Description: Wave reflection is thought to be important in the augmentation of blood pressure. However, identification of distal reflections sites remains unclear. One possible explanation for this is that wave reflection is predominately determined by an amalgamation of multiple proximal small reflections rather than large discrete reflections originating from the distal peripheries. In 19 subjects (age, 35–73 years), sensor-tipped intra-arterial wires were used to measure pressure and Doppler velocity at 10-cm intervals along the aorta, starting at the aortic root. Incident and reflected waves were identified and timings and magnitudes quantified using wave intensity analysis. Mean wave speed increased along the length of the aorta (proximal, 6.8±0.9 m/s; distal, 10.7±1.5 m/s). The incident wave was tracked moving along the aorta, taking 55±4 ms to travel from the aortic root to the distal aorta. However, the timing to the refection site distance did not differ between proximal and distal aortic measurement sites (proximal aorta, 48±5 ms versus distal aorta, 42±4 ms; P =0.3). We performed a second analysis using aortic waveforms in a nonlinear model of pulse-wave propagation. This demonstrated very similar results to those observed in vivo and also an exponential attenuation in reflection magnitude. There is no single dominant refection site in or near the distal aorta. Rather, there are multiple reflection sites along the aorta, for which the contributions are attenuated with distance. We hypothesize that rereflection of reflected waves leads to wave entrapment, preventing distal waves being seen in the proximal aorta.

Description: Exercise hypertension independently predicts cardiovascular mortality, although little is known about exercise central hemodynamics. This study aimed to determine the contribution of arterial wave travel and aortic reservoir characteristics to central blood pressure (BP) during exercise. We hypothesized that exercise central BP would be principally related to forward wave travel and aortic reservoir function. After routine diagnostic coronary angiography, invasive pressure and flow velocity were recorded in the ascending aorta via sensor-tipped intra-arterial wires in 10 participants (age, 55±10 years; 70% men) free of coronary artery disease with normal left ventricular function. Measures were recorded at baseline and during supine cycle ergometry. Using wave intensity analysis, dominant wave types throughout the cardiac cycle were identified (forward and backward, compression, and decompression), and aortic reservoir and excess pressure were calculated. Central systolic BP increased significantly with exercise (=19±12 mm Hg; P 〈0.001). This was associated with increases in systolic forward compression waves (=12 x 10 6 ±17 x 10 6 W·m –2 ·s –1 ; P =0.045) and forward decompression waves in late systole (=9 x 10 6 ±6 x 10 6 W·m –2 ·s –1 ; P 〈0.001). Despite significant augmentation in BP (=9±6 mm Hg; P =0.002), reflected waves did not increase in magnitude (=–1 x 10 6 ±3 x 10 6 W·m –2 ·s –1 ; P =0.2). Excess pressure rose significantly with exercise (=16±9 mm Hg; P 〈0.001), and reservoir pressure integral fell (=–5 x 10 5 ±5 x 10 5 Pa·s; P =0.010). Change in reflection coefficient negatively correlated with change in central systolic BP ( r =–0.68; P =0.03). We conclude that elevation of exercise central BP is principally because of increases in aortic forward traveling waves generated by left ventricular ejection. These findings have relevance to understanding central BP waveform morphology and pathophysiology of exercise hypertension.

Description: Background— Evidence regarding the use of direct oral anticoagulants (DOACs) in the elderly, particularly bleeding risks, is unclear despite the presence of greater comorbidities, polypharmacy, and altered pharmacokinetics in this age group. Methods and Results— We performed a systematic review and meta-analysis of randomized trials of DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban) for efficacy and bleeding outcomes in comparison with vitamin K antagonists (VKA) in elderly participants (aged ≥75 years) treated for acute venous thromboembolism or stroke prevention in atrial fibrillation. Nineteen studies were eligible for inclusion, but only 11 reported data specifically for elderly participants. The efficacy in managing thrombotic risks for each DOAC was similar or superior to VKA in elderly patients. A nonsignificantly higher risk of major bleeding than with VKA was observed with dabigatran 150 mg (odds ratio, 1.18; 95% confidence interval, 0.97–1.44) but not with the 110-mg dose. Significantly higher gastrointestinal bleeding risks with dabigatran 150 mg (1.78, 1.35–2.35) and dabigatran 110 mg (1.40, 1.04–1.90) and lower intracranial bleeding risks than VKA for dabigatran 150 mg (0.43, 0.26–0.72) and dabigatran 110 mg (0.36, 0.22–0.61) were also observed. A significantly lower major bleeding risk in comparison with VKA was observed for apixaban (0.63, 0.51–0.77), edoxaban 60 mg (0.81, 0.67–0.98), and 30 mg (0.46, 0.38–0.57), whereas rivaroxaban showed similar risks. Conclusions— DOACs demonstrated at least equal efficacy to VKA in managing thrombotic risks in the elderly, but bleeding patterns were distinct. In particular, dabigatran was associated with a higher risk of gastrointestinal bleeding than VKA. Insufficient published data for apixaban, edoxaban, and rivaroxaban indicate that further work is needed to clarify the bleeding risks of these DOACs in the elderly. Systematic Review Registration— http://www.crd.york.ac.uk/PROSPERO . Unique identifier: PROSPERO CRD42014007171/

Description: Background— The optimal dosing strategy of low-molecular-weight heparins for the treatment of antenatal venous thromboembolism is not known. The physiological changes associated with pregnancy alter the pharmacokinetic profile of low-molecular-weight heparins, which has led to controversy and subsequent variation in practice, when pregnant women with venous thromboembolism are treated with low-molecular-weight heparins. Our objective was to develop a robust pharmacokinetic model of enoxaparin during the antenatal period to address this problem. Method and Results— Women prescribed antenatal enoxaparin were eligible to enroll in the study. Recruited women were reviewed monthly and had up to 3 anti-Xa activities (trough and 1 and 3 hours after dose) drawn at each clinic attendance. Compartmental pharmacokinetic modeling was conducted using nonlinear mixed-effects modeling. One hundred twenty-three patients contributed 795 anti-Xa activities for pharmacokinetic modeling purposes. Both enoxaparin clearance and volume of distribution were increased during pregnancy. Simulations of once- versus twice-daily enoxaparin administration demonstrated that both dosing regimens would reach target 3-hour plasma concentrations throughout the duration of the pregnancy. When trough anti-Xa activity was simulated, both once- and twice-daily regimens exhibited an increase in trough anti-Xa activity with the progression of pregnancy. This is explained by the significant increase in volume of distribution observed during pregnancy. Conclusions— The half-life of enoxaparin is prolonged with the progression of pregnancy, and our work provides compelling evidence for prescribing once-daily enoxaparin for the treatment of antenatal venous thromboembolism. National and international guideline recommendations should be reconsidered.

Description: Background— In chronic ischemic heart disease, focal stenosis, diffuse atherosclerotic narrowings, and microcirculatory dysfunction (MCD) contribute to limit myocardial flow. The prevalence of these ischemic heart disease levels in fractional flow reserve (FFR) interrogated vessels remains largely unknown. Methods and Results— Using intracoronary measurements, 91 coronaries (78 patients) with intermediate stenoses were classified in 4 FFR and coronary flow reserve (CFR) agreement groups, using FFR〉0.80 and CFR〈2 as cutoffs. Index of microcirculatory resistance (IMR) and atherosclerotic burden (Gensini score) were also assessed. MCD was assumed when IMR≥29.1 (75 th percentile). Fifty-four (59.3%) vessels had normal FFR, from which only 20 (37%) presented both normal CFR and IMR. Among vessels with FFR〉0.80, most (63%) presented disturbed hemodynamics: abnormal CFR in 28 (52%) and MCD in 18 (33%). Vessels with FFR〉0.80 presented higher IMR [adjusted mean 27.6 (95% confidence interval, 23.4–31.8)] than those with FFR≤0.80 [17.3 (95% confidence interval, 13.0–21.7), p=0.001]. Atherosclerotic burden was inversely correlated with CFR ( r =–0.207, P =0.055), and in vessels with FFR〉0.80 and CFR〈2 (n=28, 39%), IMR had a wide dispersion (7–72.7 U), suggesting a combination of diffuse atherosclerotic narrowings and MCD. Vessels with FFR≤0.80 and normal CFR presented the lowest IMR, suggesting a preserved microcirculation. Conclusions— A substantial number of coronary arteries with stenoses showing an FFR〉0.80 present disturbed hemodynamics. Integration of FFR, CFR, and IMR supports the existence of differentiated patterns of ischemic heart disease that combine focal and diffuse coronary narrowings with variable degrees of MCD.

Description: Excess pressure integral (XSPI), a new index of surplus work performed by the left ventricle, can be calculated from blood pressure waveforms and may indicate circulatory dysfunction. We investigated whether XSPI predicted future cardiovascular events and target organ damage in treated hypertensive individuals. Radial blood pressure waveforms were acquired by tonometry in 2069 individuals (aged, 63±8 years) in the Conduit Artery Functional Evaluation (CAFE) substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Measurements of left ventricular mass index (n=862) and common carotid artery intima media thickness (n=923) were also performed. XSPI and the integral of reservoir pressure were lower in people treated with amlodipine±perindopril than in those treated with atenolol±bendroflumethiazide, although brachial systolic blood pressure was similar. A total of 134 cardiovascular events accrued during a median 3.4 years of follow-up; XSPI was a significant predictor of cardiovascular events after adjustment for age and sex, and this relationship was unaffected by adjustment for conventional cardiovascular risk factors or Framingham risk score. XSPI, central systolic blood pressure, central augmentation pressure, central pulse pressure, and integral of reservoir pressure were correlated with left ventricular mass index, but only XSPI, augmentation pressure, and central pulse pressure were associated positively with carotid artery intima media thickness. Associations between left ventricular mass index, XSPI, and integral of reservoir pressure and carotid artery intima media thickness and XSPI were unaffected by multivariable adjustment for other covariates. XSPI is a novel indicator of cardiovascular dysfunction and independently predicts cardiovascular events and targets organ damage in a prospective clinical trial.

Description: Objective— Aortic reservoir pressure indices independently predict cardiovascular events and mortality. Despite this, there has never been a study in humans to determine whether the theoretical principles of the mathematically derived aortic reservoir pressure (RP derived ) and excess pressure (XP derived ) model have a real physiological basis. This study aimed to directly measure the aortic reservoir (AR direct ; by cyclic change in aortic volume) and determine its relationship with RP derived , XP derived , and aortic blood pressure (BP). Approach and Results— Ascending aortic BP and Doppler flow velocity were recorded via intra-arterial wire in 10 men (aged 62±12 years) during coronary artery bypass surgery. Simultaneous ascending aortic transesophageal echocardiography was used to measure AR direct . Published mathematical formulae were used to determine RP derived and XP derived . AR direct was strongly and linearly related to RP derived during systole ( r =0.988; P 〈0.001) and diastole ( r =0.985; P 〈0.001). Peak cross-correlation ( r =0.98) occurred at a phase lag of 0.004 s into the cardiac cycle, suggesting close temporal agreement between waveforms. The relationship between aortic BP and AR direct was qualitatively similar to the cyclic relationship between aortic BP and RP derived , with peak cross-correlations occurring at identical phase lags (AR direct versus aortic BP, r =0.96 at 0.06 s; RP derived versus aortic BP, r =0.98 at 0.06 s). Conclusions— RP derived is highly correlated with changes in proximal aortic volume, consistent with its physiological interpretation as corresponding to the instantaneous volume of blood stored in the aorta. Thus, aortic reservoir pressure should be considered in the interpretation of the central BP waveform.

Description: Several morphological parameters based on the central aortic pressure waveform are proposed as cardiovascular risk markers, yet no study has definitively demonstrated the incremental value of any waveform parameter in addition to currently accepted biomarkers in elderly, hypertensive patients. The reservoir-wave concept combines elements of wave transmission and Windkessel models of arterial pressure generation, defining an excess pressure superimposed on a background reservoir pressure. The utility of pressure rate constants derived from reservoir-wave analysis in prediction of cardiovascular events is unknown. Carotid blood pressure waveforms were measured prerandomization in a subset of 838 patients in the Second Australian National Blood Pressure Study. Reservoir-wave analysis was performed and indices of arterial function, including the systolic and diastolic rate constants, were derived. Survival analysis was performed to determine the association between reservoir-wave parameters and cardiovascular events. The incremental utility of reservoir-wave parameters in addition to the Framingham Risk Score was assessed. Baseline values of the systolic rate constant were independently predictive of clinical outcome (hazard ratio, 0.33; 95% confidence interval, 0.13–0.82; P =0.016 for fatal and nonfatal stroke and myocardial infarction and hazard ratio, 0.38; 95% confidence interval, 0.20–0.74; P =0.004 for the composite end point, including all cardiovascular events). Addition of this parameter to the Framingham Risk Score was associated with an improvement in predictive accuracy for cardiovascular events as assessed by the integrated discrimination improvement and net reclassification improvement indices. This analysis demonstrates that baseline values of the systolic rate constant predict clinical outcomes in elderly patients with hypertension and incrementally improve prognostication of cardiovascular events.