Number 23, 2004
Hibernation preconditioning

Featured research

Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study
Sastry BK, Narasimhan C, Reddy NK, Raju BS. J Am Coll Cardiol. 2004; 43(7):1149–53.

Objectives: In a randomized, double-blind, crossover design, we compared the efficacy of sildenafil with placebo in patients with primary pulmonary hypertension (PPH). The primary end point was the change in exercise time on treadmill using the Naughton protocol. Secondary end points were change in cardiac index and pulmonary artery systolic pressure as assessed by Doppler echocardiography and quality of life (QOL) as assessed by a questionnaire.
Background: Primary pulmonary hypertension is a disorder with limited treatment options. Uncontrolled studies had shown sildenafil to be beneficial in the treatment of PPH.
Methods: After initial clinical evaluation, including Doppler echocardiography and treadmill exercise test, patients were randomized to placebo or sildenafil with dosages ranging from 25 to 100mg thrice daily on the basis of body weight. The evaluation was repeated after six weeks. Then patients were crossed over to alternate therapy. Final evaluation was performed after another six weeks of treatment.
Results: Twenty-two patients completed the study. Exercise time increased by 44% from 475 +/− 168s at the end of placebo phase to 686 +/− 224s at the end of sildenafil phase (P <0.0001). With sildenafil, cardiac index improved from 2.80 +/− 0.9l/m2 to 3.45 +/− 1.1l/m(2) (P <0.0001), whereas pulmonary artery systolic pressure decreased insignificantly from 105.23 +/− 17.82mm Hg to 98.50 +/− 24.38mm Hg. There was significant improvement in the dyspnea and fatigue components of the QOL questionnaire. During the placebo phase, one patient died and another had syncope. There were no serious side effects with sildenafil.
Conclusion: Sildenafil significantly improves exercise tolerance, cardiac index, and QOL in patients with PPH.

Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and mid-term effects.
Mikhail GW, Prasad SK, Li W, et al. Eur Heart J. 2004; 25(5):431–6.

Aim: The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease.
Methods and results: Ten patients (8 females, mean age 34.5+/−3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8+/−5.9 to 50.4+/−6.1mmHg, P=0.038 ) and pulmonary vascular resistance (from 10.1+/−1.7 to 8.6+/−1.5 Wood units, P=0.009 ), and an increase in cardiac output (from 4.7+/−0.3 to 5.0+/−0.4l/min, P=0.15). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list.
Conclusion: Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary hemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.

Commentary
Issue 22 of Heart and Metabolism focused on endothelial dysfunction and mentioned in the editorial Phosphodiesterase type 5 (PDEJ) inhibitors and their role, not just in treating erectile dysfunction but also their effect throughout the vascular tree. Primary pulmonary hypertension is a disorder of unknown aetiology, which is invariably fatal over approximately 3 years, as a result of progressive elevation of pulmonary vascular resistance and right heart failure. Quality of life becomes progressively impaired with a poor exercise ability due to dyspnea. Case reports of the benefits from PDE5 inhibitors have been impressive and now we have two formal studies showing that sildenafil (Viagra) is well tolerated in a thrice daily dosing regime, improving pulmonary hemodynamics exercise tolerance, cardiac index and quality of life. To date there is no evidence of tolerance but long term follow up is clearly necessary. PDE5 inhibitors possess important effects on the endothelium and enhance smooth muscle relaxation. Their role in diabetes, hypertension, cardiac failure and Raynauds phenomena is just being realized. By acting within the cell to prevent the degradation of cyclic guanosine mono phosphate they have potentially important metabolic and hemodynamic effects. These two studies represent the beginning of a new therapeutic entity, which could be prognostically, as well as symptomatically, important.

Graham Jackson

Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure
Lei B, Lionetti V, Young ME, et al. J Mol Cell Cardiol. 2004; 36:567–576

An altered utilization of metabolic substrates is recognized as one of the biochemical hallmarks of the failing heart. It has been hypothesized that profound changes in the rate of free fatty acids (FFA) and carbohydrate oxidation might play a role in the complex pathophysiological mechanisms leading to decompensated heart failure. The aim of this work was to quantify changes in FFA and glucose oxidation in vivo, in dogs with normal and failing hearts. At the end of the in vivo experiment, clamp-frozen biopsies were harvested from the left ventricle. The results show that, in failing hearts, the capacity of the carbohydrate oxidative pathway is not enhanced. Rather it is moderately downregulated, despite a marked enhancement in glucose oxidation flux. In light of recent data in the same model demonstrating a downregulation of the fatty acid oxidation pathway [1], the results of the present investigation suggest that (1) the increase in glucose oxidation observed in the failing heart in vivo is principally due to impaired oxidation of the competing substrate fatty acid, and (2) that the capacity for both fatty acid and carbohydrate oxidation are suppressed in heart failure.

Commentary
Studies performed over the past forty years have provided solid evidence that in experimental heart failure, cardiac FFA oxidation rates are depressed during decompensation. Clinical studies on this topic are still limited and, in part, in conflict with experimental studies, probably due to indirect methods of measurement, heterogeneous groups of heart failure patients, and sometimes the absence of a control group. However, the only clinical investigation that has employed three cardiac substrates labelled with positron emitting isotopes showed decreased FFA consumption in patients with idiopathic dilated cardiomyopathy, with an increase in the utilization of the competing substrate glucose [2]. Taken together, the findings in both patients and animal models have led the authors to hypothesize that the failing heart reverts to a fetal metabolic phenotype, characterized by prevalent utilization of carbohydrate as a source of energy. Fewer studies, however, have explored possible changes in the myocardial carbohydrate oxidative pathway to determine whether this is potentiated in heart failure. In the present study, direct measurements of FFA and glucose oxidation were performed in vivo, followed by measurements of the expression (both gene and protein) and activity of key regulatory enzymes ex vivo. The authors observed the anticipated depression of fatty acid oxidation, and concomitant increase in glucose oxidation, in the failing heart. However, the report also indicates that the expression of all genes encoding for proteins involved in carbohydrate metabolism were downregulated in the failing dog heart. This is consistent with previous observations in failing human hearts [3]. Therefore, the previous study by Razeghi et al. [3] and the present one, lead to a similar conclusion that the failing heart represses the expression of all metabolic enzymes, rather than selectively potentiating the carbohydrate pathway. It remains to be demonstrated whether glucose oxidation can be pharmacologically enhanced in end stage heart failure when the capacity for carbohydrate metabolism appears to be impaired.

REFERENCES

Danielle Feuvray

Angina Pectoris Prior to Myocardial Infarction Protects Against Subsequent Left Ventricular Remodeling
Solomon SD, Anavekar NS, Greaves S, et al. Journal of the American College of Cardiology 2004; 43(9):1511–1514

Objectives: To investigate the hypothesis that prior angina pectoris confers protection from remodelling occurring after myocardial infarction (MI), we analysed echocardiograms from the Healing and Early Afterload Reducing Therapy (HEART) trial.
Background: Ischemia occurring before MI has been shown to reduce infarct size in experimental models and to improve outcomes in patients. The extent to which ischemia occurring before MI influences subsequent changes in ventricular size and function is unclear.
Methods: We studied 283 patients enrolled in the HEART trial who had echocardiograms at days 1 and 90 after MI. Left ventricular (LV) dilation from days 1 to 90 was used as a measure of LV remodelling. We explored the relationship between symptomatic angina occurring before infarction and subsequent remodelling.
Results: In patients who reported angina (n=111) during the three months preceding MI, LV volume change was −0.73±2.6ml over the 90-day post-MI period, compared with 6.8±2.6ml for patients (n=172) without angina (P=0.017). In contrast there were no differences in changes in ejection fraction based on prior angina. Maximal creatine kinase was significantly lower in patients with prior angina (2,119±1,729 vs 2,701±2,088, P=0.016). In a multivariate model, prior angina remained protective for ventricular remodelling after adjusting for age, gender, baseline ejection fraction, Killip class, baseline and end-diastolic volume, and drug treatment group (P=0,042). However, the protective effect of pre-infarction angina appeared to be attenuated in diabetic patients.
Conclusion: Ischemic symptoms occurring before MI may protect against LV remodelling. These protective effects may be secondary to recruitment of collaterals or ischemic preconditioning of the myocardium and they appear to be attenuated in diabetic patients.

Commentary
Ischemic preconditioning is the term used to describe the phenomenon where a short period of myocardial ischemia reduces the infarction that results from subsequent more prolonged ischemia. Ischemic preconditioning was initially described, and subsequently extensively studied, in animal hearts. Since first being described 18 years ago there have been a number of clinical studies designed to detect its presence in patients. By necessity these studies have had to be observational, making use of the varying patterns of myocardial ischemia that may presage ST elevation MI. There is now a substantial literature that demonstrates patients with ST elevation MI that have preceding angina, have a more benign in-hospital course and smaller myocardial infarcts than those patients with unheralded infarction. However the interpretation of such observational studies are always clouded by differences in use of aspirin, β-blockers, ACE-I and door to needle/balloon times that are likely to exist in patients that do, or do not, have angina prior to MI. Furthermore, there is evidence to suggest that patients with prior angina more rapidly achieve TIMI 3 flow in their infarct related arteries than those that do not. In addition, it is also likely that patients with pre-infarction angina have better developed collateral flow beyond the unstable atherosclerotic plaque. Despite these caveats, which are difficult to control, there seems little doubt that myocardial infarction is reduced in patients with pre-infarction angina whatever the exact underlying mechanism. However what has not so far been demonstrated is whether this reduction in infarction is reflected by indices of more benign LV remodelling.
The above study adds further to this already extensive literature. Solomon et al enrolled almost 300 patients presenting with ST elevation MI in the anterior territory. Infarcts in this territory are most prone to cause adverse LV remodelling. Echocardiography was performed within 24hours of MI and at 90 days. Patients were categorised as having antecedent angina or an unheralded myocardial infarction on the basis of an admission questionnaire. In keeping with other investigators a history of angina was associated with a reduction in CK-derived infarct size. However, Solomon et al were also able to show that preinfarction angina was associated with blunted LV remodelling since there was no change in LV end diastolic volume between day one and 90 in patients with prior MI, whilst in those without angina this parameter increased by approximately 7ml (p=0.017). In a multivariate model prior angina remained predictive of less remodelling after adjusting for age, gender, baseline ejection fraction and endiastolic volume, Killip class, diabetes, and drug treatment. Unfortunately the study did not measure collateral support to the infarct related artery but there were no differences in pain to presentation time between groups. Yet again this study supports the counterintuitive hypothesis that preinfarction angina is beneficial and demonstrates an additional benefit in terms of post-MI remodelling. It seems angina is a cloud with a silver lining.

Michael Marber