Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis.

BACKGROUND: Anaemia is common among patients with heart failure (HF) and is an important prognostic marker. AIM: We sought to determine the prognostic importance of anaemia in a large multinational pooled dataset of prospectively enrolled HF patients, with the specific aim to determine the prognostic role of anaemia in HF with preserved and reduced ejection fraction (HF-PEF and HF-REF, respectively). DESIGN: Individual person data meta-analysis. METHODS: Patients with haemoglobin (Hb) data from the MAGGIC dataset were used. Anaemia was defined as Hb < 120 g/l in women and <130 g/l in men. HF-PEF was defined as EF ≥ 50%; HF-REF was EF < 50%. Cox proportional hazard modelling, with adjustment for clinically relevant variables, was undertaken to investigate factors associated with 3-year all-cause mortality. RESULTS: Thirteen thousand two hundred and ninety-five patients with HF from 19 studies (9887 with HF-REF and 3408 with HF-PEF). The prevalence of anaemia was similar among those with HF-REF and HF-PEF (42.8 and 41.6% respectively). Compared with patients with normal Hb values, those with anaemia were older, were more likely to have diabetes, ischaemic aetiology, New York Heart Association class IV symptoms, lower estimated glomerular filtration rate and were more likely to be taking diuretic and less likely to be taking a beta-blocker. Patients with anaemia had higher all-cause mortality (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 1.25-1.51), independent of EF group: aHR 1.67 (1.39-1.99) in HF-PEF and aHR 2.49 (2.13-2.90) in HF-REF. CONCLUSIONS: Anaemia is an adverse prognostic factor in HF irrespective of EF. The prognostic importance of anaemia was greatest in patients with HF-REF.

Genetic markers of repolarization and arrhythmic events after acute coronary syndromes.

BACKGROUND: There is a genetic contribution to the risk of ventricular arrhythmias in survivors of acute coronary syndromes (ACS). We wished to explore the role of 33 candidate single nucleotide polymorphisms (SNPs) in prolonged repolarization and sudden death in patients surviving ACS. METHODS: A total of 2,139 patients (1680 white ethnicity) surviving an admission for ACS were enrolled in the prospective Coronary Disease Cohort Study. Extensive clinical, echocardiographic, and neurohormonal data were collected for 12 months, and clinical events were recorded for a median of 5 years. Each SNP was assessed for association with sudden cardiac death (SCD)/cardiac arrest (CA) and prolonged repolarization at 3 time-points: index admission, 1 month, and 12 months postdischarge. RESULTS: One hundred six SCD/CA events occurred during follow-up (6.3%). Three SNPs from 3 genes (rs17779747 [KCNJ2], rs876188 [C14orf64], rs3864180 [GPC5]) were significantly associated with SCD/CA in multivariable models (after correction for multiple testing); the minor allele of rs17779747 with a decreased risk (hazard ratio [HR] 0.68 per copy of the minor allele, 95% CI 0.50-0.92, P = .012), and rs876188 and rs386418 with an increased risk (HR 1.52 [95% CI 1.10-2.09, P = .011] and HR 1.34 [95% CI 1.04-1.82, P = .023], respectively). At 12 months postdischarge, rs10494366 and rs12143842 (NOS1AP) were significant predictors of prolonged repolarization (HR 1.32 [95% CI 1.04-1.67, P = .022] and HR 1.30 [95% CI 1.01-1.66, P = .038], respectively), but not at earlier time-points. CONCLUSION: Three SNPs were associated with SCD/CA. Repolarization time was associated with variation in the NOS1AP gene. This study demonstrates a possible role for SNPs in risk stratification for arrhythmic events after ACS.

The obesity paradox in heart failure patients with preserved versus reduced ejection fraction: a meta-analysis of individual patient data.

BACKGROUND: In heart failure (HF), obesity, defined as body mass index (BMI) ≥30 kg m(-2), is paradoxically associated with higher survival rates compared with normal-weight patients (the 'obesity paradox'). We sought to determine if the obesity paradox differed by HF subtype (reduced ejection fraction (HF-REF) versus preserved ejection fraction (HF-PEF)). PATIENTS AND METHODS: A sub-analysis of the MAGGIC meta-analysis of patient-level data from 14 HF studies was performed. Subjects were divided into five BMI groups: <22.5, 22.5-24.9 (referent), 25-29.9, 30-34.9 and ≥35 kg m(-2). Cox proportional hazards models adjusted for age, sex, aetiology (ischaemic or non-ischaemic), hypertension, diabetes and baseline blood pressure, stratified by study, were used to examine the independent association between BMI and 3-year total mortality. Analyses were conducted for the overall group and within HF-REF and HF-PEF groups. RESULTS: BMI data were available for 23 967 subjects (mean age, 66.8 years; 32% women; 46% NYHA Class II; 50% Class III) and 5609 (23%) died by 3 years. Obese patients were younger, more likely to receive cardiovascular (CV) drug treatment, and had higher comorbidity burdens. Compared with BMI levels between 22.5 and 24.9 kg m(-2), the adjusted relative hazards for 3-year mortality in subjects with HF-REF were: hazard ratios (HR)=1.31 (95% confidence interval=1.15-1.50) for BMI <22.5, 0.85 (0.76-0.96) for BMI 25.0-29.9, 0.64 (0.55-0.74) for BMI 30.0-34.9 and 0.95 (0.78-1.15) for BMI ≥35. Corresponding adjusted HRs for those with HF-PEF were: 1.12 (95% confidence interval=0.80-1.57) for BMI <22.5, 0.74 (0.56-0.97) for BMI 25.0-29.9, 0.64 (0.46-0.88) for BMI 30.0-34.9 and 0.71 (0.49-1.05) for BMI ≥35. CONCLUSIONS: In patients with chronic HF, the obesity paradox was present in both those with reduced and preserved ventricular systolic function. Mortality in both HF subtypes was U-shaped, with a nadir at 30.0-34.9 kg m(-2).

Chronic fluoxetine treatment induces structural plasticity and selective changes in glutamate receptor subunits in the rat cerebral cortex.

It has been postulated that chronic administration of antidepressant drugs induces delayed structural and molecular adaptations at glutamatergic forebrain synapses that might underlie mood improvement. To gain further insight into these changes in the cerebral cortex, rats were treated with fluoxetine (flx) for 4 weeks. These animals showed decreased anxiety and learned helplessness. N-methyl-d-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor subunit levels (NR1, NR2A, NR2B, GluR1 and GluR2) were analysed in the forebrain by both western blot of homogenates and immunohistochemistry. Both methods demonstrated an upregulation of NR2A, GluR1 and GluR2 that was especially significant in the retrosplenial granular b cortex (RSGb). However, when analysing subunit content in postsynaptic densities and synaptic membranes, we found increases of NR2A and GluR2 but not GluR1. Instead, GluR1 was augmented in a microsomal fraction containing intracellular membranes. NR1 and GluR2 were co-immunoprecipitated from postsynaptic densities and synaptic membranes. In the immunoprecipitates, NR2A was increased while GluR1 was decreased supporting a change in receptor stoichiometry. The changes of subunit levels were associated with an upregulation of dendritic spine density and of large, mushroom-type spines. These molecular and structural adaptations might be involved in neuronal network stabilization following long-term flx treatment.

Can retrograde cardioplegia alone provide adequate protection for cardiac valve surgery?

BACKGROUND: When aortic insufficiency is present, antegrade delivery of cardioplegia requires coronary cannulation. Use of retrograde cardioplegia simplifies administration. The efficacy of the retrograde route alone in ensuring adequate myocardial protection may be assessed by the clinical outcome. METHODS AND RESULTS: We used closed transatrial coronary sinus perfusion as the sole method of cardioplegia delivery in 100 patients who underwent valve operations, either isolated or combined with coronary (n=24), ascending aortic aneurysm (n=8), or other procedures. Eighty-one patients were in New York Heart Association (NYHA) Class III or IV; 23 had undergone previous heart operations; 23 were admitted from the coronary care unit (CCU); and 20 had left ventricular ejection fraction (LVEF) of < or = 40%. Operative mortality was 2%. An intra-aortic balloon pump was required in eight patients. On univariate analysis, perioperative use of inotropes (n=26) was related to age > or = 70 years (p=0.02), COPD (p=0.05), pulmonary hypertension (p=0.005), higher NYHA Class (p=0.0006), preoperative heart failure (p=0.006), lower LVEF (p=0.0003), urgency (p=0.00001), admission from the CCU (p=0.006), repeat operation (p=0.03), coronary artery disease (p=0.02), and longer ischemic (p=0.02) and bypass times (p=0.0003). On multivariate stepwise logistic regression analysis, use of inotropes was related to preoperative lower LVEF (p=0.02) and urgency of operation (p=0.0002). Perioperative complications included ventricular arrhythmia in six, heart block in one, renal dysfunction in nine, and stroke in two patients; no patient had myocardial infarction. CONCLUSION: Good clinical results can be obtained by using retrograde cardioplegia alone without prior doses of antegrade cardioplegia in all valve operations.

Spontaneous ventricular tachycardia treated by antitachycardia pacing. Cadence Investigators.

The database of the registry for an implantable cardioverter defibrillator was analyzed to determine the efficacy and safety of antitachycardia pacing for the termination of ventricular tachycardia. In 22,339 episodes treated, termination occurred in 94% and acceleration in only 1.4%.

Hemodynamic effects of different pacing ratios in chronic dynamic double cardiomyoplasty.

BACKGROUND: Dynamic cardiomyoplasty is being used clinically worldwide, and evaluated by a clinical trial (phase III) in the United States. Some centers stimulate the skeletal muscle wrap with every heart beat (1:1 [muscle:heart]), whereas others use every other heart beat (1:2). Recent concern over the possible deleterious effects of too-frequent stimulation of the muscles motivated the attempt to evaluate, in a canine model of chronic, double cardiomyoplasty, the effects of two different pacing ratios on several hemodynamic parameters of interest. METHODS: Double cardiomyoplasty was performed using both latissimus dorsi muscles in 11 dogs. Fatigue resistance was achieved using the clinical transformation protocol. At a final experiment, acute cardiac failure was induced by administration of propranolol. Hemodynamic measurements of eight physiologic variables were averaged over complete pacing cycles, including the nonpaced beat at a 1:2 pacing ratio. RESULTS: The net effects of latissimus dorsi muscle stimulation at each of two pacing ratios were compared using nonparametric statistics. With the exception of left ventricular pressure (p = 0.0262) and its first derivative, dP/dt (p = 0.0099), there was no significant difference between hemodynamic performance at the two pacing ratios. CONCLUSIONS: In this canine model, pacing every other beat produces hemodynamic results that are statistically similar to pacing every beat. Less frequent stimulation of the latissimus dorsi muscle may preserve its function and improve clinical results without compromising hemodynamic benefit.

Evolution of surgical techniques for aneurysms of the descending thoracic aorta: twenty-nine years experience with 659 patients.

Between 1953 and 1993, 659 patients underwent descending thoracic aneurysm resection. The most common etiology was atherosclerosis. Pain was the main presenting symptom. Perioperative mortality fell from 24.2% between 1953 and 1964 to 14.3% between 1970 and 1993. Paraplegia occurred in 4.1% (27/659) patients overall and was little affected by time of operation or use of atriofemoral bypass. Paraparesis occurred in 5.9% (39/659) patients and was reduced by use of atriofemoral bypass. The low rate of paraparesis in the earlier experience was offset by the higher perioperative mortality from hemorrhage, attributable to the use of systemic heparin. The use of heparin-free circuits with centrifugal pumps should be considered in patients likely to have a clamp time greater than 30 minutes. The major source of perioperative morbidity and mortality was cardiac causes (48%) followed by perioperative hemorrhage (14.4%), pulmonary complications (14.4%), and rupture of another aneurysmal segment (12.0%). Late mortality occurred most commonly from cardiac causes (30.6% of deaths) and rupture of another aneurysm (16.3% of deaths). Improvement in results was due to general refinements of management in all areas rather than any single factor. These results indicate that complete preoperative assessment of the patient and the entire aorta is essential and that regular life-long follow-up is critical in order to avoid unnecessary morbidity and mortality from cardiac, cerebrovascular, or subsequent aneurysmal complications.

Acute impairment of coronary blood flow by dynamic cardiomyoplasty.

The aim of this study was to quantify the effects of three different configurations of cardiomyoplasty on coronary blood flow in an acute dog model. Thirteen dogs had both latissimus dorsi muscles harvested and transposed to the chest. Coronary blood flow was measured using Doppler cuff probes on the left anterior descending and circumflex coronary arteries during each of three cardiomyoplasty configurations: left posterior, right anterior, and double. Multiple beat measures were made of systolic and diastolic flow during a control protocol and a subsequent protocol with the muscle(s) paced. Significant flow reductions during pacing were observed in the left anterior descending coronary artery during left posterior (17%, p = 0.003), right anterior (29%, p < 0.0001), and double (35%, p = 0.0001) myoplasty. Similar reductions occurred in the circumflex artery (14%, p = 0.0009; 20%, p = 0.001; 27%, p = 0.0053). The net flow over an entire pacing cycle also was reduced significantly: left anterior descending artery (11%, p = 0.0035; 23%, p = 0.0001; 23%, p = 0.0047) and circumflex artery (10%, p = 0.0025; 17%, p = 0.0018; 21%, p = 0.0091). Thus, in the acute setting cardiomyoplasty depresses coronary blood flow. A chronic setting will be needed to determine the ultimate significance of these results.

New configuration of double cardiomyoplasty based on studies of the length-tension properties of the latissimus dorsi muscle.

A new configuration of double cardiomyoplasty was designed according to studies of the length-tension properties of the linear latissimus dorsi muscle. Four dogs had both their right and left latissimus dorsi muscles dissected from the chest wall and attached to a tensiometer to measure force of contraction. The maximum active tension obtained with stimulation of the linear latissimus dorsi muscle was observed when the muscle was at its resting anatomic length and up to 5% above this length. Eight dogs had a double cardiomyoplasty in which the resting anatomic length of both muscles was maintained. Control hemodynamic parameters obtained with the muscles at rest were compared with stimulated muscle protocols. In a normal heart state, stimulation of the double cardiomyoplasty increased the cardiac output 32% (p < 0.05), the stroke volume 39% (p < 0.05), and the left ventricular pressure 42% (p < 0.05). When acute heart failure was induced with high-dose intravenous propranolol (5 mg/kg), stimulation of the double cardiomyoplasty increased the cardiac output 32% (p = 0.01), the stroke volume 32% (p < 0.05), rate of pressure rise 39% (p < 0.01), and myocardial thickening 39% (p < 0.01). The study demonstrated that this configuration of double cardiomyoplasty provides significant hemodynamic assistance in the normal and acutely failing canine heart.

Long-term fate of the aortic root and aortic valve after ascending aneurysm surgery.

OBJECTIVE: The authors determined in which patients tube graft replacement could be used. SUMMARY BACKGROUND DATA: Tube graft replacement of ascending aortic aneurysms requires no coronary anastomoses and preserves the native aortic valve, but aortic insufficiency or aortic root aneurysms may develop requiring reoperation. Use of Bentall or Cabrol composite valve graft procedures obviates these problems but requires prosthetic valve replacement and coronary reattachment, both of which are associated with complications. These two procedures have been applied increasingly but because of renewed interest in aortic valve preservation and reconstruction, the authors determined in which patients tube replacement could be used. METHODS: The authors analyzed the fate of 277 patients, mean age 49 +/- 14 years, operated on between 1953 and 1992 by techniques that preserved the aortic root. The most common pathology was atherosclerosis in 104 patients. Perioperative mortality since 1975 was 14%. RESULTS: Fifteen patients required reoperation on the ascending aorta or aortic root; ascending aneurysm reoperation (6 patients); aortic valve replacement (8 patients), and a combined procedure (1 patient). Of these 15 patients, 8 had Marfan's syndrome, 10 had dissections, and 5 had medial degeneration/necrosis. CONCLUSIONS: Simple tube graft replacement of the ascending aorta was a durable technique in patients without Marfan's syndrome or medial degeneration/necrosis and allowed preservation of the native aortic valve in many patients.

Long-term results of coronary bypass surgery. Analysis of 1698 patients followed 15 to 20 years.

Between 1968 and 1975, 1698 patients underwent coronary artery bypass with autogenous saphenous vein and were followed for up to 20 years. Age at operation was 53.9 +/- 8.4 years, and 1485 were men (88%). Angina was present in 1637 patients (96%). There was single-vessel disease in 306 patients (18%), double-vessel in 642 (38%), triple-vessel in 550 patients (32%) and left main stenosis in 200 (12%). Preoperative left ventricular quality was good in 1185 (70%), poor in 508 (30%), and unknown in five patients. Survival at 20 years was as follows: for single-vessel disease, 40%; double-vessel, 26%; triple-vessel, 20%; and left main, 25%. At 20 years of follow-up, 67% of surviving patients were asymptomatic and 26% were improved. Antianginal drug therapy consisted of nitrates in 49% of patients and beta-blockers in 26%. Graft patency at 0 to 5 years was 633 of 780 grafts (81%); at 6 to 10 years, 415 of 606 grafts (68%); at 11 to 15 years, 271 of 449 grafts (60%); and at 16 to 20 years, 65 of 140 grafts (46%). Coronary bypass reoperation was performed in 324 patients (19%) and survival of these patients was 62% compared to 37% for nonreoperation patients (p less than 0.05). Cox analysis demonstrated that the major determinants of survival related to age at operation, extent of coronary disease, quality of ventricle, history of stroke, and preoperative congestive heart failure. At 20 years of follow-up of this early experience with coronary bypass, 76% of surviving patients had one or more patent grafts and the probability of freedom from reoperation was 0.62.

Factors predictive of results of direct ablative operations for drug-refractory ventricular tachycardia. Analysis of 80 patients.

During a 9-year period 80 patients with drug-resistant sustained ventricular tachycardia underwent direct surgical ablation of arrhythmogenic myocardium. Sixty-nine were male (86%) and 11 female (14%), with 1.9 +/- 1.1 (standard deviation) ventricular tachycardia morphologies per patient. The mean number of drugs failed was 3.7 +/- 1.6 per patient. The preoperative left ventricular ejection fraction was 36.4% +/- 14.4%. Complete preoperative endocardial mapping data (greater than 4 endocardial sites in each ventricular tachycardia) were available for 60 of the 80 patients (75%) and intraoperative endocardial data in the clinical ventricular tachycardia was obtained in 37 (46.3%) of the patients. In 17 patients mapped intraoperatively by computer-assisted techniques, complete epicardial and endocardial data in the clinical ventricular tachycardia were obtained in 14 patients (82.4%). Overall, 73 of 80 (91.3%) had some mapping data available. Hospital mortality occurred in 10 patients (12.5%) at a mean interval of 13.5 days, range 0 to 62 days. Postoperatively the clinical ventricular tachycardia has not recurred in 65 of 70 surviving patients (92.9%). Nonclinical ventricular tachycardia occurred in another four patients. All nine patients with postoperative ventricular tachycardia responded to drugs. The major factors predictive of hospital mortality were prolonged cardiopulmonary bypass (greater than 150 minutes), preoperative ejection fraction less than 31%, and incomplete preoperative mapping. Hospital mortality in patients with an ejection fraction below 31% was significantly associated with a history of amiodarone usage. At 3 years of follow-up, freedom from sudden cardiac death was 95.7%, and 86.7% of patients were free of ventricular tachycardia on no antiarrhythmic drugs. These results suggest that direct ventricular tachycardia operations are an effective form of therapy for patients with sustained monomorphic ventricular tachycardia.

Randomized, double-blind trial of Lithostat (acetohydroxamic acid) in the palliative treatment of infection-induced urinary calculi.

In a prospective, double-blind, placebo-controlled study, the efficacy and safety of acetohydroxamic acid (AHA) in preventing urinary calculogenesis was evaluated in 94 patients with chronic urinary infection. Stone growth occurred in 17% of the AHA group and in 46% of the placebo group (p less than 0.005). Completely reversible side effects consisting predominantly of psychoneurologic and musculo-integumentary symptoms were more prevalent in the AHA group (p less than 0.01). Side effects which were judged 'intolerable' were experienced by 10 (22.2%) of patients in the AHA group and 2 (4.1%) in the placebo group. It is concluded that AHA treatment is effective, relatively safe, and clinically useful in preventing infection-induced urinary calculogenesis.