Background
An increased aortic pulse wave velocity (PWV), a marker of arterial stiffness, is associated with poor prognosis in various diseases. In patients with heart failure (HF), an increased aortic PWV is associated with low peak exercise oxygen consumption, which is a strong risk factor of adverse clinical outcomes. However, it remains unknown if an increased aortic PWV predicts poor prognosis in patients with HF, independent of peak exercise oxygen consumption.
Methods and Results
We enrolled 156 patients with HF and left ventricular ejection fraction <45%, who were followed up for a mean (SD) period of 36 ± 19 months. At baseline, all the patients underwent a complete echocardiography with aortic PWV as measured by Doppler ultrasonography and peak exercise oxygen consumption as measured by bicycle exercise testing with expiratory gas exchange monitoring. During the follow-up period, 20 patients (12.8%) died and 15 patients (9.6%) were hospitalized for worsening HF. In the Kaplan-Meier analysis, patients in the first tertile of aortic PWV had a lower risk of developing cardiac death or hospitalization (combined end point) than those in the second and third tertile combined ( P < .001). In Cox regression analysis, increased aortic PWV (both as a continuous and categorical variable) was significantly associated with an increased risk of adverse clinical outcomes after adjustment for peak exercise oxygen consumption and other clinical risk factors ( P < .05).
Conclusions
Increased aortic PWV, as measured by echocardiography, independently predicted adverse clinical outcomes (cardiac death or hospitalization) among patients with HF.
Heart failure (HF) is a complex systemic syndrome characterized by important alterations of both cardiac and vascular function. Recently, we and other investigators showed that reduced aortic distensibility is a strong determinant of exercise intolerance and low peak exercise oxygen consumption (peak VO 2 ), which, in turn, plays a key role in defining the clinical severity of HF and in predicting cardiovascular outcomes in patients with HF. The elastic properties of the aorta are crucial for optimal ventricular-vascular coupling. A decreased aortic distensibility may alter its buffering capacity and increase aortic pulse wave velocity (PWV), which may cause an earlier return of the reflected wave that arises from peripheral vascular arterial sites. Consequently, the premature reflected wave moving from diastole to systole impairs coronary perfusion, increases left ventricular (LV) systolic stress, imposing an additional systolic load to the heart, and induces LV relaxation and filling pressures. Recently, an impaired flow-mediated vasodilation of muscular arteries has been shown to predict adverse clinical outcomes in patients with HF.
However, to our knowledge, the prognostic role of aortic PWV, as measured by echocardiography, has never been clarified in detail with patients with HF. This is noteworthy because decreased aortic distensibility has been found to be associated with poor prognosis in different clinical settings, such as end-stage renal disease, hypertension, diabetes and/or glucose intolerance, and aging. We, therefore, aimed to examine whether increased aortic PWV, as measured by echo-Doppler, is associated with poor prognosis (defined as death or hospitalization) in an outpatient sample of individuals with systolic HF, independent of peak VO 2 and other potential confounding variables.
Methods
Patients
We prospectively studied a sample of 156 outpatients (129 men; mean age, 65 years) with diagnosed HF, who regularly attended the HF clinic of the cardiology division at the University Hospital of Verona. Each patient had a diagnosis of HF, which was based on the presence of LV systolic dysfunction (i.e., LV ejection fraction < 45% and end-diastolic LV volume > 90 mL/m 2 ). Inclusion criteria of the study were stable clinical conditions for at least 6 months and the presence of optimal medical standard therapy for HF. Exclusion criteria were as follows: (1) structurally abnormal mitral or aortic valves with regurgitation or stenosis of at least moderate severity, (2) clinical or echocardiographic features of amyloidosis or constrictive pericarditis, (3) atrial fibrillation or flutter, and (4) resynchronization therapy within 6 months.
The length of the study follow-up was 5 years (mean [SD] follow-up, 36 ± 19 months). The combined end point of the study was inclusive of cardiac death and of hospitalization for worsening HF or cardiac transplantation (status 1). Patients who underwent cardiac transplantation (not status 1) or those who died of noncardiac causes were censored as either alive at the time of transplantation or dead, respectively. Data about hospitalization and death were ascertained for all the participants by reviewing the hospital clinical records or death certificates. The local ethics committee approved the study protocol, and all participants gave written informed consent for participation in medical research.
Echocardiographic Evaluation
All echocardiographic examinations were performed at our institution by an experienced cardiologist (A.R.), who was blinded to the participants’ details. LV end-diastolic and end-systolic volumes and ejection fraction (LVEF) were measured from the apical 4-chamber view with the monoplane area-length method. The left atrial (LA) diameter was measured from the parasternal view (long axis) with M-mode echocardiography. Mitral E and A wave velocities, E-A ratio, and E wave deceleration time (Dte) were measured at the mitral flow-Doppler examination by placing the pulsed Doppler sample volume at the tip of the mitral leaflets. Stroke volume (SV) was measured as the product of the LV outflow tract annulus (LVOT) area and time velocity integral. The LVOT diameter was measured from the parasternal long axis in the early systole just below the aortic valve leaflets insertion. The LVOT time-velocity integral was measured by placing the pulsed Doppler sample volume at the same level from apical 5-chamber view.
Vascular Function Indexes
Aortic PWV is considered a reliable marker of aortic distensibility, because it strongly correlates with direct measurements of arterial stiffness. According to the Moens-Koerteweg equation, PWV, which is proportional to the square root of the Young elastic modulus, travels faster in stiffer arteries. As schematically reported in Figure 1 , pulsed Doppler was used to measure the time taken by the pulse wave to travel along the thoracic aorta. To measure the flow at the level of the aortic arch, the transducer was placed at the suprasternal notch, and the sample volume was placed distal to the origin of the left subclavian artery. The distance (D 1 ) between the transducer and the sample volume was then measured in a two-dimensional (2D) frame. The flow in the abdominal aorta was determined from the subcostal approach. The distance (D 2 ) from the suprasternal notch to the position of the probe in the abdomen was then measured with a tape measure at the skin level. The distance (D) between the 2 sample volumes was then calculated as the difference between D 2 and D 1 . The R wave of the QRS complex of a simultaneously recorded electrocardiogram was used as a fixed reference time point. The time (t) between the R wave on the electrocardiogram and the foot of each flow wave was subtracted to calculate the transit time, and aortic PWV was then calculated as the distance traveled by the pulse wave divided by the time required, PWV (m/sec) = D/t. An index of total arterial compliance was also calculated as the SV to pulse pressure (PP) ratio (SV-PP). PP was calculated as the difference between systolic and diastolic blood pressure.
Cardiopulmonary Exercise Testing
All the patients underwent a symptom-limited bicycle ergometer exercise test at a constant cadence of 60 rpm. A continuous ramp protocol was used in which the work rate was increased by 10 W/min. Gas exchange was monitored during the exercise test with a computerized metabolic cart (Vmax 229; SensorMedics, Homestead, Florida). Oxygen uptake (peak VO 2 ) was measured online every 10 sec by a standard inert gas dilution technique. Peak VO 2 was defined as the highest VO 2 achieved during exercise and was expressed as mL/kg/min.
Statistical Analysis
Data are presented as mean (SD) and percentages. Comparison between the groups was made by using the one-way analysis of variance (for continuous variables) and the χ 2 test (for categorical variables). The event-free survival was estimated by the Kaplan-Meier analysis, with the follow-up period, starting at the index echocardiogram and the differences assessed by the log-rank test. Cox proportional hazard regression analysis was performed to examine the association between aortic PWV (included as either continuous or categorical variable) and the risk of developing the combined end point, inclusive of cardiac death and hospitalization for worsening HF. The covariates included together with aortic PWV in the multivariate Cox regression models were chosen as potential confounding factors on the basis of their significance in univariate analyses or on the basis of their biologic plausibility. All analyses were performed by using statistical package Stat-view 4.5 (Abacus Concepts, SAS Institute, Cary, NC), and statistical significance was assessed at the two-tailed .05 threshold.
Results
During a follow-up period of 5 years (mean [SD] follow-up period of 36 ± 19 months), there were 20 cardiac deaths and 15 hospitalizations for worsening HF. Three patients received nonurgent cardiac transplantation, and, accordingly, they were censored as alive at the date of surgery. No patients died from noncardiac causes during the follow-up period. The baseline characteristics of patients with HF grouped according to the occurrence of any clinical events at follow-up are summarized in Table 1 . At baseline, patients who developed clinical events at follow-up (cardiac death or hospitalization) were significantly older and were more likely to be more symptomatic, and had a higher heart rate, worse systolic and diastolic LV functions, and lower peak VO 2 than those who did not. Notably, they also had higher aortic PWV. No significant differences were found with sex, blood pressure, PP, SV, LA diameter, and proportion of ischemic etiology of HF between the 2 groups.
