An outcome-driven threshold for pulse pressure amplification

Abstract

Pulse pressure amplification (PPA) is the brachial-to-aortic pulse pressure ratio and decreases with age and cardiovascular risk factors. This individual-participant meta-analysis of population studies aimed to define an outcome-driven threshold for PPA. Incidence rates and standardized multivariable-adjusted hazard ratios (HRs) of cardiovascular and coronary endpoints associated with PPA, as assessed by the SphygmoCor software, were evaluated in the International Database of Central Arterial Properties for Risk Stratification (n = 5608). Model refinement was assessed by the integrated discrimination (IDI) and net reclassification (NRI) improvement. Age ranged from 30 to 96 years (median 53.6). Over 4.1 years (median), 255 and 109 participants experienced a cardiovascular or coronary endpoint. In a randomly defined discovery subset of 3945 individuals, the rounded risk-carrying PPA thresholds converged at 1.3. The HRs for cardiovascular and coronary endpoints contrasting PPA < 1.3 vs ≥1.3 were 1.54 (95% confidence interval [CI]: 1.00-2.36) and 2.45 (CI: 1.20-5.01), respectively. Models were well calibrated, findings were replicated in the remaining 1663 individuals analyzed as test dataset, and NRI was significant for both endpoints. The HRs associating cardiovascular and coronary endpoints per PPA threshold in individuals <60 vs ≥60 years were 3.86 vs 1.19 and 6.21 vs 1.77, respectively. The proportion of high-risk women (PPA < 1.3) was higher at younger age (<60 vs ≥60 years: 67.7% vs 61.5%; P < 0.001). In conclusion, over and beyond common risk factors, a brachial-to-central PP ratio of <1.3 is a forerunner of cardiovascular coronary complications and is an underestimated risk factor in women aged 30-60 years. Our study supports pulse wave analysis for risk stratification.

Keywords: Pulse pressure amplification, Waveform analysis, Cardiovascular risk, Population science.

Fig. 1

Cumulative incidence of the cardiovascular and coronary endpoints by tertiles of pulse pressure amplification. Cumulative incidence of the cardiovascular (A) and coronary (B) endpoints was derived by Cox regression with adjustment for cohort, sex and age. P values denote the overall significance of the difference between the PPA categories. Vertical lines denote the SE. Tabulated data are the number of participants at risk at 5-year intervals

Fig. 2

Threshold and calibration of pulse pressure amplification (PPA) in the discovery sample including 3945 participants. Hazard ratios (HRs) express the risk at each PPA level relative to the average risk in the whole discovery sample for cardiovascular (A) and coronary endpoints (B). The upper confidence limit crosses unity, denoted by the vertical line, at 1.28 and 1.26 for cardiovascular and coronary endpoints, signifying decreased risk. The PPA levels yielding equivalent 5-year risks compared with a systolic blood pressure of 140 mmHg were 1.28 and 1.29 for the cardiovascular (C) and coronary (D) endpoints, respectively. Model calibration for the cardiovascular (E) and coronary (F) endpoints demonstrated that across PPA quintiles the predicted risk was similar compared with the overoptimism-corrected Kaplan–Meier estimates. All analyses were multivariable adjusted for cohort (random effect), sex, age, body mass index, heart rate, smoking and drinking, total-to-HDL serum cholesterol ratio, estimated glomerular filtration rate, antihypertensive drug intake, history of cardiovascular disease, and diabetes

Fig. 3

Hazard ratios expressing the risk of cardiovascular and coronary endpoints per the 1.3 pulse pressure amplification threshold by subgroups. Hazard ratios, given with 95% confidence interval accounted for cohort (random effect), sex, age, body mass index, heart rate, smoking and drinking, the total-to-HDL serum cholesterol ratio, the estimated glomerular filtration rate, antihypertensive drug intake, history of cardiovascular disease and diabetes. Adjustment for sex, age and antihypertensive treatment was omitted, if these variables defined the strata. Squares represent the point estimates of the hazard ratios (HR). Horizontal lines denote 95% confidence interval. NLE/NLR vs NHE/NHR refer to the number of participants with an event/number of participants at risk dichotomized by the threshold of pulse pressure amplification (<1.3 vs ≥1.3, respectively)