Arterial Stiffness and Coronary Ischemia: New Aspects and Paradigms.

PURPOSE OF REVIEW: Aortic stiffness (AS) is widely associated with hypertension and considered as a major predictor of coronary heart disease (CHD). AS is measured using carotid-femoral pulse wave velocity (PWV), particularly when this parameter is associated with an index involving age, gender, heart rate, and mean blood pressure. The present review focuses on the interest of measurement of PWV and the calculation of individual PWV index for the prediction of CHD, in addition with the use of new statistical nonlinear models enabling results with very high levels of accuracy. RECENT FINDINGS: PWV index may so constitute a substantial marker of large arteries prediction and damage in CHD and may be also used in cerebrovascular and renal circulations models. PWV index determinations are particularly relevant to consider in angiographic CHD decisions and in the presence of vulnerable plaques with high cardiovascular risk. Due to the variability in symptoms and clinical characteristics of patients, together with some imperfections in results, there is no very simple adequate diagnosis approach enabling to improve the so defined CHD prediction in usual clinical practice. In recent works in relation to "artificial intelligence" and involving "decision tree" models and "artificial neural networks," it has been possible to determine consistent pathways introducing predictive medicine and enabling to obtain efficient algorithm classification models of coronary prediction.

Added value of aortic pulse wave velocity index for the detection of coronary heart disease by elective coronary angiography.

Background: Non-invasive tests leading to elective coronary angiography (CAG) have low diagnostic yield for obstructive coronary heart disease (CHD). Aortic stiffness, an independent predictor of CHD events can be easily measured by pulse wave velocity (PWV). We aimed at retrospectively evaluating the diagnostic accuracy PWV index to detect CHD in consecutive patients with suspected CHD that underwent CAG.Method: In population of 86 healthy patients with available PWV data, a theoretical PWV was derived. In different population of 62 individuals who underwent CAG for suspected CHD, PWV index was calculated as index [(measured PWV - theoretical PWV)/theoretical PWV]. Logistic regression and comparisons between ROC curves were used to add value of CAG indication performance of PWV index.Results: Out of 62, seventeen patients presented obstructive CHD and 22 patients had non-obstructive CHD. PWV index and severity of CHD were positively correlated (p < 0.0001). After applying several models that included classical CHD predictor, the higher performance to detect abnormal CAG was obtained with the combined classifier PWV index/carotid plaque with 87% sensitivity, 93% specificity, 0.92 accuracy and 0.31 threshold. To detect obstructive CAG, individual classifier PWV index presents 94% sensitivity, 91% specificity, 0.95 accuracy and 0.46 threshold.Conclusion: PWV index is individualized approach that optimizes CHD diagnostic strategies and thus might be clinically useful for reducing the rate of unnecessary invasive CAG.

Optimal blood pressure target in stroke prevention.

PURPOSE OF REVIEW: A generalized single blood pressure (BP) goal may appear not suitable to achieve an optimal stroke prevention at the individual level. The aim of the present review is to consider the clinical relevance of individualized BP goal according to patient's age, comorbidities and established cerebrovascular disease. RECENT FINDINGS: Observational and interventional data support heterogeneity in target organ prevention in that lower BP values than recommended by hypertension guidelines are associated with further stroke risk reduction. However, more ambitious BP treatment targets appear not broadly applicable to ageing hypertensive individuals or patients with established cerebrovascular disease. SUMMARY: Strict BP control in early diagnosed hypertensive individuals, without established arterial disease, should be a priority in primary stroke prevention. In ageing hypertensive individuals, difficult to control SBP can be considered as a marker of increased systemic arterial disease in the brain, the heart and the kidneys. A delayed aggressive intervention to reduce BP in these high-risk patients may be associated with a J-shaped relationship between BP level and adverse events. Moreover, patients suffering from stroke frequently presented with a high burden of small cerebral vessel lesions that are associated with an increased risk of cognitive decline progression, particularly with stringent BP levels.

Should blood pressure goal be individualized in hypertensive patients?

The aim of the present review is to consider the clinical relevance of individualized blood pressure (BP) goal under treatment in hypertensive patients according to their age, comorbidities or established cardiovascular (CV) disease. Evidence from large-scale randomized trials to support a lower BP goal, as initially recommended by guidelines in high-risk hypertensive patients, were lacking. Recently, the randomized intervention SPRINT trial studied two treatment targets for systolic BP (120mm Hg versus 140mm Hg in the intensive and standard treatment group, respectively) among high-risk hypertensive patients, without diabetes and without a history of prior stroke. The trial was stopped prematurely owing to a significantly lower rate of the primary composite outcome and all-cause mortality in the intensive treatment group. Several practical questions have to be considered. First, using an automated measurement system at an office visit during the SPRINT protocol, while the patient was seated alone after 5min of quiet rest, may likely have resulted in lower BP values than would normally be obtained with the routine BP measurement. A target systolic of 120mm Hg in SRPINT trial may be thus equated to a target systolic BP of 130mm Hg in the real-world office setting. Second, careful and repeated examinations of SPRINT participants may have led to fewer adverse events (more frequent in the intensive treatment group) than that expected in the real-world setting. The safety profile of this intensive treatment approach should therefore remain a matter of concern in clinical practice, especially in elderly patients, in diabetic patients or with established CV or renal disease. Orthostatic hypotension should alert the clinician to withhold up titration. Third, beyond the question of BP goal, choice of antihypertensive medication and effective 24-h BP control are important to consider in the context of BP-lowering strategy. In particular, ambulatory BP measurements and during nighttime should be considered for an individualized hypertension care.

Aortic Aging in ESRD: Structural, Hemodynamic, and Mortality Implications.

Aging incurs aortic stiffening and dilation, but these changes are less pronounced in peripheral arteries, resulting in stiffness and geometry gradients influencing progression of the forward and reflected pressure waves. Because premature arterial aging is observed in ESRD, we determined the respective roles of stiffness and aortic geometry gradients in 73 controls and 156 patients on hemodialysis. We measured aortic pulse wave velocity (PWV) and brachial PWV to evaluate the stiffness gradient [(brachial PWV/aortic PWV)(0.5)] and ascending aortic and aortic bifurcation diameters to assess aortic taper (ascending aortic diameter/aortic bifurcation diameter). The global reflection coefficient was estimated from characteristic impedance and vascular resistance. Cox proportional hazard models were used to determine mortality risk. The age-associated increase in aortic PWV was higher in patients (P<0.001). In controls, aortic ascending and bifurcation diameters increased with age, with an unchanged aortic taper. In patients on hemodialysis, age did not associate with increased ascending aortic diameter but did associate with increased aortic bifurcation diameter and decreased aortic taper, both of which also associated with abdominal aortic calcifications and smaller global reflection coefficient (P<0.001). In patients, multivariate models revealed all-cause and cardiovascular mortality associated with age, aortic PWV, and aortic bifurcation diameter with high specificity and sensitivity. Using stiffness gradient, aortic taper, or global reflection coefficient in the model produced similar results. Thus, whereas aortic stiffness is a known independent predictor of mortality, these results indicate the importance of also evaluating the aortic geometry in patients on hemodialysis.

Renal function decline in recipients and donors of kidney grafts: role of aortic stiffness.

BACKGROUND/AIMS: Renal function decreases over time as a result of reduction in the number of functioning nephrons with age. In recipients and donors of kidney grafts, renal function decline may be linked differently to various parameters, namely arterial stiffness. METHODS: We conducted a prospective cohort study including 101 recipients of kidney grafts and their donors aiming at determining the factors correlated to the renal function decline over time. Aortic stiffness was evaluated by the non-invasive measurement of aortic pulse wave velocity. The glomerular filtration rate was estimated using the Modification of Diet in Renal Disease (MDRD) equation and the annualized change was determined. RESULTS: Decline in renal function was estimated at 1-year post-transplantation and annually thereafter (median follow-up 8 years, range 3.6-18.3), as the mean of the annualized decrease in the glomerular filtration rate. In recipients, filtration rate decreased by 4.8 ± 19.7 ml/min/1.73 m(2) the first post-transplant year and at a yearly rate of 2.2 ± 3.8 ml/min/1.73 m(2) thereafter. The first-year decline was related to smoking and acute rejection. Later decline was significantly associated with donor age and aortic stiffness. In living donors, renal function decline after the first year corresponded to 0.7 ml/min/1.73 m(2), was significantly lower than that of recipients (p < 0.001), and was determined by donor age at nephrectomy. CONCLUSION: Recipients of kidney grafts show a glomerular filtration rate decline over time that is significantly associated with donor age and aortic stiffness after the first post-transplant year, while donors demonstrate a lower decline that is mostly determined by age at nephrectomy.

Assessment of aortic stiffness by transesophageal echocardiography.

BACKGROUND: Aortic stiffness, often measured by the carotid/femoral pulse-wave velocity (PWV) method, has become an attractive predictor for cardiovascular (CV) risk. Although noninvasive, PWV requires additional equipment and training. Aortic diameters measured at transesophageal echocardiography (TEE) provide high spatial resolution images as an alternative to PWV, and permit a more routine assessment of aortic stiffness. The purpose of this study was to measure aortic diameters at TEE, calculate aortic stiffness and compare these data to those of the more established PWV as estimates of CV risk and survival. METHODS: Systolic and diastolic aortic dimensions were measured retrospectively in 500 consecutive patients who had a clinically indicated TEE. Aortic compliance, distensibility, and stiffness index were calculated using the aortic diameters and corrected brachial cuff blood pressures (BP). RESULTS: Compliance significantly related to age and mean BP (both P < 0.0001) and nearly significantly to chronic renal disease (P = 0.064). The results for distensibility and stiffness index were similar. When analyzed by Kaplan-Meier curves, all stiffness tertiles were significantly predictive of 4.5- to 7.5-year survival. These calculated values behaved similar to those of PWV reported in the literature. CONCLUSIONS: This study showed that in patients undergoing routine TEE, aortic stiffness can be readily measured and that the derived values offer relationships comparable to those of PWV, including survival prediction. The method may also find use in assessing aortic stiffness in the TEE evaluation of patients with a bicuspid aortic valve or in preparation for transcatheter aortic valve replacement.

Pulse pressure, arterial stiffness, and end-organ damage.

Whereas larger arteries participate in the dampening of blood pressure (BP) oscillations resulting from intermittent ventricular ejection, smaller arteries steadily deliver an adequate supply of blood from the heart to the peripheral organs. Numerous active mechanisms are involved in this process. Cyclic stress acts differently from steady stress, inducing stronger and stiffer material of the vessel wall than under static conditions. Cyclic strain participates in the phenotypic plasticity of smooth muscle cells, initiates transduction mechanisms and induces the transcriptional profile of mechanically induced genes. Finally, the autoregulatory mechanism protecting the brain, heart and kidney from cardiovascular (CV) damage differ markedly according to their localization. Whereas the heart is dependent on pulsatile forces, owing to the diastolic perfusion of coronary arteries, the brain and the kidney are rather influenced by steady mechanical forces. For the kidney, the transmission of pulsatile pressure may greatly contribute to glomerular sclerosis in the elderly.

Tissue factor pathway inhibitor: a new link among arterial stiffness, pulse pressure, and coagulation in postmenopausal women.

OBJECTIVE: To investigate in women older than 60 whether aortic stiffness or pulse pressure (PP) is associated with selected procoagulant or anticoagulant factors and to examine whether pulsatile stretch influences these factors in human vascular smooth muscle cells (VSMCs) in vitro. METHODS AND RESULTS: Aortic pulse wave velocity (PWV) and carotid PP were studied in 123 apparently healthy postmenopausal women. PWV, PP, von Willebrand factor, and free tissue factor pathway inhibitor (TFPI), but not mean arterial pressure, increased with age. Free TFPI and PWV were positively correlated, even after adjustment for age and PP and other confounding parameters. In vitro, 5% or 10% pulsatile stretch (at 1 Hz) enhanced TFPI synthesis and secretion by VSMCs in a time-independent manner (1 to 48 hours) without changes in protein level of smooth muscle myosin heavy chain. Application of 5% static stretch had no effect. CONCLUSIONS: In postmenopausal women, free TFPI increases as vascular wall function deteriorates and PP increases. These findings are supported by the increase in TFPI synthesized by VSMCs in response to cyclic stress in vitro. They suggest that VSMCs require pulsatility to interfere with the coagulation process and highlight the relevance of plasma free TFPI levels to cardiovascular diseases.

Prediction of cardiovascular events and all-cause mortality with central haemodynamics: a systematic review and meta-analysis.

AIMS: To calculate robust quantitative estimates on the predictive value of central pressures and derived central haemodynamic indices for cardiovascular (CV) outcomes and all-cause mortality by meta-analysis of longitudinal studies. METHODS AND RESULTS: We meta-analysed 11 longitudinal studies that had employed measures of central haemodynamics and had followed 5648 subjects for a mean follow-up of 45 months. The age- and risk-factor-adjusted pooled relative risk (RR) of total CV events was 1.088 (95% CI 1.040-1.139) for a 10 mmHg increase of central systolic pressure, 1.137 (95% CI 1.063-1.215) for a 10 mmHg increase of central pulse pressure (PP), and 1.318 (95% CI 1.093-1.588) for a 10% absolute increase of central augmentation index (AIx). Furthermore, we found that a 10% increase of central AIx was associated with a RR of 1.384 (95% CI 1.192-1.606) for all-cause mortality. When compared with brachial PP, central PP was associated with marginally but not significantly higher RR of clinical events (P = 0.057). CONCLUSION: Central haemodynamic indexes are independent predictors of future CV events and all-cause mortality. Augmentation index predicts clinical events independently of peripheral pressures, while central PP has a marginally but not significantly (P = 0.057) better predictive ability when compared with peripheral PP.

Aortic wave reflection in women and men.

Augmentation index (AIx), a marker of the number of aortic wave reflections (AWRs), is influenced not only by the magnitude of incident and reflected pressure waves but also by the time of return. A new triangulation method has been developed, enabling us to better quantify AWRs and to determine their sex differences, which may relate to body size or pulse pressure (PP) amplification, measured from the brachial PP-to-carotid PP (B/C) ratio. With the use of pulse wave analysis, AWRs were evaluated in 51 women and 72 men treated for hypertension and studied in relationship to age, blood pressure, and pulse wave velocity. When women were compared with men, AIx (expressed in %PP and adjusted to heart rate) was significantly higher, together with a significant decrease of the B/C ratio and an increase of the reflection magnitude and of the amplitude (but not the timing) of the backward pressure wave. The significance of the amplitude difference between men and women was enhanced after an adjustment to heart rate or pulse wave velocity but was abolished after an adjustment to body height or the B/C ratio. In the overall population, AIx and the reflection magnitude index were positively (r(2) = 0.39) and independently associated, after excluding confounding factors such as drug treatment. In conclusion, when compared with men, women treated for hypertension have increased AIx, related to the increased amplitude, and not timing, of backward pressure waves. This finding relates to sex differences in body size and mostly brachial-carotid PP amplification, a parameter highly related to the sex difference of cardiovascular risk.

Cuff and aortic pressure differences during dobutamine infusion: a study of the effects of systolic blood pressure amplification.

BACKGROUND: Central aortic systolic blood pressures (SBPs) differ from and are preferable to cuff pressures when calculating cardiac work, left ventricular wall stress, and rate-pressure product. Despite the widespread use of dobutamine, differences between aortic and brachial SBP (pulse amplification) and pulse transmission during dobutamine infusion have not been previously studied. This study assessed these differences and used applanated radial pulses with the Sphygmocor (AtCor Medical, Sydney, Australia) device to investigate the effects of dobutamine on arterial pulse transmission and pulse amplification. METHODS: Using a cuff oscillometer, brachial arterial pressures were measured simultaneously with directly recorded aortic pressures at rest and during increasing dobutamine infusion rates in 25 patients. In 15 of those patients, applanated radial pulses were fed into the Sphygmocor device and calibrated in 2 ways to predict aortic pressures. RESULTS: At peak dobutamine infusion, SBP amplification averaged 14.9 mm Hg, with a maximum difference of 43 mm Hg. When radial artery pulses were calibrated using cuff pressures, the Sphygmocor underestimated the aortic SBP at all dobutamine doses. However, when radial artery pulses were calibrated using the more accurate aortic mean and diastolic BPs, the Sphygmocor accurately predicted the aortic SBP at baseline, but not at the higher dobutamine doses. CONCLUSIONS: Similar to exercise, dobutamine induced cuff SBPs and pulse pressures higher than those measured in the aorta-uncorrected by the cuff-calibrated Sphygmocor. This increasing pulse amplification was explained by the effects of dobutamine on the properties of the conduit arterial walls, on changes in pulse wave velocity, on increasing heart rate, and on reflected waves.

Prevalence and prognosis of left ventricular diastolic dysfunction in the elderly: The PROTEGER Study.

BACKGROUND: Left ventricular diastolic dysfunction (LVDD) was reported as a significant predictor of mortality, mainly in patients with heart failure. However, prospective data are scarce in the hospitalized elderly population. METHODS: We studied the association of severe LVDD, defined by conventional echocardiographic parameters, with cardiovascular and all-cause mortality in a population of 331 hospitalized elderly patients with a history of cardiovascular disease (mean age +/- SD, 87 +/- 7 years). After a mean follow-up of 378 days, 110 deaths occurred. RESULTS: Compared with left ventricular systolic dysfunction (LVSD), subjects with severe diastolic dysfunction had a similar prevalence (12% vs 10%) and similar cardiovascular and all-cause mortality (18% vs 19%, 49% vs 50%). Both cardiovascular and all-cause mortality increased progressively and significantly with increasing number of diagnostic criteria of LVDD (P = .035, P = .013) and reached 48.7% for all-cause mortality when at least 2 criteria were met. In addition to cardiovascular risk factors and LVSD, severe LVDD provided incremental and independent prognostic information of all-cause mortality with increased chi(2) value of Cox regression model (48.1 vs 43.5, P = .022). CONCLUSIONS: Severe LVDD, diagnosed by conventional echocardiography, has similar prevalence and prognosis as LVSD and provides incremental prognostic value, which highlights the clinical significance of routine evaluation of LVDD in risk assessment strategies of the hospitalized elderly.

Can antihypertensive treatment reverse large-artery stiffening?

In some controlled therapeutic trials for hypertension, a selective reduction of systolic blood pressure has been obtained with long-term treatment. The greatest effects on cardiovascular outcomes stem from a decrease of central blood pressure through a significant reduction of arterial stiffness, wave reflections, or both. Until now, all protocols have used angiotensin II blockade, mainly through angiotensin-converting enzyme inhibition. Cardiovascular outcomes have been significantly improved when compared with controls, but most of them have been treated with beta blockers. Such "de-stiffening" therapies are important to consider and require additional trials.

The Cardiovascular Continuum extended: aging effects on the aorta and microvasculature.

The 'Cardiovascular Continuum' was described by Dzau and colleagues in 2006 to explain the development over many years of coronary disease with its complications, then end-stage heart failure. The Continuum identified different points along the way where the process could be interrupted by drug therapies or interventions, then described the trials that have been undertaken over the last three decades to establish their value. The approach summarized the major steps in cardiology through modern times, but it had an emphasis on coronary atherosclerosis in prosperous nations, and did not account fully for the problems of aging, which occur in all societies. Aging of the aorta and elastic arteries causes arterial stiffening and leads to development of cardiac failure and microvascular disease in highly perfused organs such as the brain and kidneys. The 'Vascular Aging Continuum' which we introduce, dovetails with the late phases of the Cardiovascular Continuum and provides a more comprehensive explanation, especially for vascular diseases in nations with little atherosclerosis. It will become more common in the Western World where attention to risk factors and widespread use of statins are responsible for a decrease in atherosclerotic disease, prolongation of life, and dominance of macrovascular and microvascular arterial disease, as well as of cardiac failure.

Arterial Stiffness in Hypertension and Function of Large Arteries.

BACKGROUND: Arterial stiffness-typically assessed from non-invasive measurement of pulse wave velocity along a straight portion of the vascular tree between the right common carotid and femoral arteries-is a reliable predictor of cardiovascular risk in patients with essential hypertension. METHODS: We reviewed how carotid-femoral pulse wave velocity increases with age and is significantly higher in hypertension (than in age- and gender-matched individuals without hypertension), particularly when hypertension is associated with diabetes mellitus. RESULTS: From the elastic aorta to the muscular peripheral arteries of young healthy individuals, there is a gradual but significant increase in stiffness, with a specific gradient. This moderates the transmission of pulsatile pressure towards the periphery, thus protecting the microcirculatory network. The heterogeneity of stiffness between the elastic and muscular arteries causes the gradient to disappear or be inversed with aging, particularly in long-standing hypertension. CONCLUSIONS: In hypertension therefore, pulsatile pressure transmission to the microcirculation is augmented, increasing the potential risk of damage to the brain, the heart, and the kidney. Furthermore, elevated pulse pressure exacerbates end-stage renal disease, particularly in older hypertensive individuals. With increasing age, the elastin content of vessel walls declines throughout the arterial network, and arterial stiffening increases further due to the presence of rigid wall material such as collagen, but also fibronectin, proteoglycans, and vascular calcification. Certain genes, mainly related to angiotensin and/or aldosterone, affect this aging process and contribute to the extent of arterial stiffness, which can independently affect both forward and reflected pressure waves.

Relationship between BMI and aortic stiffness: influence of anthropometric indices in hypertensive men and women.

BACKGROUND: Increased aortic stiffness could be one of the mechanisms by which obesity increases cardiovascular risk independently of traditional risk factors. Studies have suggested that anthropometric indices may be predictors of cardiovascular risk but few studies have investigated their relations with aortic stiffness in high cardiovascular risk population. We investigated the strength of correlation between different anthropometric indices with aortic stiffness in hypertensive and diabetic patients. METHODS: A cross-sectional study was performed in 474 hypertensive patients. Anthropometric indices were calculated: BMI, waist circumference, waist-hip ratio, and waist-height ratio (WHtR). Aortic stiffness was assessed by measurement of carotid-femoral pulse wave velocity (PWV). Correlations between indices and PWV were investigated by linear regression analyses and hierarchical analyses after adjusting for cardiovascular risk factors. RESULTS: Regional anthropometric indices were more strongly correlated with PWV than BMI in both sexes. In linear regression analyses, WHtR presented the highest correlation with PWV than other indices in our study population. In adjusted hierarchical regression used, WHtR had the highest additive value on top of BMI while there no additive value of BMI on top of WHtR. These differences remained after adjustment on cardiovascular events. In men WHtR was more closely correlated with PWV than others. In women, waist-hip ratio and WHtR were equally correlated with PWV compared with BMI. CONCLUSION: Regional anthropometric indices are more closely correlated with PWV than BMI in hypertensive patients. WHtR presents the highest correlation with PWV beyond BMI. REGISTRATION: The study was registered in the French National Agency for Medicines and Health Products Safety (No. 2013-A00227-38) and was approved by the Advisory Committee for Protection of Persons in Biomedical Research.