Andrew D. Flapan

Prospective Study of Heart Rate Variability and Mortality in Chronic Heart Failure Results of the United Kingdom Heart Failure Evaluation and Assessment of Risk Trial (UK-Heart)

BACKGROUND Patients with chronic heart failure (CHF) have a continuing high mortality. Autonomic dysfunction may play an important role in the pathophysiology of cardiac death in CHF. UK-HEART examined the value of heart rate variability (HRV) measures as independent predictors of death in CHF. METHODS AND RESULTS In a prospective study powered for mortality, we recruited 433 outpatients 62+/-9.6 years old with CHF (NYHA functional class I to III; mean ejection fraction, 0.41+/-0.17). Time-domain HRV indices and conventional prognostic indicators were related to death by multivariate analysis. During 482+/-161 days of follow-up, cardiothoracic ratio, SDNN, left ventricular end-systolic diameter, and serum sodium were significant predictors of all-cause mortality. The risk ratio for a 41.2-ms decrease in SDNN was 1.62 (95% CI, 1.16 to 2.44). The annual mortality rate for the study population in SDNN subgroups was 5.5% for >100 ms, 12.7% for 50 to 100 ms, and 51.4% for <50 ms. SDNN, creatinine, and serum sodium were related to progressive heart failure death. Cardiothoracic ratio, left ventricular end-diastolic diameter, the presence of nonsustained ventricular tachycardia, and serum potassium were related to sudden cardiac death. A reduction in SDNN was the most powerful predictor of the risk of death due to progressive heart failure. CONCLUSIONS CHF is associated with autonomic dysfunction, which can be quantified by measuring HRV. A reduction in SDNN identifies patients at high risk of death and is a better predictor of death due to progressive heart failure than other conventional clinical measurements. High-risk subgroups identified by this measurement are candidates for additional therapy after prescription of an ACE inhibitor.

18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial.

BACKGROUND The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers (18)F-sodium fluoride ((18)F-NaF) and (18)F-fluorodeoxyglucose ((18)F-FDG). METHODS In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent (18)F-NaF and (18)F-FDG PET-CT, and invasive coronary angiography. (18)F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of (18)F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction. FINDINGS In 37 (93%) patients with myocardial infarction, the highest coronary (18)F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40-2·25] vs highest non-culprit 1·24 [1·06-1·38], p<0·0001). By contrast, coronary (18)F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 [1·40-2·13] vs 1·58 [1·28-2·01], p=0·34). Marked (18)F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal (18)F-NaF uptake (maximum tissue-to-background ratio 1·90 [IQR 1·61-2·17]) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 [1·09-1·19] vs 1·01 [0·94-1·06]; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% [21-29] vs 18% [14-22], p=0·001). INTERPRETATION (18)F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease. FUNDING Chief Scientist Office Scotland and British Heart Foundation.

Omega 3 fatty acids and cardiovascular disease—fishing for a natural treatment

Omega 3 fatty acids from fish and fish oils can protect against coronary heart disease. Both health professionals and the public are increasingly interested in their role in the prevention and management of coronary heart disease. In this era of multiple pharmacological treatments for cardiovascular disease many believe that simple dietary interventions or nutritional supplements may be a more natural and acceptable method of providing benefits. Several areas of uncertainty remain. The optimal intake of omega 3 fatty acids is not firmly established, nor is their mechanism of action fully understood. Some studies have produced conflicting results, and concerns have been increasing about environmental contamination of certain fish. This article reviews the current evidence regarding fish oils and cardiovascular disease, their possible mechanism of action, and potential future developments and research strategies.

Decreased cardiac parasympathetic activity in chronic heart failure and its relation to left ventricular function.

BACKGROUND--Activation of the sympathetic nervous system has been extensively studied in patients with chronic heart failure, but the parasympathetic nervous system has received relatively little attention. The objective in this study was to investigate cardiac parasympathetic activity in chronic heart failure and to explore its relation to left ventricular function. METHODS--Heart rate variability was measured from 24 hour ambulatory electrocardiograms by counting the number of times each RR interval exceeded the preceding RR interval by more than 50 ms (counts). This method provided a sensitive index of cardiac parasympathetic activity. RESULTS--Mean (range) of counts were: waking 48 (1-275)/h, sleeping 62 (0-360)/h, and total 1310 (31-7278)/24 h. These were lower than expected, and in 26 (60%) of the 43 patients counts fell below the lower 95% confidence intervals (95% CI) for RR counts in normal subjects. A significant correlation between total 24 hour RR counts and left ventricular ejection fraction was present (r = 0.49, p less than 0.05). CONCLUSIONS--These results indicate that most patients with chronic heart failure have reduced heart rate variability and therefore reduced cardiac parasympathetic activity. The degree of parasympathetic dysfunction is related to the severity of left ventricular dysfunction. This may be relevant to the high incidence of ventricular arrhythmias and poor prognosis of patients with chronic heart failure.

Acute Cardiovascular Effects of Apelin in Humans Potential Role in Patients With Chronic Heart Failure

Background— Apelin, the endogenous ligand for the novel G protein–coupled receptor APJ, has major cardiovascular effects in preclinical models. The study objectives were to establish the effects of acute apelin administration on peripheral, cardiac, and systemic hemodynamic variables in healthy volunteers and patients with heart failure. Methods and Results— Eighteen patients with New York Heart Association class II to III chronic heart failure, 6 patients undergoing diagnostic coronary angiography, and 26 healthy volunteers participated in a series of randomized, double-blind, placebo-controlled studies. Measurements of forearm blood flow, coronary blood flow, left ventricular pressure, and cardiac output were made by venous occlusion plethysmography, Doppler flow wire and quantitative coronary angiography, pressure wire, and thoracic bioimpedance, respectively. Intrabrachial infusions of (Pyr1)apelin-13, acetylcholine, and sodium nitroprusside caused forearm vasodilatation in patients and control subjects (all P<0.0001). Vasodilatation to acetylcholine (P=0.01) but not apelin (P=0.3) or sodium nitroprusside (P=0.9) was attenuated in patients with heart failure. Intracoronary bolus of apelin-36 increased coronary blood flow and the maximum rate of rise in left ventricular pressure and reduced peak and end-diastolic left ventricular pressures (all P<0.05). Systemic infusions of (Pyr1)apelin-13 (30 to 300 nmol/min) increased cardiac index and lowered mean arterial pressure and peripheral vascular resistance in patients and healthy control subjects (all P<0.01) but increased heart rate only in control subjects (P<0.01). Conclusions— Acute apelin administration in humans causes peripheral and coronary vasodilatation and increases cardiac output. APJ agonism represents a novel potential therapeutic target for patients with heart failure.

Obesity paradox in a cohort of 4880 consecutive patients undergoing percutaneous coronary intervention.

AIMS We sought to investigate the impact of body mass index (BMI) on long-term all-cause mortality in patients following first-time elective percutaneous coronary intervention (PCI). METHODS AND RESULTS We used the Scottish Coronary Revascularisation Register to undertake a cohort study of all patients undergoing elective PCI in Scotland between April 1997 and March 2006 inclusive. We excluded patients who had previously undergone revascularization. There were 219 deaths within 5 years of 4880 procedures. Compared with normal weight individuals, those with a BMI > or =27.5 and <30 were at reduced risk of dying (HR 0.59, 95% CI 0.39-0.90, 95%, P = 0.014). There was no attenuation of the association after adjustment for potential confounders, including age, hypertension, diabetes, and left ventricular function (adjusted HR 0.59, 95% CI 0.39-0.90, P = 0.015), and there were no statistically significant interactions. The results were unaltered by restricting the analysis to events beyond 30 days of follow-up. CONCLUSION Among patients undergoing percutaneous intervention for coronary artery disease, increased BMI was associated with improved 5 year survival. Among those with established coronary disease, the adverse effects of excess adipose tissue may be offset by beneficial vasoactive properties.

Previous Coronary Stent Implantation and Cardiac Events in Patients Undergoing Noncardiac Surgery

Background—Noncardiac surgery performed after coronary stent implantation is associated with an increased risk of stent thrombosis, myocardial infarction, and death. The influence of stent type and period of risk still have to be defined. Methods and Results—We linked the Scottish Coronary Revascularisation Register with hospital admission data to undertake a Scotland-wide retrospective cohort study examining cardiac outcomes in all patients who received drug-eluting or bare-metal stents between April 2003 and March 2007 and subsequently underwent noncardiac surgery. Of 1953 patients, 570 (29%) were treated with at least 1 drug-eluting stent and 1383 (71%) with bare-metal stents only. There were no differences between drug-eluting and bare-metal stents in the primary end point of in-hospital mortality or ischemic cardiac events (14.6% versus 13.3%; P=0.3) or the secondary end points of in-hospital mortality (0.7% versus 0.6%; P=0.8) and acute myocardial infarction (1.2% versus 0.7%; P=0.3). Perioperative death and ischemic cardiac events occurred more frequently when surgery was performed within 42 days of stent implantation (42.4% versus 12.8% beyond 42 days; P<0.001), especially in patients revascularized after an acute coronary syndrome (65% versus 32%; P=0.037). There were no temporal differences in outcomes between the drug-eluting and bare-metal stent groups. Conclusions—Patients undergoing noncardiac surgery after recent coronary stent implantation are at increased risk of perioperative myocardial ischemia, myocardial infarction, and death, particularly after an acute coronary syndrome. For at least 2 years after percutaneous coronary intervention, cardiac outcomes after noncardiac surgery are similar for both drug-eluting and bare-metal stents.

Effect of captopril on cardiac parasympathetic activity in chronic cardiac failure secondary to coronary artery disease

Thirty-two patients with chronic cardiac failure underwent 24-hour ambulatory electrocardiographic monitoring on 2 separate occasions: 20 patients before and during treatment with captopril, and 12 acting as controls. Heart rate variability was calculated by counting the number of times successive RR interval differences were greater than 50 ms (this measurement being a reliable index of cardiac parasympathetic activity). During treatment with captopril, group mean total counts increased to 1,032 (range 48 to 7,437) from 482 (range 23 to 6,120) (p = 0.002). There was no change in mean hourly waking or sleeping heart rates. In the control group, no changes were seen: group mean total counts on the first occasion were 340 (range 120 to 3,255) and on the second occasion 400 (range 154 to 3,300) (p = not significant). These results show that treatment with angiotensin-converting enzyme inhibitors increases cardiac parasympathetic activity in patients with chronic cardiac failure. This may be relevant to the improved prognosis of this group of patients when treated with angiotensin-converting enzyme inhibitors.

Measurement of parasympathetic activity from 24-hour ambulatory electrocardiograms and its reproducibility and sensitivity in normal subjects, patients with symptomatic myocardial ischemia, and patients with diabetes mellitus

The parasympathetic nervous system plays a major role in the pathophysiology of many cardiovascular disease, particularly in modulating myocardial electrical stability. Measurements of heart rate variability have been widely used to assess parasympathetic activity. The reproducibility of measurements obtained from 24-hour ambulatory electrocardiograms has not been well documented. We have developed a technique for measuring parasympathetic activity from clinical quality 24-hour ambulatory electrocardiograms by counting beat-to-beat increases in RR interval that are > 50 ms. To determine the reproducibility and sensitivity of our technique, we analyzed repeated 24-hour electrocardiograms of 173 subjects (19 normal subjects, 67 patients with ischemic heart disease, and 87 diabetics) followed up over periods of 2 to 16 weeks. In all subject groups, mean values for repeated measurements were virtually identical. Measurements were stable in all 3 groups throughout the course of the study, as assessed by intraclass correlation coefficients. This technique is sensitive enough to detect relatively small changes in parasympathetic activity in subjects, as demonstrated by the calculated Bland and Altman coefficients of repeatability. Reproducibility and sensitivity of our technique are particularly good in normal subjects and in patients with ischemic heart disease. The results obtained with this technique imply that other related measurements of parasympathetic activity will show similar excellent short- and long-term reproducibility and sensitivity.

Cell adhesion molecules in cardiovascular disease: a clinical perspective

In summary, there is increasing evidence that cell adhesion molecules play an important role in cardiovascular pathology. They are involved in the main processes that underlie cardiac disease including thrombosis, leucocyte infiltration, smooth muscle proliferation, and cell migration. Anti-integrin treatment is already widely used to treat thrombotic complications, and it seems likely that manipulation of other cell adhesion molecules will be used clinically in the near future.