Predictors of Peripheral Artery Disease Progression. Is there Any Role for Vascular Age?

Background. Peripheral artery disease (PAD) is a distinct atherosclerotic syndrome marked by stenosis or occlusion of the arteries, particularly of the lower extremities. The major risk factors for PAD are similar to those for coronary and cerebrovascular disease, comprising smoking, hypertension, hypercholesterolemia and diabetes. The factors involved in the progression of PAD are less well defined. Vascular age (VA) is represented by the apparent age of the vascular system derived from the associated cardiovascular risk factors. This concept has been used so far mainly in primary prevention, being usefull for communication with the patient.

Aim. The purpose of the study was to investigate the factors involved in the progression of arterial stenosis in patients already having PAD. Moreover, we tried to determine the utility of VA in increasing patient compliance with therapeutic decisions.

Methods. Between 1st February 2015 - 31st December 2015, 270 consecutive patients (pts) referred for vascular echo-Doppler assessment were enrolled in the study. 106 pts with non-significant arterial stenosis were prospectively evaluated. All pts underwent complete clinical examination, carotid, femoral ultrasound, echocardiography and laboratory evaluation. Presence of atherosclerotic plaques in the carotid arteries were recorded. Medical history, drug use, smoking behavior, blood pressure, duration of diabetes, presence of premature atherosclerotic PAD in relatives, characterized by disease diagnosis before the age of 50 years, were evaluated. Serum total cholesterol (TC), HDL cholesterol (HDL-C), serum glucose, A1c hemoglobine (HbA1c), serum creatinine, estimated glomerular filtration rate (eGFR) were determined. VA was estimated using Framingham score and intima-media thickness (IMT). The primary end-point was the occurrence of significant peripheral artery stenosis (PAS), defined as a two-fold increase Doppler velocity across the stenosis.

Results. At baseline, median age of enrolled pts was 57 years, with male predominance (69,8%). Less than 40% had high blood pressure (39.3%), 36.4% had treated hypertension.

The median left ventricular mass index (LVMI) was 108.5 g/m² and concentric hypertrophy was present in 29.9% of patients. Patients with hypertension had LVMI of 113.12 g/m² and those without hypertensiun, had 105.6 g/m². Diabetes mellitus (DM) was present in 20.6% of patients, majority treated (88%). Among them, 10.3% had more than 10 years duration of DM. Median HbA1c was 5.8%. The majority of the patients are smokers (75.5%). Mean pack-years of smoking was 29.8. During the 4.5 years follow-up, 31.25% quit smoking. The median ejection fraction (EF) was 51.6%.

The median TC concentration was 191.6 mg/dl and median HDL-c level was 62.9 mg/dl. 45.8% of the patients received treatment with statins. Premature atherosclerotic PAD in relatives was present in 25.2 % of the patients, and carotid atheromas (CA) in 35.5%. Aortic calcifications (AC) were found in 37.4% of the patients. Median arterial elastance (Ea) was 2.07 mmHg/ml. Median serum creatinine was 1.03 mg/dl and eGFR was 75.6 ml/ml/1.73 m². Median value of the VA calculated by IMT (VA-IMT) was 65.5 years and the median VA calculated by cardiovascular risk factors (VA-RF) was 62.9 years. After 4.5 years of follow-up, 35 (32.7%) patients developed significant PAS. 22 patients had popliteal artey stenosis (62.85%) and 13 patients had superficial femoral artery stenosis (37.15%). During the 4.5 years follow-up, 25 patients (31.25%) quit smoking. Median age of population who developed significant PAS at follow-up was 62.6 years and 39.2% were males.

Individuals who developed stenosis tended to be smokers, older, receiving hypertensive and statin therapy, having diabetes, especially more than 10 years duration, having dyslipidemias and CA. They all had higher VA-IMT and VA-RF values compared to patients that did not develop PAS. Median value of VA-IMT was 72.6 years and VA-RF was 74.2 years (p<0,001 for both parameters). They also had significantly higher values of Ea, with median value of 2.16 mmHg/ml. There were no statistically significant differences between the two groups in cardiac performance, LV mass, percentage of LV concentric hypertrophy, presence of AC, premature PAD in relatives, renal function and blood pressure values. In logistic regression analysis, pack-years of smoking, HbA1c %, presence of CA and HDL-C were independently associated with significant PAS progression. From the 25 patients which quit smoking, only 6 developed significant PAS (24%), as compared to 29 (52.7%) from the 55 patients which remained active smokers (p =0.016).

Conclusion. We demonstrated that some of the classical cardiovascular risk factors were involved in PAD progression: smoking, dyslipidemia, diabetes, carotid atherosclerosis. At multivariate analysis the independent variables associated with PAD progression were pack-years of smoking, glycosilated hemoglobin and HDL-cholesterol values and presence of CA. VA assessed by cardiovascular risk scales and by directly measured IMT both predict the progression of PAD, as did Ea, but without independent predictive value for the outcome. Nevertheless, VA was usefull in comunicating with the patients, influencing their perception of disease progression and adherence to therapy, improving shared decision making, mainly quitting smoking. We have shown that even after 4.5 years of smoking cessation there was a measurable effect on PAD progression.