Archer Broughton

Adverse consequences of high sympathetic nervous activity in the failing human heart

OBJECTIVES In view of previous experimental evidence relating sympathetic nervous overactivity in the heart to myocardial necrosis and ventricular arrhythmias, we prospectively examined the hypothesis that heightened cardiac sympathetic nervous activity is associated with an adverse outcome in patients with moderate to severe heart failure. BACKGROUND Despite recent therapeutic advances, patients with heart failure continue to have high mortality from progressive hemodynamic decompensation and lethal ventricular arrhythmias. It is believed that initially compensatory increases in sympathetic nervous system activity may ultimately be maladaptive, potentially contributing to subsequent adverse events. METHODS Sixty patients with moderate to severe heart failure (left ventricular ejection fraction 18.9 +/- 0.9% [mean +/- SE]) were studied prospectively. In addition to the compilation of a hemodynamic, biochemical and electrocardiographic profile for each patient, whole-body and cardiac sympathetic activity were determined by isotope dilution. The relation of these variables to outcome was determined by Cox proportional hazards analysis. RESULTS The mean follow-up period of the study group was 7 +/- 1 months (range 1 to 24) with a 12-month actuarial survival of 75%. Deaths (14 in all) were accounted for either by sudden death or progressive heart failure in equal numbers. The rate of release of norepinephrine from the heart was significantly higher in patients with heart failure than in healthy subjects (402 +/- 37 vs. 105 +/- 19 pmol/min, p < 0.01), although the values for heart failure ranged widely from normal to 10 times normal. By univariate Cox proportional hazards analysis, pulmonary capillary wedge pressure (p < 0.01), mean pulmonary artery pressure (p < 0.001), serum sodium levels (p < 0.01) and cardiac norepinephrine spill-over rate (p < 0.001) were identified as significant prognostic markers. In a multivariate analysis, cardiac norepinephrine spillover rate was identified as the most powerful prognostic marker (p = 0.0006) of those evaluated in this study. CONCLUSIONS These results suggest that activation of the sympathetic nervous system in patients with heart failure, specifically the cardiac sympathetic nerves, may contribute to the poor prognosis associated with severe heart failure. The data therefore provide a rationale for the use of drugs such as beta-adrenergic blocking agents in the management of patients with heart failure.

Evidence of a Selective Increase in Cardiac Sympathetic Activity in Patients with Sustained Ventricular Arrhythmias

BACKGROUND Although enhanced efferent cardiac sympathetic nervous activity has been proposed as an important factor in the genesis of ventricular arrhythmias and sudden cardiac death, direct clinical evidence has been lacking. METHODS We measured the rates of total and cardiac norepinephrine spillover into the plasma, which reflect respectively overall and cardiac sympathetic nervous activity, in 12 patients who had recovered from a spontaneous, sustained episode of ventricular tachycardia or ventricular fibrillation outside the hospital 4 to 48 days earlier. The results were compared with those from three age-matched reference groups without a history of ventricular arrhythmias: 12 patients with coronary artery disease, 6 patients with chest pain but normal coronary arteries, and 12 healthy, normal subjects. RESULTS The patients who had had ventricular arrhythmias had reduced left ventricular ejection fractions, as compared with the patients with coronary artery disease or chest pain (mean [+/- SE], 46 +/- 3 percent vs. 58 +/- 4 percent and 69 +/- 5 percent, respectively; P less than 0.003). The rates of total norepinephrine spillover into the plasma were similar in the three reference groups, but 80 percent higher in the patients with ventricular arrhythmias (P less than 0.005). The rate of cardiac norepinephrine spillover was 450 percent higher in these patients (176 +/- 39 pmol per minute, as compared with 32 +/- 8 pmol per minute in the normal subjects; P less than 0.001), a disproportionate increase relative to the increase in total spillover, which indicated selective activation of the cardiac sympathetic outflow. This increase in cardiac norepinephrine spillover was probably caused by a reduction in left ventricular function. CONCLUSIONS These results suggest that in some patients major ventricular arrhythmias are associated with and perhaps caused by sustained and selective cardiac sympathetic activation. We speculate that depressed ventricular function was present before the ventricular arrhythmia occurred, and that this resulted in reflex cardiac sympathetic activation, which in turn contributed to the genesis of the arrhythmia.

Combined dyssynchrony and scar imaging with cardiac magnetic resonance imaging predicts clinical response and long-term prognosis following cardiac resynchronization therapy.

AIMS Cardiac resynchronization therapy (CRT) is advocated in advanced heart failure; however, patient selection remains challenging. We examined the utility of multi-sequential cardiac magnetic resonance imaging (CMR) in predicting outcome after CRT. METHODS AND RESULTS We performed multi-sequential CMR on 40 subjects with cardiomyopathy and advanced heart failure, despite optimized medical therapy. All patients had been recommended for CRT according to accepted clinical guidelines. Patients were defined by CMR as likely responders if they had significant mechanical dyssynchrony (> or =65 ms delay between septal and posterolateral wall contraction on cine imaging), and no transmural scarring of the anteroseptal or posterolateral wall on delayed contrast-enhanced imaging. Clinical composite score was recorded at baseline and 6 months post-CRT. Long-term follow-up (transplant-free survival) was 497 +/- 55 days post-CRT. A clinical response was achieved in 19/26 (73%) of the CMR-predicted responders and 2/12 (17%) of the CMR-predicted non-responders (P < 0.01, chi(2)). The sensitivity of CMR for prediction of clinical response to CRT was 90%, with a specificity of 59%. Transplant-free survival post-CRT was achieved in 88% of the CMR-predicted responders and 58% of the CMR-predicted non-responders (P < 0.05, Kaplan-Meier survival analysis). CONCLUSION Multi-sequential CMR identifies patients with severe cardiomyopathy who will respond to CRT with a favourable long-term prognosis.

Induction of ventricular arrhythmias by programmed ventricular stimulation: a prospective study on the effects of stimulation current on arrhythmia induction.

A protocol for programmed ventricular stimulation is described in which the effect of increasing stimulation current on ventricular refractoriness and arrhythmia induction was specifically examined. The protocol was evaluated prospectively in 70 patients undergoing electrophysiological study for documented or suspected ventricular arrhythmias. Programmed electrical stimulation was performed at the right ventricular apex and outflow tract using single and double extrastimuli and burst pacing. Stimulation currents of 2, 5, 10, and 20 mA were used in ascending order. The initial (lowest) current was never less than twice diastolic threshold and was maintained during each stimulation run until refractoriness was reached. The current was then increased to the next level to facilitate premature capture until refractoriness was encountered at 20 mA or a sustained arrhythmia occurred. Ventricular arrhythmias were induced in 34 patients, 31 of whom had presented with a sustained ventricular arrhythmia. The incidence of induced arrhythmias was low in those patients who had presented with symptoms alone, a non-sustained arrhythmia, or a sustained arrhythmia in association with a predisposing clinical event. Only one patient with a negative result had further ventricular arrhythmias during the mean follow up period of 15 months. Although each increase in stimulation current caused a decrease in measured ventricular refractoriness, this resulted in only four arrhythmias. Only one arrhythmia was induced above 5 mA. These results suggest that this simple protocol using two extrastimuli and a single stimulation current of 5 mA will reliably identify most patients who have symptomatic ventricular arrhythmias.

Left ventricular blood flow during aortic pressure reduction in hypertensive dogs.

We measured left ventricular blood flow with radioactive microspheres during aortic pressure reduction in 10 open-chest, anesthetized dogs with left ventricular hypertrophy due to chronic hypertension and in 10 matched normotensive dogs. Heart rate and left atrial pressure were held constant, and autonomic reflexes were abolished with ganglionic blockade. Aortic diastolic pressure was lowered from baseline to 90, 75, and 60 mm Hg with an arteriovenous fistula. During aortic pressure reduction, a stepwise decline in the endocardial-to-epicardial flow ratio in hypertrophied hearts from 1.23±0.04 at baseline to 0.96±0.09 at a diastolic pressure of 75 mm Hg parallelled that in normal hearts and was not associated with any deterioration in left ventricular performance. However, a further fall in the endocardial-to-epicardial flow ratio to 0.76±0.10 at a diastolic pressure of 60 mm Hg in hypertrophied hearts exceeded that in normal hearts (0.92±0.05, p< 0.05) and was accompanied by evidence of left ventricular isovolumic and end-systolic dysfunction. We conclude that in hearts with pressure-overload left ventricular hypertrophy, aortic pressure reduction causes a transmural blood flow redistribution from subendocardial to subepicardial muscle layers. At moderately low aortic pressures, this redistribution is more pronounced than in normal hearts and is associated with functional evidence of myocardial ischemia.

Review of the current management of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia. Its prevalence is increasing and accordingly, so is its burden on healthcare systems throughout the world. The pathophysiology of AF is complex and poorly understood, which of itself presents a major challenge to the management of this important condition. AF is associated with increased morbidity and mortality, particularly in patients with underlying left ventricular dysfunction. Once AF occurs, it is often difficult to ‘cure’ and as such, the major focus of therapy is currently divided essentially between a rate control strategy and a need to revert to and maintain sinus rhythm. Both approaches seek to minimise the associated symptoms and complications. Over the past two decades, numerous pharmacological approaches to the management of AF have been employed, many of which have been shown to be relatively ineffective or confounded by major complications. Accordingly, recent research and interest has focused on non-pharmacological electrophysiological therapies to either cure AF or improve symptoms. This review summarises the current approaches to the management AF and provides some new insights into emerging therapies for this common clinical problem.

Left Ventricular Ejection Fraction and Absence of ACE Inhibitor/Angiotensin II Receptor Blocker Predicts Appropriate Defibrillator Therapy in the Primary Prevention Population

Introduction: Implantable cardioverter defibrillators (ICD) significantly reduce mortality in patients with left ventricular (LV) dysfunction. However, little is known of the predictors of appropriate device activation in the primary prevention population. The aim of the present study was to determine predictors of appropriate device therapy in patients receiving ICDs for primary prevention.

Cardiac resynchronisation therapy for heart failure

Heart failure (HF) is increasingly common and, despite advances in pharmacotherapeutic management, often progresses. Progression is marked by structural and electrical changes–remodelling. In approximately one‐third of patients, ventricular dilatation is accompanied by intraventricular conduction delays, most commonly the left bundle branch block (LBBB). The presence of LBBB is associated with mechanical dyssynchrony of the heart. Cardiac resynchronisation therapy (CRT), the use of special pacemakers with or without implantable cardioverter defibrillators, aims to resynchronise the failing heart, improving myocardial contraction without increased energetics. Several, large, randomised clinical trials have now established the benefit of CRT in a select group of HF patients, providing functional and, recently shown, mortality benefits. However, a substantial proportion of patients are considered non‐responders to CRT, and studies are now underway to identify the patients most likely to respond to CRT.

ROLE OF CARDIAC AND VASCULAR AMPLIFIERS IN THE MAINTENANCE OF HYPERTENSION AND THE EFFECT OF REVERSAL OF CARDIOVASCULAR HYPERTROPHY

1. Changes in amplifying capacities of the hypertrophied heart and resistance vessels account for the characteristic evolution of haemodynamic patterns in the course of essential hypertension.

Trends and Clinical Outcomes in Patients Undergoing Primary Percutaneous Revascularisation for ST-Elevation Myocardial Infarction: A Single Centre Experience

BACKGROUND Primary percutaneous coronary intervention (PPCI) is the preferred therapy for patients presenting with ST-elevation myocardial infarction (STEMI). We reviewed patients undergoing PCI for STEMI over a 6-year period to evaluate changes in procedural characteristics and clinical outcomes given recent changes to STEMI guidelines. METHODS All patients presenting to the Alfred Hospital, a tertiary referral hospital, between 1 January 2010 and 31 December 2015 undergoing PCI for STEMI were identified. Detailed review of their procedure reports was performed and 30-day and 12-month clinical outcomes were recorded including major adverse cardiac events (MACE). RESULTS There was a total of 445 patients aged 60.6±12.4 years with 369 (82.9%) male. There was a significant increase in radial access use over the 6-year period 0/49 (0%) in 2010 vs 56/113 (49.6%) in 2015 (p<0.01). There was a significant reduction in the use of IIb/IIIa receptor antagonists during the period 29/49 (59%) in 2010 vs 24/113 (21%) in 2015 (p<0.01) and use of aspiration thrombectomy 15/49 (31%) in 2010 vs 19/113 (17%) in 2015 (p<0.01). There was no significant reduction in major bleeding over this period with 2/49 (4%) in 2010 vs 5/108 (5%) in 2015 (p=0.32). Thirty-day and 12-month mortality was also unchanged. CONCLUSION Between 2010 and 2015 there has been a significant increase in the use of radial access and a reduction in the use of glycoprotein IIb/IIIa antagonists and aspiration thrombectomy in patients undergoing PPCI. This was not associated with changes in major bleeding or 30-day or 12-month mortality.