Heart and Metabolism

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Abstracts and commentaries

Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women’s Health Initiative observational study
Pradhan A, Manson JE, Rossouw JE, et al. JAMA. 2002;288:980–987.

Postmenopausal hormone replacement therapy (HRT) has been shown to elevate C-reactive protein (CRP) levels. Several inflammatory biomarkers, including CRP, are associated with increased cardiovascular risk. However, whether the effect of HRT on CRP represents a clinical hazard is unknown. The study objectives were to assess the association between baseline levels of CRP and interleukin 6 (IL-6) and incident coronary heart disease (CHD), and to examine the relationship between baseline use of HRT, CRP, and IL-6 levels as they relate to subsequent vascular risk. This was a prospective, nested case-control study of postmenopausal women, forming part of the Women’s Health Initiative, a large, nationwide, observational study. Among 75,343 women with no history of cardiovascular disease or cancer, 304 women who developed incident CHD were defined as cases and matched by age, smoking status, ethnicity, and follow-up time with 304 study participants who remained event-free during a median observation period of 2.9 years. The main outcome measure was the incidence of first myocardial infarction or death from CHD. Median baseline levels of CRP (0.33 vs 0.25 mg/dL; interquartile range [IQR] 0.14–0.71 vs 0.10–0.47; P < 0.001) and IL-6 (1.81 vs 1.47 pg/mL; IQR 1.30–2.75 vs 1.05–2.15; P < 0.001) were significantly higher among cases compared with controls. In matched analyses, the odds ratio for incident CHD in the highest vs lowest quartile was 2.3 for CRP (95% CI 1.4–3.7; P for trend = 0.002) and 3.3 for IL-6 (95% CI 2.0–5.5; P for trend < 0.001). After additional adjustment for lipid and nonlipid risk factors, both inflammatory markers were significantly associated with a twofold increase in odds for CHD events. As anticipated, current use of HRT was associated with significantly elevated median CRP levels. However, there was no association between HRT and IL-6. In analyses comparing individuals with comparable baseline levels of either CRP or IL-6, those taking or not taking HRT had similar CHD odds ratios. In analyses stratified by HRT, we observed a positively graded relationship between plasma CRP levels and the odds ratio for CHD among both users and nonusers of HRT across the full spectrum of baseline CRP. These prospective findings indicate that CRP and IL-6 independently predict vascular events among apparently healthy postmenopausal women and that HRT increases CRP. However, use or nonuse of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6.

Commentary
The failure in randomized trials of HRT to replicate the benefit seen in observational studies has been an enormous disappointment. One of the mechanisms postulated is the increase in markers of systemic inflammation following oral unopposed estrogen and oral combination therapy. In this study (the senior author is Paul Ridker, who has published extensively on inflammatory biomarkers) an observational subset of a much larger study (304 of 75,343 women) were evaluated to assess the potential link between elevated CRP and IL-6 and subsequent incidence of first myocardial infarction or death from CHD. The authors demonstrated that both CRP and IL-6 predict cardiovascular risk in healthy postmenopausal women irrespective of whether or not they use HRT. HRT was associated with elevated CRP but not IL-6, possibly pointing to the absence of a generalized inflammatory effect. Importantly, the risk for a CAD event was the same for HRT users and nonusers, suggesting that HRT was of less importance than baseline levels of CRP or IL-6. The reduction of cardiovascular risk should therefore be focused on established therapies (lifestyle, aspirin, statins) rather than HRT. It is unlikely that HRT forms that do not impact on inflammatory markers (eg, transdermal preparations) will reduce CHD risk in the context of the information already available. In contrast, the anti-inflammatory properties of the statins suggest benefit beyond low-density lipoprotein cholesterol reduction.
(See link: Statins as potent anti-inflammatory drugs. Circulation. 2002;106:2041–2042).

Graham Jackson

Effects of hyperglycemia and fatty acid oxidation inhibition during aerobic conditions and demand-induced ischemia
Chavez PN, Stanley WC, McElfresh TA, Huang H, Sterk JP, Chandler MP. Am J Physiol Heart Circ Physiol. 2003.

Metabolic interventions improve performance during demand-induced ischemia by reducing myocardial lactate production and improving regional systolic function. We tested the hypotheses that: (1) stimulation of glycolysis would increase lactate production and improve ventricular wall motion; and (2) the addition of fatty acid oxidation inhibition would reduce lactate production and further improve contractile function. Measurements were made in anesthetized open-chest swine hearts. Three groups, hyperglycemia (HG), hyperglycemia + oxfenicine (HG + Oxf), and control (CTRL), were treated under aerobic conditions and during demand-induced ischemia. During demand-induced ischemia, HG resulted in greater lactate production and tissue lactate content but had no significant effect on glucose oxidation. HG + Oxf significantly lowered lactate production and increased glucose oxidation compared with both CTRL and HG. Myocardial energy efficiency was greater in HG and HG + Oxf under aerobic conditions but did not change during demand-induced ischemia. Thus, enhanced glycolysis resulted in increased energy efficiency under aerobic conditions, but significantly enhanced lactate production, with no further improvement in function during demand-induced ischemia. Partial inhibition of free fatty acid oxidation in the presence of accelerated glycolysis increased energy efficiency under aerobic conditions and significantly reduced lactate production and enhanced glucose oxidation during demand-induced ischemia.

Commentary
Although glycolysis is not a major contributor to overall energy production in the normal heart, it is thought to be a much more important source of energy during myocardial ischemia. However, accumulation within the myocardium of glycolytic byproducts, namely lactate and protons, during ischemia is a potential adverse effect of high rates of glycolysis. Lactate and protons accumulate when glucose oxidation is inhibited while glycolytic rates are either maintained or accelerated. This problem is exacerbated if fatty acid oxidation rates are high, since this further decreases glucose oxidation rates. While the accumulation of glycolytic byproducts can be detrimental to the severely ischemic heart, it is controversial whether this is a problem in moderately ischemic hearts.
In the study by Chavez et al, demand-induced ischemia was produced in pig hearts exposed to high glucose levels. This increased lactate production and decreased cardiac efficiency during ischemia. However, inhibition of fatty acid oxidation resulted in an increase in glucose oxidation, a decrease in lactate production, and an increase in cardiac efficiency in these ischemic hearts. This study supports previous studies that show that inhibition of fatty acid oxidation (such as with trimetazidine) can improve cardiac efficiency and benefit the ischemic heart.

Gary Lopaschuk

Association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction
Iwakura K, Ito H, Ikushima M, et al. J Am Coll Cardiol. 2003;41:1–7.

We investigated the association between hyperglycemia and the no-reflow phenomenon in patients with acute myocardial infarction (AMI). Hyperglycemia is associated with increased risk of heart failure, cardiogenic shock, and death after AMI, but its underlying mechanism remains unknown. A total of 146 consecutive patients with a first AMI were studied by intracoronary myocardial contrast echocardiography after successful reperfusion within 24 hours of symptom onset. Two-dimensional echocardiography was recorded on day 1 and again 3 months later to determine the change in wall motion score (DWMS; sum of 16 segmental scores: dyskinesia = 4 to normokinesia = 0). The no-reflow phenomenon was found in 49 (33.6%) of 146 patients; their glucose levels on hospital admission were significantly higher than those of patients who did not exhibit this phenomenon (209 ± 79 vs 159 ± 56 mg/dL; P < 0.0001). There was no difference in glycosylated hemoglobin nor in the incidence of diabetes mellitus between the two subsets of patients. The no-reflow phenomenon was more often observed in the 75 patients with hyperglycemia (³160 mg/dL) than in those without hyperglycemia (52.0% vs 14.1%; P < 0.0001). Patients with hyperglycemia had a higher peak creatine kinase level (2497 ± 1603 vs 1804 ± 1300 IU/L; P = 0.005) and a lower DWMS (3.7 ± 4.8 vs 5.7 ± 4.3; P = 0.01) than did those without hyperglycemia. The blood glucose level was an independent prognostic factor for no-reflow, along with age, gender, absence of preinfarction angina, complete occlusion of the culprit lesion, and anterior AMI. Hyperglycemia might be associated with impaired microvascular function after AMI, resulting in a larger infarct size and poorer functional recovery.

Commentary
It has long been observed that there is an association between admission glucose levels and morbidity and mortality following myocardial infarction. This holds true for patients with and for those without known diabetes mellitus. In a recent meta-analysis, Capes et al [1] reported that patients without diabetes who had glucose concentrations ³6.1 to 8.0 mmol/L had a 3.9-fold higher risk of death than patients without diabetes who had lower glucose concentrations. Glucose concentrations >8.0 to 10.0 mmol/L on admission were associated with an increased risk of congestive heart failure or cardiogenic shock in patients without diabetes. In patients with diabetes who had glucose concentrations ³10.0 to 11.0 mmol/L the risk of death was moderately increased (relative risk 1.7). The relation between admission glucose levels vs morbidity and mortality remains unchanged despite modern infarction treatment with primary PTCA, thrombolysis, antithrombotics, b-blockers, and ACE inhibitors [2].
The mechanisms underlying the unfavorable relation between hyperglycemia and infarct prognosis are unclear, but there are a number of factors which may explain it. High catecholamine levels are found during infarction, which adversely affect glucose and fatty acid metabolism. High fatty acid levels may be toxic to the myocardium and may increase O2 demand and reduce contractility. Hyperglycemia induces capillary plugging by leukocytes and diminishes endothelium-dependent vasodilatation, increases thrombus formation, reduces macrophage and lymphocyte function, results in less ischemic preconditioning, and reduces collateral flow. Hyperglycemia may reduce circulating volume by osmotic diuresis. Finally, stress hyperglycemia may be a marker of more extensive myocardial damage in acute infarction. More damage leads to a greater rise in stress hormones, increasing myocardial oxygen consumption, and more congestive heart failure. However, the relationship between hyperglycemia and infarct size has been questioned as some studies have only found a weak relation or no relationship at all between infarct size and hyperglycemia.
In the present study the authors correlated the absence of reflow (by contrast echocardiography) with hyperglycemia. They found that no-reflow was more frequently observed in patients with high glucose levels on admission and that these patients had larger infarctions and poorer recovery of ventricular function during follow-up.
This study carries two important messages. First, the data nicely confirm, in patients, some of the mechanisms described above. Second, despite modern treatment of infarction by thrombolysis or primary PTCA (which have clearly reduced infarct size and prognosis), hyperglycemia plays an important role in the ultimate damage caused by infarction. Further studies are needed to demonstrate that insulin intervention reduces infarct size and improves prognosis in patients undergoing thrombolysis or primary PTCA.

REFERENCES

1: Lancet. 2000 Mar 4;355(9206):773-8.