Heme oxygenase-1 in patients with idiopathic left ventricular and coronary microvascular dysfunction: relationship with diabetes/insulin resistance

Purpose: Heme oxygenase (HO-1) induction in the myocardium is an important cardioprotective adaptation that mitigates pathological left ventricular (LV) remodeling in the failing heart and reduces myocardial and coronary microvascular damage secondary to oxidative stress and ischemia. In experimental diabetes, however, HO-1 response is downregulated thus potentially contributing to enhance susceptibility of the diabetic heart. Purpose of the present study was to first measure circulating levels of HO-1 in a clinical model of primitive myocardial coronary microvascular dysfunction in relationship with glucose metabolic profiles. Methods: Fifty-five consecutive patients (40 males, age 60±10 yrs,) with variable LV function (LV ejection fraction 37±9%, 39 NYHA class II-III) were studied. Patients were characterized for presence of type II diabetes (NIDD) or insulin resistance (IR, HOMA index>2). Age, sex, cholesterol levels, blood pressure and BMI values were also recorded. Coronary microvascular function was evaluated by positron emission tomography. Absolute myocardial blood flow (MBF) was measured using 13N-Ammonia as flow tracer, both at rest and during dipyridamole infusion (0.56 mg/kg I.V. over 4 min). MBF reserve <2 was defined as abnormal. Plasma HO-1 was measured by a specific ELISA. Results: In the study population circulating HO-1 levels were increased proportionally to the severity of clinical disease [3.75 ng/mL (0.45-27.9), median (5°-95° percentiles), in NYHA class I vs. 8.75 (0.55-28.2) in NYHA class II-III; p=0.004]. Moreover, HO-1 levels were related with the presence of coronary microvascular dysfunction [8.75 ng/mL (0.41-29.1) in pts with MBF reserve <2 vs. 5.75 (0.57-26.80) in pts with MBF reserve >2, p=0.05]. Patients with NIDD/IR showed lower value of HO-1 [8.1 ng/mL (0.3-26.7) NIDD/IR pts vs. 15.5 (5.1-31.3) no NIDD/IR pts, p=0.06] and increased frequency of severe coronary dysfunction [68% NIDD/IR vs. 33% NIDD/IR, p=0.023]. No significant relationship was found between HO-1 and extent of LV dysfunction. Conclusion: This study first demonstrates that circulating levels of HO-1 are related with disease severity and coronary microvascular dysfunction in a clinical model of idiopathic heart failure and are modulated by NIDD/IR. Present results suggest HO-1 testing as a potential new marker of individual response to myocardial/coronary damage.