John N. Townend

Remote Ischemic Preconditioning in Human Coronary Artery Bypass Surgery From Promise to Disappointment

Background— We assessed whether remote ischemic preconditioning (RIPC) improves myocardial, renal, and lung protection after on-pump coronary surgery. Methods and Results— This was a single-center, prospective, randomized (1:1), placebo-controlled trial. Patients, investigators, anesthetists, surgeons, and critical care teams were blinded to group allocation. Subjects received RIPC (or placebo) stimuli (×3 upper limb (or dummy arm), 5-minute cycles of 200 mm Hg cuff inflation/deflation) before aortic clamping. Anesthesia, perfusion, cardioplegia, and surgical techniques were standardized. The primary end point was 48-hour area under the curve (AUC) troponin T (cTnT) release. Secondary end points were 6-hour and peak cTnT, ECG changes, cardiac index, inotrope and vasoconstrictor use, renal dysfunction, and lung injury. Hospital survival was 99.4%. Comparing placebo and RIPC, median (interquartile range) AUC 48-hour cTnT (ng/mL−1/48 h−1); 28 (19, 39) versus 30 (22, 38), 6-hour cTnT (ng/mL−1); 0.93(0.59, 1.35) versus 1.01(0.72, 1.43), peak cTnT (ng/mL−1); 1.02 (0.74, 1.44) versus 1.04 (0.78, 1.51), de novo left bundle-branch block (4% versus 0%) and Q waves (5.3% versus 5.5%), serial cardiac indices, intraaortic balloon pump usage (8.5% versus 7.5%), inotrope (39% versus 50%) and vasoconstrictor usage (66% versus 64%) were not different. Dialysis requirement (1.2% versus 3.8%), peak creatinine (median [interquartile range], 1.2 mg/dL−1 (1.1, 1.4) versus 1.2 (1.0, 1.4)), and AUC urinary albumin-creatinine ratios 69 (40, 112) versus 58 (32, 85) were not different. Intubation times; median (interquartile range), 937 minutes(766, 1402) versus 895(675, 1180), 6-hour; 278 (210, 338) versus 270 (218, 323) and 12-hour pO2:FiO2 ratios 255 (195, 323) versus 263 (210, 308) were similar. Conclusions— In contrast to prior smaller studies, RIPC did not reduce troponin release, improve hemodynamics, or enhance renal or lung protection. Clinical Trial Registration— URL: http://www.ukcrn.org.uk. Unique identifier: 4659.

Predictive value of dobutamine echocardiography and positron emission tomography in identifying hibernating myocardium in patients with postischaemic heart failure

Objective To compare the predictive value of dobutamine echocardiography (DE) and positron emission tomography (PET) in identifying reversible chronic left ventricular (LV) dysfunction (hibernating myocardium) in patients with coronary artery disease (CAD) and overt heart failure. Patients 30 patients (four women) with CAD and heart failure undergoing coronary artery bypass grafting (CABG). Methods Myocardial viability was assessed with DE (5 and 10 μg/kg/min) and PET with [18F] 2-fluoro-2-deoxy-D-glucose (FDG) under hyperinsulinaemic euglycaemic clamp. Regional (echo) and global LV function (MUGA) were assessed at baseline and six months after CABG. Results 192 of the 336 (57%) dysfunctional LV segments improved function following CABG (hibernating) and the LV ejection fraction (EF) increased from 23(7) to 32(9)% (p < 0.0001) (in 17 patients > 5%). DE and PET had similar positive predictive values (68% and 66%) in the identification of hibernating myocardium, but DE had a significantly lower negative predictive value than PET (54% v 96%; p < 0.0001). A significant linear correlation was found between the number of PET viable segments and the changes in EF following CABG (r = 0.65; p = 0.0001). Stepwise logistic regression identified the number of PET viable segments as an independent predictor of improvement in EF > 5%, whereas the number of DE viable segments, the baseline LVEF, and wall motion were not. Conclusions DE has a higher false negative rate than PET in identifying recoverable LV dysfunction in patients with severe postischaemic heart failure. The amount of PET viable myocardium correlates with the functional outcome following CABG.

Suppression of Inflammation in Primary Systemic Vasculitis Restores Vascular Endothelial Function: Lessons for Atherosclerotic Disease?

BackgroundChronic inflammatory rheumatic disorders are associated with excess cardiovascular mortality. This may result from arteriosclerosis following inflammatory damage to the vessel wall by vasculitis. Our hypothesis that vasculitis results in arteriosclerosis by causing vascular endothelial dysfunction was tested in patients with primary systemic necrotizing vasculitis (SNV). Methods and ResultsEndothelial function was assessed in cross-sectional and longitudinal studies of patients with primary SNV by measuring flow-mediated, endothelium-dependent brachial artery vasodilatation. These patients exhibited marked endothelial dysfunction compared with controls. Remission induction in patients with active primary SNV restored endothelial function. ConclusionsEndothelial function is significantly impaired in adults with primary SNV, supporting the hypothesis that premature arteriosclerosis in chronic inflammatory rheumatic disorders results from endothelial dysfunction secondary to vasculitis. Normalization of endothelial function after the treatment of primary SNV suggests that early suppression of disease activity in chronic inflammatory rheumatic disorders may reduce long-term vascular damage. The role of inflammation in atheroma formation is increasingly appreciated; this work raises questions regarding the potential for anti-inflammatory therapy in atherosclerosis itself.

Mortality, cardiac vagal control and physical training - what's the link?

There is little doubt that regular exercise results in increases in life expectancy and protects against adverse cardiac events in both healthy subjects and patients with cardiovascular disease. The mechanism of action of physical training remains unclear but a variety of evidence points towards an enhancement in cardiac vagal activity protecting against lethal arrhythmias. Just how physical training increases cardiac vagal activity is an area that is ill understood but plausible mechanisms include mediation via angiotensin II or NO. Further research is needed in this area. Exercise training is demanding and difficult, particularly for patients with cardiac disease. If the mechanism of increase in cardiac vagal activity with training can be determined it may be possible to use pharmacological approaches to mimic the effects of exercise with potentially beneficial effects.

Does folic acid decrease plasma homocysteine and improve endothelial function in patients with predialysis renal failure

BACKGROUND Considerable evidence suggests that hyperhomocysteinemia is an independent vascular risk factor that promotes atherosclerosis by inducing endothelial dysfunction. Although folic acid reduces hyperhomocysteinemia, the effect on adverse vascular events is unknown. We hypothesized that in patients with chronic renal failure, a condition associated with both hyperhomocysteinemia and atherosclerosis, treatment with folic acid would improve endothelial function. METHODS AND RESULTS In a prospective, double-blind protocol, 100 patients (mean age 62 years, 67 men) with predialysis chronic renal failure were randomized to 5 mg folic acid or placebo daily for 12 weeks. Endothelial function was assessed by measuring (1) endothelium-dependent dilation of the brachial artery, (2) combined serum nitrite/nitrate concentrations, and (3) plasma von Willebrand factor concentration. Baseline characteristics of the 2 groups were similar. At the end of the study, both serum and red cell folate concentrations were greater in the folic acid group than the placebo group [mean (95% CI) 39.0 (29.8 to 51.0) versus 7.7 (6.6 to 8.9) microg/L and 739 (613 to 891) versus 220 (184 to 262) microg/L, respectively; both P<0.001]. Despite a reduction in hyperhomocysteinemia in the folic acid group compared with the placebo group [15.1 (14.1 to 16.2) versus 20.1 (18.2 to 22.2) micromol/L; P<0.001], there were no significant differences in endothelium-dependent dilation, combined serum nitrite/nitrate concentrations, or plasma von Willebrand factor concentration between the 2 groups. CONCLUSIONS High-dose folic acid lowers but fails to normalize hyperhomocysteinemia in patients with predialysis chronic renal failure. This was not accompanied by an improvement of endothelial function and suggests that treatment with folic acid may not reduce the burden of vascular disease in uremia.

LIPID-LOWERING DRUGS AND HOMOCYSTEINE

0·0–3·3). The only cancer was a testis cancer. In daughters the overall cancer risk was high (5 observed; 1·2 expected [RR 4·2; 95% CI 1·4–9·9]). The cancers were one melanoma and one non-melanoma skin cancer and 3 breast cancers at ages 27, 34, and 36 years. Breast cancer occurred in excess of the expected, RR 16·4 (CI 95% 3·3–47·7). None of the cases had mothers with breast cancer, contrary to a previous report from Finland. Excess breast-cancer risk in daughters of male breast-cancer patients corroborates our hypothesis and is in line with previous studies of breast-cancer susceptibility genes. The mean age of our cohort was 32 years, and all breast cancer patients were below 40 years of age, which is in line with findings in Iceland, where 12 out of 49 breast cancers occurred before age 40 years. This high risk may justify screening for BRCA mutations in the offspring of male breast-cancer patients and other measures for early diagnosis of breast cancer.

Aortic distensibility and arterial–ventricular coupling in early chronic kidney disease: a pattern resembling heart failure with preserved ejection fraction

Objectives: To examine arterial and left ventricular function and their interaction in patients with early-stage chronic kidney disease (CKD). Design and setting: Cross-sectional observational study in a university teaching hospital. Patients: 117 patients with stage 2 (60–89 ml/min/1.73 m2) or stage 3 (30–59 ml/min/1.73 m2) non-diabetic CKD, without overt cardiovascular disease were compared with 40 controls. Interventions: Aortic distensibility and left ventricular mass were assessed using cardiac magnetic resonance imaging. Systolic and diastolic ventricular function and arterial–ventricular elastance (stiffness) were assessed by transthoracic echocardiography. Main outcome measures: Arterial stiffness as measured by aortic distensibility and arterial elastance. Left ventricular mass, left ventricular systolic and diastolic function, including end-diastolic and end-systolic elastance and their relationship with arterial elastance. Results: Compared with controls, patients with CKD 2 and CKD 3 had reduced aortic distensibility (4.12 (1.3) vs 2.94 (1.8) vs 2.18 (1.8)×10–3 mm Hg, p<0.01), increased arterial elastance (1.4 (1.3) vs 1.65 (0.40) vs 1.74 0.48) mm Hg, p<0.05) and increased end-systolic (1.88 (0.48) vs 2.43 (0.83) vs 2.42(0.78) mm Hg/ml, p<0.05) and end diastolic elastances (0.07 (0.04) vs 0.11 (0.04) vs 0.12 (0.04, p<0.01). Aortic distensibility was positively correlated with estimated glomerular filtration rate (r = 0.349, p<0.01) and indices of elastance were inversely correlated (r =  0.284, p<0.05). Systolic function was not impaired in patients with early CKD compared with controls but diastolic filling velocities (Em) were reduced (8.1 (0.9) vs 7.9 (0.6) vs 7.5 (0.7) cm/s, p<0.01) while mean left atrial pressure (E/Em) was increased (5.6 (1.1), vs 7.4 (1.8) vs 8.0 (2.4), p<0.01) and end-diastolic elastance was increased. Conclusions: Early-stage CKD is characterised by reduced aortic distensibility and increases in arterial, ventricular systolic and diastolic stiffness; arterial–ventricular coupling is preserved. This pattern of pathophysiological abnormalities resembles that seen in heart failure with preserved ejection fraction and may account for the high levels of cardiovascular morbidity and mortality in patients at all stages of CKD. Trial Registration Number: NCT00291720

Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting.

Background— Both glucose-insulin-potassium (GIK) and tri-iodothyronine (T3) may improve cardiovascular performance after coronary artery surgery (CABG) but their effects have not been directly compared and the effects of combined treatment are unknown. Methods and Results— In 2 consecutive randomized double-blind placebo-controlled trials, in patients undergoing first time isolated on-pump CABG between January 2000 and September 2004, 440 patients were recruited and randomized to either placebo (5% dextrose) (n=160), GIK (40% dextrose, K+ 100 mmol · L−1, insulin 70 u · L−1) (0.75 mL · kg−1 h−1) (n=157), T3 (0.8 &mgr;g · kg−1 followed by 0.113 &mgr;g · kg−1 h−1) (n=63) or GIK+T3 (n=60). GIK/placebo therapy was administered from start of operation until 6 hours after removal of aortic cross-clamp (AXC) and T3/placebo was administered for a 6-hour period from removal of AXC. Serial hemodynamic measurements were taken up to 12 hours after removal of AXC and troponin I (cTnI) levels were assayed to 72 hours. Cardiac index (CI) was significantly increased in both the GIK and GIK/T3 group in the first 6 hours compared with placebo (P<0.001 for both) and T3 therapy (P=0.009 and 0.029, respectively). T3 therapy increased CI versus placebo between 6 and 12 hours after AXC removal (P=0.01) but combination therapy did not. Release of cTnI was lower in all treatment groups at 6 and 12 hours after removal of AXC. Conclusions— Treatment with GIK, T3, and GIK/T3 improves hemodynamic performance and results in reduced cTnI release in patients undergoing on-pump CABG surgery. Combination therapy does not provide added hemodynamic effect.

Coronary revascularisation for postischaemic heart failure: how myocardial viability affects survival

OBJECTIVE To assess the impact of revascularisation of viable myocardium on survival in patients with postischaemic heart failure. METHODS 35 patients (mean (SD) age 58 (7) years) with severe heart failure (New York Heart Association (NYHA) functional class ⩾ III), mean left ventricular ejection fraction (LVEF) 24 (7)% (range 10–35%), and limited exercise capacity (peak oxygen consumption (VO 2) 15 (4) ml/kg/min) were studied. 21/35 patients had no angina. Myocardial viability was assessed with quantitative positron emission tomography and the glucose analogue18F-fluorodeoxyglucose (FDG) (viable segment = FDG uptake ⩾ 0.25 μmol/min/g) in all patients before coronary artery bypass grafting. Patients were divided into two groups: group 1, ⩾ 8 viable dysfunctional segments (mean 12 (2), range 8–15); and group 2, < 8 viable dysfunctional segments (mean 3.5 (3), range 0–7). The two groups were comparable for age, sex, NYHA class, LVEF, and peak VO 2. RESULTS Two patients died perioperatively and seven patients died during follow up (mean 33 (14) months). All deaths were from cardiac causes. Kaplan-Meyer survival analysis showed 86% survival for group 1 patients versus 57% for group 2 (p = 0.03). Analysis by Cox proportional hazard model revealed three independent factors for cardiac event free survival: presence of ⩾ 8 viable segments (p = 0.006); preoperative LVEF (p = 0.002); and patient age (p = 0.01). CONCLUSION Revascularisation for postischaemic heart failure can be associated with good survival, which is critically dependent upon the amount of viable myocardium.

Myocardial strain measurement with feature-tracking cardiovascular magnetic resonance: normal values.

AIMS Myocardial deformation is a key to clinical decision-making. Feature-tracking cardiovascular magnetic resonance (FT-CMR) provides quantification of motion and strain using standard steady-state in free-precession (SSFP) imaging, which is part of a routine CMR left ventricular (LV) study protocol. An accepted definition of a normal range is essential if this technique is to enter the clinical arena. METHODS AND RESULTS One hundred healthy individuals, with 10 men and women in each of 5 age deciles from 20 to 70 years, without a history of cardiovascular disease, diabetes, renal impairment, or family history of cardiovascular disease, and with a normal stress echocardiogram, underwent FT-CMR assessment of LV myocardial strain and strain rate using SSFP cines.Peak systolic longitudinal strain (Ell) was -21.3 ± 4.8%, peak systolic circumferential strain (Ecc) was -26.1 ± 3.8%, and peak systolic radial strain (Err) was 39.8 ± 8.3%. On Bland-Altman analyses, peak systolic Ecc had the best inter-observer agreement (bias 0.63 ± 1.29% and 95% CI -1.90 to 3.16) and peak systolic Err the least inter-observer agreement (bias 0.13 ± 6.41 and 95% CI -12.44 to 12.71). There was an increase in the magnitude of peak systolic Ecc with advancing age, which was greatest in subjects over the age of 50 years (R(2) = 0.11, P = 0.003). There were significant gender differences (P < 0.001) in peak systolic Ell, with a greater magnitude of deformation in females (-22.7%) than in males (-19.3%). CONCLUSION Normal values for myocardial strain measurements using FT-CMR are provided. All circumferential and longitudinal based variables had excellent intra- and inter-observer variability.