Cardiac autonomic neuropathy predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy

OBJECTIVE: Cardiac autonomic neuropathy (CAN) has been associated with a poor prognosis in patients with diabetes. Because CAN is common in patients with diabetic nephropathy, we evaluated the predictive value of CAN in type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: In a prospective observational follow-up study, 197 type 1 diabetic patients with diabetic nephropathy and a matched group of 191 patients with long-standing type 1 diabetes and normoalbuminuria were followed for 10.1 years (range 0.0-10.3 years). At baseline, CAN was assessed by heart rate variation (HRV) during deep breathing. HRV was evaluated as a predictor of the primary end point: cardiovascular morbidity and mortality. As secondary end points, all-cause mortality and the influence of HRV on progression of diabetic nephropathy (decline in glomerular filtration rate GFR]) was evaluated. RESULTS: During the follow-up, 79 patients (40%) with nephropathy reached the combined primary end point vs. 19 patients (10%) with normoalbuminuria (log-rank test, P < 0.0001). The unadjusted hazard ratio (HR) for reaching the primary end point when having an abnormal HRV (< or =10 bpm) measured at baseline compared with a normal HRV was 7.7 (range 1.9-31.5; P = 0.004) in patients with nephropathy. Similarly in the normoalbuminuric patients, the unadjusted HR was 4.4 (1.4-13.6; P = 0.009). In patients with nephropathy, abnormal HRV was significantly associated with fatal and nonfatal cardiovascular disease after adjustment for cardiovascular risk factors. The adjusted HR for reaching the primary end point in a patient with nephropathy and an abnormal HRV was 6.4 (1.5-26.3, P = 0.010), as compared with a normal HRV. The unadjusted HR for dying when having an abnormal HRV compared with a normal HRV was 3.3 (95% CI 1.0-10.7; P = 0.043) in patients with diabetic nephropathy. After adjustment for confounding factors, the impact of HRV on all-cause mortality in patients with nephropathy was no longer significant (P = 0.293). There was no relationship between abnormal HRV and rate of decline in GFR. CONCLUSIONS: HRV is an independent risk factor for cardiovascular morbidity and mortality in type 1 diabetic patients with nephropathy.