at biweekly visits and at 1, 2, 3, and 4 h postdose after the first dose of double-blind medication. At endpoint, adjusted mean reductions from baseline sitting DBP were 8.4, 8.8, and 8.9 mm Hg in the moexipril 3.75-, 7.5-, and 15-mg groups, respectively, as compared with a reduction of 4.6 mm Hg in the placebo group (p = 0.003). The differences in systolic BP (SBP) reductions were statistically significant in favor of each of the moexipril groups over the placebo group at all trough time-points. Adjusted mean changes in sitting SBP were 10.9, 12.0, and 11.7 mm Hg, respectively, as compared with a reduction of 0.6 mm Hg in the placebo group (p0.001). Our results indicate that moexipril and HCTZ constitute a clinically valuable combination in treatment of patients with moderate to severe hypertension.

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.

Intravenous amiodarone is a recognised treatment alternative for the conversion of atrial fibrillation to sinus rhythm.1–3 Consensus regarding dosage and duration of treatment has not been reached.4,5 Our coronary care unit routinely uses intravenous amiodarone for conversion of supraventricular arrhythmia in various clinical settings. Following a loading dose of 300 mg/30 mins, two alternative dosages of intravenous maintenance treatment—50 mg/hour and 100 mg/hour—employed. We compared the efficacy and safety of these two regimens in an open randomised study. Patients with atrial fibrillation or flutter with duration of less than 48 hours were included. Patients with ECG evidence of transmural ischaemia, class III antiarrhythmic treatment within 14 days, cardiogenic shock, uncontrolled thyroid disease, previous symptomatic bradycardia without pacemaker, and tachycardia based on atrioventricular (AV) re-entrant mechanisms were not included. Patients developing signs of haemodynamic decompensation were cardioverted. The primary parameter was conversion to sinus rhythm. Secondary parameters were time to sinus rhythm and time to rate control. Heart rate, QT time, and PR interval at the time of conversion, were recorded continuously. Electrocardioversion before completion of the 24 hour period and interruption of study medication because of adverse experience were separate end points. Conduction abnormalities …

The OPTIMAAL study was a multicenter, double-blind, randomized, parallel, trial in high-risk patients who were treated early after acute myocardial infarction that compared treatment with an angiotensin-converting enzyme inhibitor (captopril) and a selective angiotensin II antagonist (losartan) on survival and morbidity. A total of 5,477 patients with heart failure during the acute phase or with a new Q-wave anterior infarction or reinfarction were recruited. This study describes the baseline data and initial course of the cohort and compares these data and patient management across countries.

It is widely believed that patients are more frequently admitted to hospital in bad weather.We evaluated all 15,060 emergency admissions to the Medical Department of Rogaland Central Hospital during a 17-month period and compared this material with meteorological data.We found no correlation between the number of admissions and "good weather" (as defined by the amount of cloud cover), but we found a significant difference of about two more patients (6.6%) being admitted on days with rain and snow. There was no correlation between the amount of precipitation and the number of admitted patients, but a small, significant inverse relation between temperature and admissions. We have also demonstrated a considerable difference in the number of admissions on the different weekdays, with the highest number on Mondays and the lowest on Saturdays.Both the incidence of disease and doctor availability may partially explain the influence of weather and the daily variation in emergency admissions to hospital.

Angiotensin converting enzyme (ACE) inhibitors and diuretics represent the first line of therapy in patients with symptomatic heart failure. Inhibition of angiotensin II production is, however, incomplete with ACE inhibitors, due to non-ACE dependent conversion pathways. Moreover, some patients are intolerant to ACE inhibitors due to side effects or renal insufficiency. Angiotensin II receptor blockers may be an alternative to, or an additional treatment in heart failure. Preliminary studies comparing the angiotensin II receptor blocker losartan with placebo have demonstrated improved haemodynamic parameters, reduced hospitalisation and mortality in patients with heart failure. Reduced morbidity and mortality have also been found with losartan treatment, as compared to the ACE inhibitor captopril. This paper discusses the role of angiotensin II receptor blockers in the treatment of heart failure. Some results from published studies and a short description of ongoing trials are presented.

To evaluate the dose response relationship of moxonidine on plasma concentration of norepinephrine during acute and chronic administration in patients with congestive heart failure (CHF).Sympathetic activation is increased in heart failure. Moxonidine is an imidazoline ligand acting on the central nervous system (CNS) receptors to decrease sympathetic activation.Ninety-seven patients with heart failure and New York Heart Association class II-III symptoms and ejection fraction40% were randomized to placebo or one of three target doses of moxonidine, 0.1, 0.2 or 0.3 mg administered twice daily. An initial dose of moxonidine 0.1 mg twice a day (b.i.d.) was followed by weekly increments of 0.1 mg b.i.d. until target dose. The second and third study days occurred after four weeks (at target dose) and after 12 weeks, respectively. At each study day, repeated blood samples were drawn.There was a significant dose-related decrease of systolic blood pressure across all three study days. Heart rate decreased significantly on study day 3 in a dose-related manner. The acute 2 h decrease in plasma norepinephrine in response to all three doses of moxonidine was significantly different compared with placebo after four and 12 weeks. There was a significant linear relation between dose and plasma norepinephrine after four and 12 weeks in both 2 h peak and the time averaged effect (8 h). The number of adverse events was similar in the moxonidine and placebo groups.The increased sympathetic activation in CHF can be reduced by moxonidine through CNS inhibition.

In 1994, a Norwegian programme for diagnosis and treatment of chronic heart failure was published. Recently the American College of Cardiology, the American Heart Association and the Task Force on Heart Failure of the European Society of Cardiology have published similar guidelines. In this article, the Working Group on Heart Failure of the Norwegian Society of Cardiology presents an updated programme for evaluation and management of patients with chronic heart failure.

Patients with acute myocardial infarction and evidence of heart failure or left ventricular dysfunction during the acute phase have an excessive mortality risk. Therapy with angiotensin-converting enzyme inhibitors attenuates the detrimental effects of angiotensin II and has been shown to substantially reduce morbidity and mortality in this population. Selective, angiotensin type 1 receptor antagonism with losartan, which inhibits the effects of angiotensin II regardless of its source at the receptor level, may provide more complete blockade of the renin-angiotensin system. The Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) study is a multicenter, double-blind, randomized, parallel, captopril-controlled trial. The primary hypothesis is that, compared with captopril, losartan will decrease the risk for all-cause mortality by 20% in high-risk patients after acute myocardial infarction. The study population will consist of 5,000 patients,or = 50 years of age, with heart failure during the acute phase or with a new Q-wave anterior infarction or reinfarction. Patients will be randomized to treatment with either losartan or captopril. All patients will be followed until 937 deaths occur (event-driven). The primary end point is total mortality (all-cause mortality). The secondary and tertiary end points are sudden death (and/or resuscitated cardiac death) and fatal/nonfatal reinfarction. Based on the assumed event rate, treatment effect and a 95% power to detect a 20% reduction in all-cause mortality at the 4.3% significance level (2-sided, adjusted for 2 interim analyses), the trial will enroll at least 5,004 patients and continue until a total number of 937 events has been reached (intention-to-treat analysis).

Patients with heart failure are particularly susceptible to the negative effects of calcium channel blockers because the failing heart demonstrates a defect in the delivery of calcium to the contractile proteins, and an attenuation of the normal sympathetic reflexes. Currently these drugs have no place in the treatment of heart failure caused by systolic dysfunction of the left ventricle. Calcium channel blockers should probably not be described for patients with coronary artery disease and left ventricular dysfunction. When the patient needs additional treatment for angina and beta-blockers or nitrates have not given satisfactory results, it may be appropriate to prescribe amlodipine or felodipine.

We compared early markers of acute myocardial infarction (AMI) in the first 6 h from the onset of symptoms in 133 non-traumatized patients arriving at the emergency department with chest pain suggestive of AMI. Clinical performance parameters were calculated on the basis of 45 patients with AMI and 88 patients with a non-AMI diagnosis. At admission and in the first 0-3 h after the onset of chest pain the creatine kinase-MB (CK-MB) subform ratio was the most sensitive test at a comparable specificity level of 0.95. In the time interval of 3-5 h, myoglobin, the CK-MB mass concentration and the CK-MB subform ratio were associated with the greatest areas under receiver operating characteristic (ROC) curves, but differences between these tests were small and non-significant. At 6 h from the onset of pain, differences in clinical performance between the same three tests were even smaller whether or not samples drawn after the start of thrombolytic treatment were included in the test comparison. For confirmation of AMI at 6 h after onset of pain, CK-MB (activity and mass concentration) demonstrated the highest positive likelihood ratio, and for exclusion of AMI at 6 h the CK-MB subform ratio was associated with the highest negative likelihood ratio. However, differences between the CK-MB subform ratio, CK-MB mass concentration and myoglobin were not significant as estimated by the substantial overlap between the confidence intervals of the likelihood ratios and the ROC areas at 6 h. Cardiac troponin T (cTnT) demonstrated an ROC area equal to the CK-MB isoform ratio and myoglobin at 6 h. However, the likelihood ratio for ruling out AMI was lower, mostly due to the elevated cTnT in unstable coronary disease not defined as AMI. We conclude that the CK-MB subform ratio, CK-MB mass concentration and myoglobin do not demonstrate any significant differences in clinical performance for ruling in or ruling out acute myocardial infarction at 6 h after the onset of chest pain.

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.

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.

The aim of the present study was to assess the short- and long-term effects of multiple doses of the angiotensin II receptor antagonist losartan in heart failure.A multicenter, placebo-controlled, oral, multidose (2.5, 10, 25, and 50 mg losartan once daily) double-blind comparison in patients with symptomatic heart failure and impaired left ventricular function (ejection fraction40%). Invasive 24-hour hemodynamic assessment was performed after the first dose and after 12 weeks of treatment. Clinical status and tolerability of treatment with losartan over the 12-week period were also evaluated. One hundred fifty-four patients were enrolled, of which 134 met the protocol criterion of baseline pulmonary capillary wedge pressureor = 13 mm Hg. During short-term administration, systemic vascular resistance (SVR) (largest reduction against placebo of 197 dyne.s-1.cm-5 at 4 hours) and blood pressure fell significantly with 50 mg, lesser decreases were seen with 25 mg, and no discernible effects were seen with 2.5 and 10 mg. After 12 weeks of treatment, similar effects were seen on SVR and blood pressure (maximal fall in SVR against placebo, 318 dyne.s-1.cm-5 at 5 hours with 50 mg). In addition, pulmonary capillary wedge pressure fell with 2.5, 25, and 50 mg (largest reduction against placebo of 6.3 mm Hg at 6 hours with 50 mg), cardiac index rose with 25 and 50 mg, and heart rate was lower with all active treatment groups. Active treatment was well tolerated, and excess cough was not reported.This study showed that oral losartan administered to patients with symptomatic heart failure resulted in beneficial hemodynamic effects with short-term administration, with additional beneficial hemodynamic effects seen after 12 weeks of therapy. Clear effects were seen with both 25 and 50 mg, with the greatest effect seen with 50 mg.

Congestive left heart failure can be treated using three main strategies: change preload to optimize the Frank-Starling relationship, decrease after-load to reduce external work and increase cardiac contractility by inotropic stimulation. The third option is reviewed in this article, which discusses the pharmacological and clinical effects of different inotropic drugs as known in 1994. It is concluded that digitalis should be considered apart from other inotropic drugs. Even when in sinus rhythm, digitalis seems reasonable as an adjuvans to after-load reduction and diuretics. Chronic use of other inotropic drugs for congestive left heart failure is not recommended.

See doi:10.1016/S1095-668X(02)00384-6for the article to which this editorial refers. Heart failure is the fourth leading cause of hospitalization in the United States and the most frequent cause in the population over 65 years of age.1 Due to the rising prevalence of heart failure in the aging population, morbidity and mortality from this disease is increasing in epidemic proportions.2 While it is impossible to measure perfectly the burden of heart failure on patients, their families and society, both the acute and chronic symptoms of heart failure eventually translate into increased hospitalization time.3 Admission to hospital due to heart failure is a clinically important event and is associated with a striking increase in the risk of death.4 However, assessment of the overall impact of hospitalization is not straightforward, and one of the challenges involved in designing and performing clinical trials in these patients is to determine the mostappropriate method. Hospitalization data does not represent reporting of surrogate endpoints. Surrogate endpoints relate to biologic mechanisms involved in the disease process. In patients with heart failure these include haemodynamic measurements, arrhythmias, exercise capacity, neurohumoral profile, ejection fraction and autonomic nervous system markers.5 …

Losartan is a specific angiotensin II receptor antagonist with no agonist properties. This agent permits evaluation of the response to selective angiotensin II antagonism in patients with congestive heart failure.A study was designed to assess the acute hemodynamic and neurohumoral response to losartan in a controlled, blinded fashion.Sixty-six patients in New York Heart Association functional class II, III or IV with a radionuclide ejection fraction of40% were randomly allocated to treatment with placebo and then sequentially to 5, 10, 25, 75 and 150 mg losartan. Hemodynamic and neurohumoral measurements were obtained at selected times for 24 h following ingestion of a single dose of losartan.Treatment with losartan led to dose-dependent vasodilation. Mean arterial pressure and systemic vascular resistance decreased progressively up to a dose of 25 mg. The higher doses of 75 and 150 mg did not produce additional vasodilation. Similarly, the decrease in pulmonary capillary wedge pressure was not greater with doses exceeding 25 mg. The increase in the cardiac index was modest and similar for all doses. No variation in the heart rate was observed at any dose. The hemodynamic changes were accompanied by marked neurohumoral changes. Large dose-related increases in plasma renin activity and angiotensin II levels were observed, especially following the 150-mg dose. Moderate reductions occurred in serum aldosterone and plasma noradrenaline. The peak effect for these parameters occurred 4-6 h after the dose, with persistent changes still evident 24 h after the dose.These data demonstrate that selective blockade of the angiotensin II receptor with losartan causes a favorable vasodilatory and neurohumoral response in patients with heart failure. Further studies are needed to determine the most effective dose in these patients. Nevertheless, losartan should be of substantial clinical use in the management of this large population.

An expert meeting on the treatment of heart failure was organized by the Swedish Medical Products Agency in 1992. There were four participants from Norway. Two of these (AW, JK), in cooperation with a group of cardiologists with a special interest in heart failure, present in this article a modified Norwegian programme for treatment of chronic heart failure. When evaluating risk for patients with chronic heart failure, it is necessary to take into account both symptoms and left ventricular systolic function determined by ejection fraction. Specific recommendations are made for treatment of asymptomatic patients with left ventricular dysfunction and for symptomatic patients with mild, moderate and severe heart failure.

The sympathetic nervous system is activated in acute myocardial infarction (MI). Scarce data exist, however, regarding the release of the sympathetic cotransmitter neuropeptide Y (NPY) during the acute and early convalescent phases after acute MI. Plasma NPY determination was obtained on days 1 and 3 after admission from 47 patients with acute MI and from eight control patients with acute chest pain without MI. Samples were also obtained on day 30 from the 39 survivors from the original MI cohort. Plasma NPY peaked on day 3 in the MI group (day 1: mean = 46.0 pmol/L, SEM = 6.4 pmol/L; day 3: mean = 60.8 pmol/L, SEM = 5.7 pmol/L; day 30: mean = 27.2 pmol/L, SEM = 4.1 pmol/L; days 1 to 3: p = 0.002; days 3 to 30: p < 0.001), whereas in the control group a nonsignificant decrease from day 1 (mean = 42.6 pmol/L, SEM = 12.3 pmol/L) to day 3 (mean = 34.0 pmol/L, SEM = 5.6 pmol/L) was observed. Plasma NPY levels were significantly increased in patients with MI on day 3 (p = 0.044), but not at baseline compared with the control group. No significant association between plasma NPY and plasma catecholamines, clinical heart failure, or 1-month survival was evident. These results suggest that increased plasma levels of the vasoconstrictory and cardiodepressant sympathetic neurotransmitter NPY are present in the recovery phase of MI, but with a plasma profile distinct from that of catecholamines.

The Nordic Enalapril Exercise Trial was a multicenter subtrial of the Cooperative New Scandinavian Enalapril Survival Study (CONSENSUS II) designed to evaluate the effect on maximal exercise performance of a 6-month period of enalapril treatment initiated early after myocardial infarction.When begun early after myocardial infarction, converting enzyme inhibition therapy has been shown to attenuate infarct expansion and reduce left ventricular volume. Therapy has been associated with improved exercise performance.Three hundred twenty-seven men (mean age 63.3 +/- 10.9 years) with documented acute myocardial infarction were randomized to treatment with enalapril or placebo on a double-blind basis. Intravenous enalaprilat or placebo therapy was initiated within 24 h after the onset of symptoms. Oral therapy was continued at a target dose of 20 mg/day. Patients exercised maximally at 1 month and 6 months after infarction to symptom-limited end points on a cycle ergometer with a 20 W/min incremental protocol.The treatment and control groups were comparable in patient age, concurrent therapy and type and site of infarction. At 1 month, for all patients, mean total work performed was 34.9 +/- 20.9 kJ in the enalapril group (n = 169) versus 28.5 +/- 20.6 kJ in the placebo group (n = 158) (difference = 18.4%, p0.01). This between-group difference in favor of enalapril was greatest in patients70 years old (difference = 41.4%, p0.01, n = 105) and those with clinical evidence of heart failure (difference = 33.0%, p0.01, n = 122). At 6 months for all patients, mean total work performed was 35.4 +/- 23.8 kJ in the enalapril group versus 34.0 +/- 23.9 kJ in the placebo group (difference = 4.1%, NS).This trial found that chronic converting enzyme inhibition initiated early after myocardial infarction was associated with significantly greater exercise capacity in men tested at 1 month. This difference was independent of type or site of infarction, patient age or the presence of clinical heart failure. The difference between the treatment and control groups was not significant at 6 months because of improvement in the placebo group. Further research is needed to elucidate the potential mechanisms involved, profile those patients most likely to profit from early therapy and establish the optimal timing and duration for intervention.

BACKGROUND Losartan is a new specific angiotensin II receptor antagonist with no agonist properties that provides the opportunity to study the consequences of angiotensin II blockade. The objective of the present study was to evaluate the hemodynamic and neurohormonal response to losartan in patients with congestive heart failure. METHODS AND RESULTS After baseline hemodynamic measurements using balloon-tipped pulmonary artery and radial arterial catheters, patients were randomized to receive a single dose of placebo or 5, 10, 25, 75, or 150 mg losartan in a double-blind, sequential fashion. Hemodynamic and neurohormonal parameters were then measured periodically for 24 hours. Losartan caused vasodilation in a dose-dependent manner. By the area-under-the-curve method, the reduction in the mean arterial pressure and systemic vascular resistance grew larger up to a dose of 25 mg, but the higher 75- and 150-mg doses did not produce additional vasodilation. In response to losartan, there were compensatory increases in both angiotensin II concentrations and in plasma renin activity, which were greatest at the highest doses. Aldosterone concentrations were significantly lowered with losartan. CONCLUSIONS Blockade of the angiotensin II receptor with the antagonist losartan causes vasodilator and neurohormonal effects in patients with congestive heart failure. The lack of additional vasodilator response with doses of more than 25 mg suggests that neurohormonal activation might limit the efficacy of high dose of losartan.

The role of digitalis therapy in patients with sinus rhythm and mild to moderate heart failure has been a subject of controversy. This review critically examines the relevant literature and specifically evaluates trials in this patient population. The pharmacokinetics and the pharmacodynamics of the most commonly prescribed agents are briefly discussed. The available evidence supports the use of this agent in patients with sinus rhythm and clinical signs of systolic dysfunction. Digitalis is not recommended as a routine when the primary cause of heart failure is diastolic dysfunction. The use of digitalis therapy in combination with diuretics and vasodilator therapy deserves further attention.

Peak cardiopulmonary exercise performance is readily evaluated. The most appropriate methodology for assessment of submaximal exercise performance, however, is a subject of controversy. Therefore, we assessed the difference between conventional methodologies using standard criteria to estimate the onset of anaerobiosis and compared them with known gas exchange and blood lactate [( La]) concentrations. Oxygen uptake (VO2) was determined at both the gas exchange anaerobic threshold (ATge) and the lactate threshold (LaT) using the following three types of commonly used methodologies in a blinded fashion: 1) conventional techniques based on manual inspection of plots of gas exchange indexes and [La] versus time, 2) computerized linear regression analysis of two-segment model plots for VCO2 versus VO2 and log [La] versus log VO2, and 3) fixed values determining the VO2 at a respiratory exchange ratio (VCO2/VO2) of 1.00 and at an [La] of 2 mmol/l. Respiratory exchange data were collected on a breath-by-breath basis in 30 men with documented myocardial infarction. Simultaneously, arterial blood was sampled for [La] every 20 seconds during maximal exercise on an upright bicycle ergometer programmed for a continuous ramp protocol of 15 W/min. The mean (+/- SD) peak VO2 was 1,463 (+/- 312) ml/min. The mean (+/- SD) VO2 values for each method were as follows: (table; see text) These results indicate that a good positive correlation exists between the gas exchange and lactate data by all three approaches. The chosen fixed values yield the highest threshold detection for both ATge and LaT. Detection was lowest using regression analysis for LaT.(ABSTRACT TRUNCATED AT 250 WORDS)

Objetivo Comparar el efecto sobre la morbilidad y la mortalidad del losartan, un antagonista de los receptores de la angiotensina II (ARA II), frente al captopril, en pacientes con infarto agudo de miocardio (IAM) reciente con sintomas clinicos de insuficiencia cardiaca (IC), disfuncion ventricular izquierda (DVI) o infarto anterior extenso Diseno Ensayo clinico aleatorizado doble ciego Emplazamiento Un total de 329 centros de 7 paises de Europa Poblacion de estudio Un total de 5.477 pacientes (29% mujeres) de igual 50 anos o mas (media: 67,4 ± 9,8) con IAM reciente (10 dias previos) considerado de alto riesgo (con IC, DVI con fraccion de eyeccion [FE] Intervencion Los pacientes fueron distribuidos aleatoriamente en dos grupos: uno de ellos (n = 2.744) recibio losartan desde 12,5 mg/dia hasta alcanzar 50 mg/dia; el otro (n = 2.733) recibio captopril (desde 12,5 mg/8 h hasta 50 mg/8 h), en ambos ademas del tratamiento convencional del IAM y eventualmente de la IC Medicion del resultado El objetivo primario del estudio fue la mortalidad por cualquier causa. La combinacion de muerte subita o resucitacion fue un objetivo secundario y el reinfarto un objetivo terciario. El ensayo fue valorado mediante analisis por intencion de tratar Resultados principales Se produjeron 499 muertes (18%) en el grupo losartan y 445 (16%) en el grupo captopril (seguimiento medio de 2,7 anos). La diferencia de la mortalidad fue favorable a captopril (riesgo relativo [RR]: 1,13; intervalo de confianza del 95% (IC del 95 %): 0,99–1,28. Para el resto de objetivos los resultados para losartan y captopril, respectivamente, fueron: muerte subita o resucitacion: 239 (9%) frente a 203 (7%) (RR: 1,19; IC del 95%: 0,98–1,43); reinfarto fatal o no fatal: 384 (14%) frente a 379 (14%) (RR: 1,03; IC del 95%: 0,89–1,18, y hospitalizacion por cualquier causa: 1.806 (66%) frente a 1.774 (65%) (RR: 1,03; IC del 95%: 0,97–1,10. El losartan fue significativamente mejor tolerado que el captopril, siendo menor el numero de pacientes en que se interrumpio el tratamiento (458 [17%] frente a 624 [23%]; RR: 0,70; IC del 95%: 0,62–0,79) Conclusion A pesar de que los resultados no alcanzan una diferencia significativa a favor de captopril, los IECA siguen siendo el tratamiento de eleccion en pacientes con IAM de alto riesgo (IC, disfuncion ventricular o IAM extenso). El losartan no debe recomendarse de forma general en estos pacientes. Sin embargo, fue mejor tolerado que el captopril. Aunque el papel de los ARA II en pacientes que no intoleran los IECA en este contexto clinico aun no esta aclarado, pueden ser considerados como una indicacion aceptable en esos pacientes

The acute hemodynamic and hormonal effects of the oral angiotensin-converting enzyme (ACE) inhibitor lisinopril (MK-521) were assessed over a period of 96 hours in 12 patients with heart failure. This compound is the lysine anologue of enalaprilat (MK-422), is biologically active following absorption, and is cleared via the urine without any known metabolic transformation. Single doses of lisinopril, ranging from 1.25 mg to 10 mg, were administered on days 1 and 3, each followed by 48 hours of intensive hemodynamic observation. Across all doses, maximal reductions in mean arterial pressure (17.2%), mean pulmonary capillary wedge pressure (28%), and systemic vascular resistance (25.6%) were observed compared to baseline values. No significant changes in heart rate were recorded. Arterial blood was sampled at frequent intervals for angiotensin II, ACE activity, plasma renin activity, renin substrate, plasma aldosterone, and serum drug levels. Right atrial blood was sampled simultaneously for angiotensin I, thus permitting assessment of the degree of pulmonary conversion to angiotensin II. The results indicate potent inhibition of the renin-angiotensin-aldosterone system along with hemodynamic efficacy over a period exceeding 24 hours. Frequent clinical follow-up on long-term chronic therapy has revealed no adverse experience.

Systemic lupus erythematosus (SLE) is a disease with a broad clinical spectrum. Cardiac involvement has been well documented (1,2) and can appear as pericarditis, myocarditis, endocarditis, or coronary artery disease. Cardiac involvement is rarely reported as the initial manifestation of the disease (2,3).Cardiac tamponade is an unusual complication in SLE and until recently only 12 such cases had been reported in the English literature (4). In only 5 of these was tamponade the initial manifestation. We describe a patient who presented with pericarditis as the initial manifestation of SLE, with the rapid development of a life-threatening pericardial tamponade.

The pharmacokinetics of the converting enzyme inhibitor, enalapril, were studied in an open, randomized, balanced crossover design in 12 hospitalized patients with stable, chronic congestive heart failure (CHF). Enalapril maleate is a prodrug requiring in vivo hepatic esterolysis to yield the active diacid inhibitor enalaprilat. CHF results in changes in regional blood flow that may affect the gastrointestinal absorption, hepatic hydrolysis and renal excretion of enalapril and enalaprilat. In order to evaluate the pharmacokinetics of enalapril in CHF, the following treatments were given: enalapril maleate 10 mg orally, enalapril maleate 5 mg intravenously and enalaprilat 5 mg intravenously. Each dose was followed by a 72 h period with frequent blood sampling and fractionated urine collection for the radioimmunoassay of enalaprilat, before and after sample hydrolysis. Mean absorption for the oral dose was 69%, hydrolysis 55%, bioavailability 38%, urinary recovery 77% and estimated first-pass effect 10%. The results were compared with available data in normal subjects. After oral administration of 10 mg enalapril maleate, the extent of absorption, the degree of hydrolysis and the bioavailability in CHF patients appear to be similar to those in normals with differences less than 10%. The rate of absorption and hydrolysis appear to be slightly slower in CHF. The serum concentrations of enalaprilat were consistently greater in CHF and maximal concentrations were reached at 6 h in CHF as compared to 4 h in normal subjects. We conclude that the presence of CHF does not appreciably alter the pharmacokinetic behaviour of enalapril. The observed differences may be associated with age as well as the disease state.

1. The pharmacokinetics of the angiotensin converting enzyme inhibitor, lisinopril, were studied in an open, randomized, balanced, two-period, crossover design in 12 in-patients with stable, chronic congestive heart failure (CHF). 2. To evaluate the pharmacokinetics of lisinopril in CHF, lisinopril was administered orally (10 mg) and intravenously (5 mg) in each patient. Each dose was followed by a 72 h period with frequent blood sampling and fractional urine collections for radioimmunoassay of lisinopril. 3. Mean urinary recovery of lisinopril was 15 and 88% following oral and intravenous administration, respectively; absorption/bioavailability of lisinopril based on urinary recovery ratios was 16%, less than that found in normal subjects. 4. Serum concentrations of lisinopril following intravenous administration were higher in this study than those previously observed in normal subjects. 5. The results of this study suggest a reduced absorption of lisinopril in CHF and altered disposition, possibly associated with age as well as the disease state.