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Aims Heart failure is characterized by recurrent hospitalizations, but often only the first event is considered in clinical trial reports. In chronic diseases, such as heart failure, analysing all events gives a more complete picture of treatment benefit. We describe methods of analysing repeat hospitalizations, and illustrate their value in one major trial. Methods and results The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity ( CHARM)-Preserved study compared candesartan with placebo in 3023 patients with heart failure and preserved systolic function. The heart failure hospitalization rates were 12.5 and 8.9 per 100 patient-years in the placebo and candesartan groups, respectively. The repeat hospitalizations were analysed using the Andersen-Gill, Poisson, and negative binomial methods. Death was incorporated into analyses by treating it as an additional event. The win ratio method and a method that jointly models hospitalizations and mortality were also considered. Using repeat events gave larger treatment benefits than time to first event analysis. The negative binomial method for the composite of recurrent heart failure hospitalizations and cardiovascular death gave a rate ratio of 0.75 [95% confidence interval ( CI) 0.62-0.91, P = 0.003], whereas the hazard ratio for time to first heart failure hospitalization or cardiovascular death was 0.86 (95% CI 0.74-1.00, P = 0.050). Conclusions In patients with preserved EF, candesartan reduces the rate of admissions for worsening heart failure, to a greater extent than apparent from analysing only first hospitalizations. Recurrent events should be routinely incorporated into the analysis of future clinical trials in heart failure. [ABSTRACT FROM AUTHOR]

Aims: It is unknown whether there is an interaction between aspirin and angiotensin receptor blockers on outcomes in patients with heart failure (HF). [ABSTRACT FROM PUBLISHER]

Aims: Heart failure (HF) and chronic obstructive pulmonary disease are common partners. Bronchodilators are associated with adverse cardiovascular outcomes in patients with pulmonary disease. The outcome of patients with HF prescribed bronchodilators is poorly defined. [ABSTRACT FROM PUBLISHER]

Aims: The prevalence and importance of liver function test (LFT) abnormalities in a large contemporary cohort of heart failure patients have not been systematically evaluated. [ABSTRACT FROM PUBLISHER]

The Trial of Preventing Hypertension (TROPHY) demonstrated the feasibility of possibly reducing the incidence of hypertension with the angiotensin receptor blocker candesartan compared with placebo. The long-term benefits of pharmacologic therapy in high-normal blood pressure, or prehypertension are not known, and the long-term effect on health-related quality of life (HRQL) has not been determined. An analysis of covariance model was used to assess treatment differences from baseline in the HRQL scores using Short Form (SF)-36, and component measures at subsequent visits. Of the 809 randomized patients, 734 had both baseline and ≥1 HRQL follow-up assessment: 95% (379 of 397) of patients receiving candesartan and 91% (355 of 388) of patients receiving placebo. There were no statistically significant between-group differences in least-squares mean physical component survey and mental component survey scores or the individual scales at each scheduled visit relative to baseline values (P >.05). In TROPHY, patients with prehypertension had relatively high baseline HRQL, and HRQL was maintained with the angiotensin receptor blocker candesartan over both the 2-year treatment period and a total 4-year trial period. [ABSTRACT FROM AUTHOR]

Abstract: Background: The efficacy and safety of adding an angiotensin receptor blocker (ARB) in heart failure (HF) patients already taking an angiotensin-converting enzyme-inhibitor (ACE-I) plus an aldosterone antagonist is uncertain (especially if taking a beta blocker as well). The CHARM-Added trial describes the largest experience of using multiple inhibitors of the renin–angiotensin–aldosterone system (RAAS) together. Methods and results: 2548 HF patients, taking an ACE-I (936 no spironolactone/no beta blocker; 1175 no spironolactone/beta blocker; 199 spironolactone/no beta blocker; 238 sprionolactone/beta blocker), were randomized to placebo or candesartan and followed for 41 months (median). The primary outcome was cardiovascular death or HF hospitalization. In patients taking both a beta blocker and spironolactone (in addition to an ACE-I) at baseline, the candesartan:placebo hazard ratio was 0.85(95% CI 0.56, 1.29), compared to 0.85(95% CI 0.75, 0.96) in all randomized patients (interaction p value 0.49). The relative risk of discontinuation of candesartan (compared to placebo) because of hypotension, increased serum creatinine or hyperkalemia was not increased in patients taking spironolactone at baseline. Conclusions: An ARB may provide added benefit, at acceptable risk, in HF patients already taking spironolactone as well as an ACE-I and beta blocker. These findings must be confirmed in a prospective randomized trial before this approach can be recommended, routinely. [Copyright &y& Elsevier]

Abstract: Background: Bundle branch block (BBB) is a powerful independent predictor of cardiovascular mortality in patients with heart failure (HF) and reduced left ventricular ejection fraction (LVEF). The prognostic implications in HF with preserved systolic function (HF–PSF) are less well understood. Methods: The Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) programme randomised 7599 patients with symptomatic HF to receive candesartan or placebo. The primary outcome comprised cardiovascular death or HF hospitalisation. The relative risk conveyed by BBB relative to a normal electrocardiogram was examined. Results: The prevalence of BBB was significantly lower in patients with preserved compared with reduced systolic function (CHARM-Preserved 14.4%, Alternative 29.6%, Added 30.5%), p <0.0001. Overall, the adjusted hazard ratio for the primary outcome was 1.48 (95% confidence interval 1.22–1.78), p <0.0001, reflecting increased risk in patients with reduced LVEF (1.72 [1.28–2.31], p =0.0003). The apparently more modest risk among patients with HF–PSF was significant in unadjusted (1.80 [1.37–2.37], p <0.0001) but not adjusted analysis (1.16 [0.88–1.54], p =0.2897). However, no formal statistical difference was observed between the two cohorts, and interpretation is limited by the unknown prevalence of left and right BBB morphologies in each. Comparing BBB presence with absence yielded qualitatively similar results. Conclusion: The simple clinical finding of BBB is a powerful independent predictor of worse clinical outcomes in patients with HF and reduced LVEF. It is less frequent, with a more modest predictive effect, in patients with preserved systolic function. [Copyright &y& Elsevier]

Abstract: Background: Limited comparative studies assessing the health-related quality of life (HRQL) in heart failure (HF) patients with preserved vs. low ejection fraction (LVEF) have been disparate. Aims: The aims of this study were a) to characterize HRQL in a large population of HF patients with preserved and low LVEF and b) to determine the factors associated with worse HRQL. Methods: Patients with symptomatic HF (NYHA Class II–IV) enrolled in the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) HRQL study completed the Minnesota Living with Heart Failure questionnaire at randomization. Patients were stratified into 2 HF cohorts: preserved LVEF (>40%) and low LVEF (≤40%). Results: In 2709 of the eligible 2744 (98.6%) patients, the summary scores ranged from 0 to 105 (mean 40.9). There were no differences in overall responses of HF patients with preserved vs. low LVEF (41.1 vs. 40.8). Independent factors associated with worse HRQL in both populations included female gender, younger age, higher body mass index, lower systolic blood pressure, greater symptom burden, and worse functional status. Conclusions: In symptomatic HF patients, HRQL is equally impaired in both preserved and low LVEF populations. Targeting improvement in symptoms and HRQL is an important treatment objective in all HF patients. [Copyright &y& Elsevier]

Abstract: Aims: To evaluate the effect of the angiotensin receptor blocker candesartan on patients'' perception of symptoms, using the McMaster Overall treatment evaluation (OTE), in a broad spectrum of patients with chronic heart failure (CHF). Methods and results: Patients with symptomatic CHF, randomised in the CHARM Programme in North America (n=2498), were studied. OTE was assessed at baseline, at 6, 14 and 26 months and the patient''s final or closing visit. Patient''s status was classified as “improved (score +1 to +7)”, “unchanged (score 0)” or “deteriorated (score −1 to −7)” at the end of the study compared to baseline. Both a simple “last visit carried forward” (LVCF) analysis and “worst rank carried forward” (WRCF) analysis (where patients who died were allocated the worst OTE score) were used. In the LVCF analysis, compared to placebo, more candesartan patients improved (37.7% versus 33.5%) and fewer worsened (10.8% versus 12.0%) in OTE (p=0.017). The WRCF analysis also showed better overall OTE scores with candesartan compared to placebo (p=0.029). There was no heterogeneity in the response to candesartan between the CHARM component trials or across four exploratory sub-groups (age, sex, NYHA class and beta-blocker). Conclusions: Candesartan was shown to be better than placebo, when using the McMaster OTE to measure patient perception of treatment. More patients treated with candesartan reported improvement and fewer reported deterioration. This benefit was obtained when candesartan was added to extensive background therapy and is consistent with the benefits of candesartan on NYHA class, hospital admission for worsening heart failure and mortality. [Copyright &y& Elsevier]

Animal models have made substantial contributions to the understanding of basic electrophysiologic principles and arrhythmia mechanisms, as well as to the development of antiarrhythmic drugs, devices and procedures. The field of clinical electrophysiology has progressed very dramatically and there have also been advances in the basic laboratory that bear relevance In the methods, design and interpretation of clinical electrophysiologic testing, and to the application of new, potential antiarrhythmic interventions. [ABSTRACT FROM AUTHOR]

We studied the effects of various pacing modes on cardiac hemodynamics and pulmonary gas alterations in chronic heart blocked dogs. Changing the pacing mode from an atrioventricular interval of 100 ms (AV100) to a ventriculo-atrial interval of 100 ms (VA100) caused a significant fall in left ventricular pressure (117.64 ± 11.91 to 95.60 ± 16.58 mmHg) and cardiac output from 2.18 ± 0.24 to 1.46 ± 0.20 L/min. Following the change in pacing mode from AV100 to VA 100, there was an increase in (he alveolar-arterial O2 gradient from 23.28 ± 6.97 to 28.74 ± 8.43 mmHg and a decrease in the arterial CO2 tension from 32.42 ± 3.22 to 29.42 ± 3.22 mmHg. There was also a decrease in arterial CO2 tension when the AV100 pacing mode was compared to asynchronous ventricular pacing (32.42 ± 3.22 versus 30.56 ± 2.82 mmHg). The minute volume of O2 also decreased when the pacing mode was changed from AV100 to asynchronous ventricular pacing (0.134 ±0.01 versus 0.126 ± 0.01 L/min) and decreased further a( VA100 to 0.114 ± 0.01 L/min. Other significant changes were also observed: the percent of expired CO2 decreased when the pacing mode was changed from AVIOO to VA100 (3.68 ± 0.13 versus 3.37 ± 0.26%) or to asynchronous ventricular pacing (3.40 ± 0.31%). The end-expiratory O2 increased and CO2 decreased when the pacing mode was changed from AV100 to VA100. The breath-by-breath correlation of end-expiratory O2 and CO2 with left ventricular systolic pressure showed an almost immediate increase in O2 and reduction in CO2 concentration associated with decreasing systolic pressure. The decrease in pulmonary gas exchange appeared in part related to alterations in cardiac hemodynamics and particularly to the fall in cardiac output. It is speculated hut not proven by these studies that alterations could be further explained by a fall in O2 consumption or reflex shunting of blood in vascular beds due to the fall in cardiac output. However, the additional deleterious effects of atrial contraction against a closed AV valve on pulmonary gas exchange and hemodynamics were also apparent. Notably, these studies could provide a physiologic basis for some symptoms associated with the pacemaker syndrome produced by the absence of AV synchrony. [ABSTRACT FROM AUTHOR]

Electrophysiologic testing represents a major advance in both the diagnosis and management of cardiac rhythm and conduction disturbances. It is a sophisticated but arduous and invasive technique that requires proper patient selection, trained personnel, and specialized equipment and facilities for its optimal application. Patients with serious or life-threatening rhythm disorders are most likely to benefit from electrophysiologic testing. Patients with cardiovascular disease and incapacitating symptoms such as syncope or near-syncope, for whom noninvasive testing fails to reveal an etiology, as well as those patients considered candidates for various pacemaker and antiarrhythmic surgical interventions, are also suitable candidates for electrophysiologic testing. This relatively young field is still rapidly evolving. The major advance to come in the field of electrophysiology will be the simple identification of patients at high risk for sudden cardiac death. It is unclear whether invasive electrophysiologic testing will ultimately fulfill this goal or whether it will be helpful instead in leading to the development of noninvasive methods which may satisfy this need. This symposium and the introductory article address the present status of electrophysiologic studies in clinical practice. [ABSTRACT FROM AUTHOR]

Discusses the role of dual atrioventricular nodal pathways in arrhythmia. Overview of studies of the mechanism of supraventricular tachycardias; Cause of supraventricular tachycardia; Methodology used to demonstrate dual atrioventricular conduction; Manifestations of dual atrioventricular nodal pathways.

The role of the middle intercaval area ("internodal pathway") in the genesis of atrial re-entry was studied using microelectrode techniques and the extrastimulus method in the rabbit heart. Following surgical interruption of the anterior and posterior internodal tracts, two patterns of re-entry were observed using the middle internodal pathway manifesting alternatively as tachy- and bradyarrhythmias. Re-entry which was produced by critically timed extrastimulation at the septal branch of the crista terminalis (CT) caused tachycardia reciprocating between the sinus node (SN) and intercaval area. Spontaneous re-enfrant impulses were also observed, particularly following the addition of cedilanid (0.04 mg/L). In addition, in association with critical prolongation of conduction in the sino-septal area, premature discharge of the dominant pacemaker fibers was observed and resulted in the appearance of bradyarrhythmias. These were commonly manifest as bigeminy and trigeminy on the surface septal electrogram. Hence concealed sinus node re-entry could manifest itself as apparent sino-atrial block or sino-atrial re-entry tachycardia. [ABSTRACT FROM AUTHOR]

Several chronic canine myocardial infarction-ventricular tachyarrhythmia models are now available for the evaluation of new antiarrhythmic drugs The available models fulfill many, but not all of the requirements for an ideal chronic arrhythmia model Sustained arrhythmias can be initiated in these animals using routine methods of programmed pacing. Presumably, the mechanism for these arrhythmias is localized re-entry, similar to that in patients with previous myocardial infarction and chronic coronary artery disease However, these models are not suitable for determining whether a new drug will abolish spontaneously-occurring ventricular extrasystoles In addition, these models are of unproven value in the study of acute spontaneously-occurring sudden death, although recently initiated, provocative work may shed further light on this subject Most importantly, the available models do seem well-suited to the evaluation of new drugs intended for use of chronic coronary artery disease patients at risk for sustained re-entrant ventricular tachycardia or fibrillation Notably, the results of preliminary electropharmacologic studies in these canine models parallel closely those findings reported in human patients with sustained life-threatening ventricular tachyarrhythmias. Therefore, increased use of these chronic models for new antiarrhythmic drug testing appears promising. [ABSTRACT FROM AUTHOR]

Carotid sinus massage affects supraventricular arrhythmias primarily through vagotonic effects on the sinus and AV nodes, but vagal innervation of the ventricle also exists and has been shown to have functional significance. The case presented here illustrates an unusual example of a ventricular tachycardia that was repeatedly converted to normal sinus rhythm by carotid sinus massage following administration of digoxin. The clinician should be aware that a wide QRS-complex tachycardia that responds to carotid sinus massage is not necessarily supraventricular in origin. [ABSTRACT FROM AUTHOR]