Microvascular disease represents the hallmark feature of systemic

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1 Arterial Stiffness Central Hemodynamics and Arterial Stiffness in Systemic Sclerosis Elena Bartoloni, Giacomo Pucci, Francesca Cannarile, Francesca Battista, Alessia Alunno, Marco Giuliani, Giacomo Cafaro, Roberto Gerli, Giuseppe Schillaci Abstract Although microvascular disease is a hallmark of systemic sclerosis (SSc), a higher prevalence of macrovascular disease and a poorer related prognosis have been reported in SSc than in the general population. The simultaneous assessment of prognostically relevant functional properties of larger and smaller arteries, and their effects on central hemodynamics, has never been performed in SSc using the state-of-the-art techniques. Thirty-four women with SSc (aged 61±15 years, disease duration 17±12 years, and blood pressure 123/70±18/11 mm Hg) and 34 healthy women individually matched by age and mean arterial pressure underwent the determination of carotid-femoral (aortic) and carotid-radial (upper limb) pulse wave velocity (a direct measure of arterial stiffness), aortic augmentation (a measure of the contribution of reflected wave to central pulse pressure), and aortobrachial pulse pressure amplification (brachial/aortic pulse pressure) through applanation tonometry (SphygmoCor). Patients and controls did not differ by carotid-femoral or carotid-radial pulse wave velocity. Aortic augmentation index corrected for a heart rate of 75 bpm (AIx@75) was higher in women with SSc (30.9±16% versus 22.2±12%; P=0.012). Patients also had a lower aortobrachial amplification of pulse pressure (1.22±0.18 versus 1.33±0.25; P=0.041). SSc was an independent predictor of AIx@75 (direct) and pulse pressure amplification (inverse). Among patients, age, mean arterial pressure, and C-reactive protein independently predicted carotid-femoral pulse wave velocity. Age and mean arterial pressure were the only predictors of AIx@75. Women with SSc have increased aortic augmentation and decreased pulse pressure amplification (both measures of the contribution of reflected wave to central waveform) but no changes in aortic or upper limb arterial stiffness. Microvascular involvement occurs earlier than large artery stiffening in SSc. (Hypertension. 2016;68: DOI: /HYPERTENSIONAHA ) Key Words: atherosclerosis blood pressure C-reactive protein cardiovascular disease prognosis Microvascular disease represents the hallmark feature of systemic sclerosis (SSc) and contributes to the pathogenesis of the main disease-specific manifestations, including pulmonary arterial hypertension, scleroderma renal crisis, Raynaud phenomenon, and digital ulcerations. In fact, dysfunction of endothelial cell lining and structural damage of small- and medium-sized arteries occur early in the disease course and are associated with subsequent development of both endothelial dysfunction and fibrosis. 1 There is recent evidence, however, that impairment of the functional properties of larger and smaller arteries may lead to arterial stiffening 2,3 and possibly contribute to the increased rate of myocardial infarction and stroke reported in SSc. 4,5 Mechanisms of atherosclerotic vascular damage in SSc are poorly understood. SSc pathogenesis is mainly characterized by obliterative vascular disease triggered by endothelial injury and fibrosis. The impaired balance of inflammatory and autoimmune mechanisms, which, in association with traditional cardiovascular risk factors, characterizes the pathogenesis of accelerated atherosclerosis in other autoimmune diseases, does not seem to be fully applicable in SSc, 6,7 where inflammation is much less prominent. 8 In an attempt to further understand the factors underlying the increase in cardiovascular events in SSc, 4,5 it may be useful to consider surrogate measures of vascular disease. In recent years, many parameters, including pulse wave velocity (PWV), aortic augmentation index (AIx), central (ascending aortic) blood pressure (BP), and central-to-peripheral BP amplification, have all been recognized as reliable, potentially reversible markers of early vascular aging and independent predictors of cardiovascular outcomes across a wide range of patient populations In particular, carotid-femoral PWV represents a recognized noninvasive gold standard measure of aortic stiffness and is one of the most powerful tools to predict future cardiovascular disease. 9 Aortic AIx gauges the contribution of peripheral wave reflection to the rise in central pulse pressure and is considered a marker of both vascular elasticity and peripheral arterial resistance, closely related with vascular alterations in small arteries. 14 A high central (aortic) BP and a low central-to-peripheral BP amplification are both associated with unfavorable hemodynamic effects for the central arteries and the heart and predict an increased risk of future cardiovascular morbidity and mortality ,15 For a given brachial pulse Received August 18, 2016; first decision August 29, 2016; revision accepted September 15, From the Rheumatology Unit, Department of Medicine, University of Perugia, Italy (E.B., G.P., F.C., F.B., A.A., M.G., G.C., R.G., G.S.); and Unit of Internal Medicine, Department of Medicine, Terni University Hospital, Italy (G.P., F.B., M.G., G.S.). Correspondence to Roberto Gerli, Rheumatology Unit, Department of Medicine, University of Perugia, via Enrico dal Pozzo, I Perugia, Italy. roberto.gerli@unipg.it 2016 American Heart Association, Inc. Hypertension is available at DOI: /HYPERTENSIONAHA

2 Bartoloni et al Systemic Sclerosis and Arterial Stiffness 1505 pressure, an individual with lower pulse pressure amplification is subjected to higher left ventricular afterload. 16 PWV has been evaluated in patients with SSc in the previous studies, with rather conflicting results. 3,16 23 The inclusion of patient populations with different disease duration and subsets, the use of different techniques for assessing vascular involvement, and the small sample size of many of those studies may partly account for such discrepancy. Moreover, aortic AIx has been evaluated only in few case control studies. 18,22,24 We undertook this study because the simultaneous assessment of all major parameters of vascular function and central hemodynamics (PWV, aortic AIx, central BP, and central-tobrachial pulse pressure amplification) had not been performed in a single study using the state-of-the-art techniques. In this report, we analyze for the first time all the above arterial functional parameters in a cohort of patients with SSc compared with a group of healthy subjects. Methods Thirty-four consecutive female patients (aged 61±15 years) with an established SSc diagnosis according to the LeRoy and Medsger criteria 25 and/or 2013 American College of Rheumatology/European League against Rheumatism classification criteria 26 were enrolled. SSc was classified as limited cutaneous SSc (lcssc) or diffuse cutaneous SSc form according to the LeRoy and Medsger criteria. 25 A series of 34 sex- and age-matched subjects were used as normal controls. Exclusion criteria included diagnosis of cardiovascular disease (ischemic coronary disease, stroke, and peripheral artery disease), atrial fibrillation or other cardiac arrhythmias, significant valvular heart disease, systemic arterial hypertension grade II or III according to the European Society of Hypertension/European Society of Cardiology 2013 guidelines, 27 glomerular filtration rate of <30 ml min 1 per 1.73 m 2 (Chronic Kidney Disease Epidemiology Collaboration equation), cancer during the past 5 years, and end-stage interstitial lung disease. Smoking habits, body mass index, diabetes mellitus, defined as a fasting plasma glucose 126 mg/dl or patient self-report of diabetes mellitus or use of hypoglycemic drugs, dyslipidemia, self-reported systemic arterial hypertension or use of antihypertensive drugs, familiarity for cardiovascular diseases were assessed at enrollment. A complete physical examination and BP registration were performed in all study participants. Disease-specific manifestations, organ involvement, anticentromere or anti Scl-70 or other antibody status, and disease-specific and concomitant drug therapy were recorded. Erythrocyte sedimentation rate, C-reactive protein, total low-density lipoprotein, and high-density lipoprotein cholesterol, triglyceride and glucose concentrations were determined as a mean of the last 5 values. A modified Rodnan skin score was performed at enrollment. Disease activity and severity were assessed by the Valentini disease activity index 28 and the Medsger disease severity score, including skin, vascular, joint/tendon, muscle, gastrointestinal tract, lung, heart, and kidney components, 29 respectively. Finally, to provide additional data on microvascular damage, nailfold videocapillaroscopy (NVC) was performed in each patient using a videocapillaroscopy optical probe, equipped with a 200 contact lens, connected to an image analysis software (Videocap; DS Medica, Milan, Italy). The same operator (F.C.), blind to patient clinical data, performed NVC the same day of hemodynamic measurements. Each subject had been inside the building for a minimum of 15 minutes before the examination at room temperature of 20 to 22 C. The nailfolds of 8 fingers were examined in each patient, after a drop of immersion oil had been placed on the nailfold bed to improve the image resolution. Fingers affected by a recent local trauma were not analyzed. On the basis of NVC abnormalities, each patient was classified in the appropriate pattern (early, active, and late) according to the published methods. 30 PWV and Central Hemodynamics Measurements All hemodynamic measurements were performed by the same physician (F.B.) who was not involved in the clinical management of the patients and had no information about the clinical status of the study participants. Subjects were asked to refrain from caffeine, smoking, and alcohol for 12 hours before the examination. After measuring BP, aortic and upper limb PWVs were determined noninvasively with the commercially available SphygmoCor system (SphygmoCor Vx; AtCor Medical, Sydney, Australia), which uses a high-fidelity applanation tonometer to measure the pressure pulse waveforms sequentially in 2 peripheral artery sites. Aortic carotid-to-femoral PWV (cf-pwv) was calculated from the measurements of common carotid and femoral artery waveforms and upper limb carotid-to-radial PWV from the common carotid and radial artery waveforms, as described previously. 31 Transit time was calculated using R wave on the surface ECG as a common reference. The path length was calculated by subtracting the distance between the carotid artery measurement site and sternal notch from the distance between the femoral (or radial, respectively) artery site and the sternal notch, all measured directly with a caliper. The average of 10 different cardiac cycles on each of the sites was used for the analysis. PWV was automatically calculated from the measurements of pulse transit time and distance between the 2 sites according to the following formula: PWV (m/s)=distance (m)/transit time (s). In our laboratory, the intraobserver coefficient of variation of aortic PWV in 50 subjects was 5.1%. 32 Central aortic waveforms and pressures were derived from the radial artery waveform, calibrated to brachial systolic and diastolic BP, using the SphygmoCor Vx system and a validated transfer function. 33 Twenty sequential radial artery waveforms were used to generate an averaged peripheral and corresponding central waveform, which was then subjected to further analysis to determine the ascending aortic pressure and AIx, the latter defined as the difference between the second (P2) and first (P1) peaks of the central arterial waveform expressed as a percentage of the pulse pressure. Because AIx is influenced by heart rate, it was corrected for a steady heart rate of 75 bpm (AIx@75) based on the built-in algorithm of the SphygmoCor device. We also corrected aortic AIx for heart rate using the regression equation of augmented pressure on heart rate developed in our study population (n=68; r= 0.31, P<0.01): regression-based aortic AIx=augmentation+( [heart rate 0.219]), where augmentation is expressed in mm Hg and heart rate in bpm. Aortic-to-brachial pulse pressure amplification was expressed as brachial pulse pressure/aortic pulse pressure. The study protocol was approved by the local ethics committee, and informed consent form was obtained from all subjects. Statistical Analysis Comparisons between patients with SSc and control subjects, as well as comparisons between subsets of SSc (anticentromere+ versus anti Scl-70, lcssc versus diffuse cutaneous SSc), were made using the paired-sample t test and the Mann Whitney test of medians for normally and non-normally distributed variables, respectively. Ageadjusted comparisons were performed using generalized linear models. The independent predictors of cf-pwv, aortic AIx@75, and pulse pressure amplification were identified through stepwise multivariate linear regression. Variables were included in the model either because they were established or putative determinants or if they achieved a significance value of <0.30 in an initial regression analysis with an entry model. The final models were evaluated for other linear relationships among variables (multicollinearity), which have the potential of rendering significance testing unreliable. A variance inflation factor <5 was assumed to exclude significant collinearity among the covariates in the models, 34 and no collinearity was found. Results Baseline demographic and clinical characteristics of patients and controls are shown in Table 1. There were no significant differences in major cardiovascular risk factors between patients and controls except for body mass index that was significantly lower in patients with SSc. About the ongoing treatments, only patients with SSc (41%) were taking calcium channel blockers, mostly for the control of Raynaud phenomenon and digital ulcers, whereas the use of renin angiotensin

3 1506 Hypertension December 2016 Table 1. Clinical and Epidemiological Characteristics of Patients With SSc and Controls Characteristics SSc (n=34) Controls (n=34) P Value Age, y 61±15 59± Female, % Limited cutaneous SSc, n (%) 22 (65) Diffuse cutaneous SSc, n (%) 12 (35) ANA, n (%) 34 (100) ACA, n (%) 18 (53) Anti Scl-70, n (%) 9 (26) Disease duration since RP, y 17±12 Disease duration since first non-rp symptom, y 11±9 RP, n (%) 34 (100) Modified Rodnan skin score, median (range) 6 (0 30) Interstitial lung disease, n (%) 17 (50) Pulmonary arterial hypertension, n (%) 5 (15) History of digital ulcers, n (%) 24 (71) Actual digital ulcers, n (%) 10 (29) Gastrointestinal involvement, n (%) 19 (56) Joint/tendon involvement, n (%) 11 (32) Myositis, n (%) 1 (3) Erythrocyte sedimentation rate, mm/h (range) 22±14 (2 50) C-reactive protein, mg/dl (range) 0.6±0.7 ( ) Glycemia, mg/dl 83±7 90± Total cholesterol, mg/dl 191±31 206± LDL cholesterol, mg/dl 112±35 124± Estimated GFR, ml min 1 per 1.73 m 2 64±20 68± Body mass index, kg m 2 23±4 27± Systemic arterial hypertension, n (%) 6 (18%) 8 (23%) 0.75 Smokers, n (%) 2 (6%) 3 (9%) 0.85 Diabetes mellitus, n (%) 1 (3%) 1 (3%) 1.00 Family history of cardiovascular events, n (%) 5 (15%) 5 (15%) 1.00 Values are mean±sd. ACA indicates anticentromere antibodies; ANA, antinuclear antibodies; GFR, glomerular filtration rate; LDL, low-density lipoprotein; SSc, systemic sclerosis; and RP, Raynaud phenomenon. system blockers, diuretics, β-blockers, and statins was comparable in the 2 groups. Within the SSc group, there was a prevalence of patients with lcssc (65%) with respect to the subjects with diffuse cutaneous SSc. All patients had Raynaud phenomenon, but only one third had evidence of digital ulcers. About 50% of patients had interstitial lung disease and gastrointestinal involvement, but none had cardiac or renal involvement. Eleven (33%) patients were treated with immunosuppressants (methotrexate, azathioprine, cyclophosphamide, mycophenolate mofetil, and rituximab), 11 (33%) with iloprost, and 6 (18%) with pulmonary arterial hypertension-specific therapy (endothelin antagonists and phosphodiesterase 5 inhibitors). None of the patients with SSc was receiving corticosteroid therapy at enrollment. Valentini disease activity index was 1.37±1.32 (mean±sd; range 0 4.5), and 15% of patients had an active disease (score>3). Medsger disease severity score resulted in 0.35±0.65 (range 0 2), and 9% of patients presented a moderate-to-severe disease mainly determined by lung and vascular involvement. The NVC pattern was late in the majority of patients (56%), active in 38%, and early in 6%. Hemodynamic and vascular parameters are reported in Table 2. Brachial and aortic BPs did not differ, although aortic systolic BP was nonsignificantly higher in patients with SSc. Aortic augmentation was higher in patients than in controls (P=0.014). AIx@75, obtained from either the built-in algorithm of the SphygmoCor device or the linear regression developed in our population (P=0.012 and P=0.038, respectively), was also greater in patients (Table 2; Figure 1A). Notably, central-to-brachial pulse pressure amplification was significantly lower in patients with SSc (P=0.041; Figure 1B). Adjustment for age did not attenuate the above differences (all

4 Bartoloni et al Systemic Sclerosis and Arterial Stiffness 1507 Table 2. Hemodynamic Parameters, PWV, and Aortic in Patients With SSc and in Healthy Controls Parameters SSc (n=34) Controls (n=34) P Value Brachial BP, mm Hg 127/72±17/20 127/72±20/ /0.85 Aortic BP, mm Hg 119/73±20/12 116/74±17/ /0.70 Brachial pulse pressure, mm Hg 55±11 54± Aortic pulse pressure, mm Hg 46±12 42± Pulse pressure amplification 1.22± ± Heart rate, bpm 70±11 67± Carotid-femoral PWV, m/s 9.2±3 9.1± Carotid-radial PWV, m/s 8.3±1 8.3± Aortic augmentation, mm Hg 16.1±8 11.5± Aortic AIx, % 33.5± ± Aortic AIx@75 (built-in algorithm), % 30.9± ± Aortic AIx@75 (regression-based), % 29.8±9 25.3± Values are mean±sd. AIx indicates augmentation index; AIx@75, augmentation index corrected for a heart rate of 75 bpm; BP, blood pressure; PWV, pulse wave velocity; and SSc, systemic sclerosis. P<0.05). No significant differences were found in cf-pwv and carotid-to-radial PWV between patients and healthy controls. Because body mass index had a significant direct correlation with cf-pwv (r=0.25; P=0.041) but not with carotid-toradial PWV (r=0.11; P=0.38), cf-pwv was further compared in patients and controls after the adjustment for body mass index, and no significant differences were found (9.4±3 versus 8.9±2 m/s; P=0.25). Subsequently, data from the entire SSc cohort were analyzed to investigate possible associations between measures of arterial function and disease-specific clinical features and/or autoantibody status. Stepwise multivariate linear regression analysis revealed that age, mean brachial BP as a measure of distending pressure, and mean levels of C-reactive protein resulted in independent predictors of cf- PWV, although AIx@75 was predicted by age and mean brachial BP (P<0.01 for all). Interestingly, within the whole study sample, SSc was an independent predictor of a higher AIx@75 (P<0.01) and of a lower pulse pressure amplification (P<0.05) after the correction for all variables included in the analysis. No significant correlation was found between arterial function parameters and other variables, including indexes of inflammation, disease activity and severity, modified Rodnan skin score, history or presence of digital ulcers, type of organ involvement, NVC pattern, cardiovascular risk factors, and treatments specific for SSc (data not shown). However, when parameters of arterial function were analyzed according to the disease subsets, patients with lcssc Figure 1. Aortic augmentation index corrected for a heart rate of 75 bpm (AIx@75; A) and aortic-brachial pulse pressure (PP) amplification (B) in patients with systemic sclerosis (SSc) (dashed bars) and in healthy controls (open bars).

5 1508 Hypertension December 2016 Figure 2. Aortic augmentation index corrected for a heart rate of 75 bpm (AIx@75; A) in patients with limited cutaneous (lc, dashed bar) and diffuse cutaneous (dc, open bar) systemic sclerosis (SSc) and (B) AIx@75 in patients with anticentromere (ACA) antibodies (dashed bar) and with anti Scl-70 antibodies (open bar). had higher values of aortic AIx@75 (36±8% versus 24±14%; P=0.022) and lower values of pulse pressure amplification (1.17±0.06 versus 1.34±0.16; P<0.001) than patients with diffuse cutaneous SSc (Figure 2A). Also, patients with circulating anticentromere showed a higher aortic AIx@75 (35±7% versus 20±14%; P=0.018) and a lower pulse pressure amplification (1.17±0.06 versus 1.39±0.15; P=0.003) than those with anti Scl-70 antibodies (Figure 2B). Discussion SSc is a multisystem disease, which is often fatal. Although lung involvement (both pulmonary hypertension and interstitial lung disease) is considered the primary cause of scleroderma-related deaths, 35 an increased risk of cardiovascular Table 3. Case Control Studies Evaluating PWV, AIx, and PP Amplification Author, y n Mean Age, y Controls, n Disease Duration, y Cardiovascular Disease Timár No Yes 9.7 vs 8.0* disease has been recently documented in SSc, as already shown in other systemic autoimmune diseases. 7,36 In 2 large matched incident cohort studies, SSc conveyed a 2- to 4-fold risk of myocardial infarction and ischemic stroke in comparison to the general population, 4,5 and cardiovascular disease may account for 30% of death in these patients. 37 Patients with SSc with atherosclerotic cardiovascular disease have a higher risk of death during hospitalization in comparison to scleroderma patients without evidence of cardiovascular disease and to patients with other systemic inflammatory diseases. 38 The role of microvascular and macrovascular involvement in the pathogenesis of cardiovascular disease in SSc still remains a challenge. 39 The complex interplay of vascular Cardiovascular Risk Factors cf-pwv, m/s cr-pwv, m/s Aortic AIx, % Cypienè No No 9.0 vs 8.3* 29 vs 19* Roustit No No 8.6 vs 8.7 Liu No No 5.6 vs vs 6.9* Peled NR No No 24 vs 11 Colaci No Yes 9.4 vs 7.3* Domsic No Yes 6.6 vs 6.4 No difference Ngian No Yes 6.9 vs vs 24* Irzyk No Yes 9.0 vs 8.3 PP Amplification, % Our study No Yes 9.2 vs vs vs 22* 1.22 vs 1.33* Comparisons represent SSc vs controls. AIx indicates augmentation index; cf-pwv, carotid-femoral pulse wave velocity; cr-pwv, carotid-radial pulse wave velocity; NR, not reported; and PP, pulse pressure. *Statistically significant differences.

6 Bartoloni et al Systemic Sclerosis and Arterial Stiffness 1509 damage, fibrosis, and autoimmunity makes SSc an intriguing model to investigate the pathophysiology of atherosclerotic damage in autoimmune systemic diseases. Interestingly, endothelial dysfunction and microvascular endothelial cell injury may be considered as not only markers of atherosclerosis but also expression of pathogenic mechanisms in SSc. 40 The investigation of surrogate measures of vascular disease and early vascular aging may help to understand the factors underlying the increased rate of cardiovascular events reported in SSc. 4,5 Although a few previous studies have investigated the issue, an overview of those studies (Table 3) shows several drawbacks, including small sample size, 3,18,21,24 the lack of data on augmentation 3,19,20,23 or its assessment at the radial but not aortic level, 17 and the lack of data on PWV at the aortic 18 or upper limb level. 22 More importantly, no study has assessed the central hemodynamic effects of vascular changes in terms of central BP and aortobrachial pulse pressure amplification, and the evaluation of all major parameters of vascular function and central hemodynamics has never been performed in a single study. cf-pwv, a direct measure of large elastic artery (aortic) stiffness, has been examined in SSc and controls, with most 3,19,21 23 but not all studies showing no difference. Between-study inconsistencies may be because of different age, disease duration, distribution of disease subsets with underlying specific pathophysiological features, small sample size, and the use of different tools to assess vascular function. However, carotid-to-radial PWV, a measure of the stiffness of a more muscular arterial path, which has no independent predictive value for cardiovascular disease, 41 has been found to be increased in SSc in 2 studies, 3,18 both with a small sample size, one more subjected to selection bias. Our study supports the concept that large artery stiffness is not increased in SSc and shows that both age and BP are major determinants of PWV in these patients, as already known in the general population. 42 Some previous papers had shown an increased aortic 18,22 or radial 17 AIx in patients with SSc, whereas 2 studies reporting no increase in AIx had a small sample size. 21,24 Our study confirms that aortic augmentation, an independent predictor of cardiovascular morbidity, which gauges the contribution of the reflected wave to central pulse pressure, 10,11 is increased in SSc. Aortic augmentation results from the interaction between the incident wave and the timing and intensity of the reflected wave at its arrival at the ascending aorta, which in turn depends on the geometry and vasomotor tone of smaller arteries. As such, our findings of increased aortic AIx and unaffected aortic and upper limb PWV support the view that small arteries are involved earlier than large ones in the natural history of SSc. One additional clinically relevant parameter of central hemodynamics is pulse pressure amplification, a physiological phenomenon arising from periodic oscillations of pressure waves, which travel and are reflected when arteries with different impedance generate an acoustic mismatch. 12 Aortic-tobrachial pulse pressure amplification decreases progressively with advancing age, and its decrease is generally considered a marker of vascular aging. 43 A low amplification of pulse pressure from the ascending aorta to the brachial artery is an expression of (1) large artery stiffness, (2) peripheral arterial resistance, (3) timing and magnitude of the reflected waves, and (4) duration of the ventricular ejection phase, which is inversely related with heart rate. 12 All the above factors affect the synchronization of incident and reflected waves, pulse pressure amplification, cardiac afterload, and cardiovascular outcomes. In systemic hypertension, reduction of left ventricular mass after 1 year of drug treatment is independently associated with the increase of pulse pressure amplification but not with the reduction in brachial pulse pressure. 16 Notably, a low pulse pressure amplification is a stronger predictor of all-cause and cardiovascular mortality than either brachial or carotid pulse pressure in subjects with end-stage renal disease and an independent harbinger of mortality in the general population. 15,44,45 Our study provides the first clinical evidence that pulse pressure amplification is significantly lower in patients with SSc than in control subjects, thus providing a further conceptual framework for explaining the increased rate of cardiovascular events observed in SSc. 4,5 Taken together, these data suggest that peripheral vascular involvement may represent a distinct, specific feature of the disease, whereas the involvement of large arteries may reflect the effect of age and disease duration on the elastic properties of macrovascular bed. Other disease-specific mechanisms may contribute to early atherosclerotic damage in these patients. In our study, C-reactive protein was a significant independent predictor of aortic PWV. Inflammation may induce both irreversible and reversible changes in the arterial wall, the former through elastin breakdown and smooth muscle cell proliferation 46 and the latter through inflammatory infiltration of the arterial wall. 47,48 Yet, inflammation seems to exert a less prominent role in SSc than in other autoimmune diseases, 8 and further studies are needed to evaluate the role of inflammatory markers in atherosclerosis progression in SSc. Finally, a noteworthy finding of our study is that high values of AIx and a low pulse pressure amplification are more prominent in patients with limited cutaneous disease and in those with circulating anticentromere. These findings are in line with the data of a recent study, showing that SSc patients with active digital ulcers have a higher aortic AIx than patients without this complication, suggesting that increased peripheral vascular tone may result in higher risk of subclinical atherosclerotic damage and digital ulcer occurrence. 49 Of note, SSc patients with circulating anticentromere have a higher prevalence of ischemic peripheral arterial disease and premature atherosclerosis than other patients with SSc, thereby confirming the microvascular vulnerability of this SSc patient subpopulation. 50 This study has limitations. The cross-sectional design does not allow to demonstrate causality. Moreover, arterial stiffness has not yet been demonstrated to predict cardiovascular events or mortality in SSc, and prospective studies with larger sample sizes and longer follow-up are needed to clarify this issue. Chronic use of corticosteroids may exert negative effect on arterial stiffness. 51 However, no SSc subject recruited in our study was on steroid therapy at enrollment, and no patient showed corticosteroid-related side effects because only occasional, low-dose and short-term therapy is usually used in these patients to avoid the risk of scleroderma renal crisis. Finally, although the overall proportion of patients and

7 1510 Hypertension December 2016 controls under antihypertensive treatment did not differ (18% versus 23%; P=0.75; Table 1), only patients with SSc were taking calcium channel blockers, mostly nifedipine. To the best of our knowledge, there is no evidence that calcium channel blockers reduce intrinsic aortic stiffness beyond the effect expected on the basis of BP reduction, 52 and their potential effects on carotid-femoral PWV are similar or inferior to those of renin angiotensin system blockers. With the aim of further exploring this relationship, the use of calcium channel blockers was added to the independent variables in the multivariate linear regression analysis of cf-pwv and was not found to be significant. Perspectives Patients with SSc are characterized by an adverse central hemodynamic profile characterized by an increased aortic AIx and a reduced aortic-to-brachial pulse pressure amplification as expression of increased magnitude and/or earlier arrival of reflected waves from the peripheral sites, which cannot be predicted by the measurement of traditional risk factors only. Conversely, large artery stiffness was not affected significantly. The above findings, which seem to be more prominent in patients with lcssc and circulating anticentromere, suggest that the involvement of small arteries may precede that of large arteries in SSc. Our data provide important clues to improve knowledge on the mechanisms involved in early vascular aging, the impact of early vascular damage on long-term prognosis, and the potential effects of targeted therapies in this complex, multisystemic disorder. Sources of Funding The position of G. Pucci as an Adjunct Assistant Professor at the University of Perugia was funded by a grant from the Fondazione Cassa di Risparmio di Terni e Narni. None. Disclosures References 1. Nicolosi PA, Tombetti E, Maugeri N, Rovere-Querini P, Brunelli S, Manfredi AA. Vascular remodelling and mesenchymal transition in systemic sclerosis. Stem Cells Int. 2016;2016: doi: /2016/ Denton CP. Systemic sclerosis: from pathogenesis to targeted therapy. Clin Exp Rheumatol. 2015;33(4 suppl 92):S3 S7. 3. Liu J, Zhang Y, Cao TS, Duan YY, Yuan LJ, Yang YL, Li Y, Yao L. Preferential macrovasculopathy in systemic sclerosis detected by regional pulse wave velocity from wave intensity analysis: comparisons of local and regional arterial stiffness parameters in cases and controls. Arthritis Care Res (Hoboken). 2011;63: doi: / acr Aviña-Zubieta JA, Man A, Yurkovich M, Huang K, Sayre EC, Choi HK. Early Cardiovascular disease after the diagnosis of systemic sclerosis. 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Women with systemic sclerosis, in particular with localized form, have higher rate-adjusted aortic augmentation index corrected for a heart rate of 75 bpm and a lower aortobrachial amplification of pulse pressure in comparison to sex- and age-matched healthy women. Systemic sclerosis is an independent predictor of a higher augmentation index corrected for a heart rate of 75 bpm and of a lower pulse pressure amplification. Novelty and Significance 41. Mitchell GF, Hwang SJ, Vasan RS, Larson MG, Pencina MJ, Hamburg NM, Vita JA, Levy D, Benjamin EJ. Arterial stiffness and cardiovascular events: the Framingham Heart Study. Circulation. 2010;121: doi: /CIRCULATIONAHA Cecelja M, Chowienczyk P. Dissociation of aortic pulse wave velocity with risk factors for cardiovascular disease other than hypertension: a systematic review. Hypertension. 2009;54: doi: / HYPERTENSIONAHA McEniery CM, Yasmin, McDonnell B, Munnery M, Wallace SM, Rowe CV, Cockcroft JR, Wilkinson IB; Anglo-Cardiff Collaborative Trial Investigators. Central pressure: variability and impact of cardiovascular risk factors: the Anglo-Cardiff Collaborative Trial II. Hypertension. 2008;51: doi: /HYPERTENSIONAHA Othmane Tel H, Nemcsik J, Fekete BC, Deák G, Egresits J, Fodor E, Logan AG, Németh ZK, Járai Z, Szabó T, Szathmári M, Kiss I, Tislér A. Arterial stiffness in hemodialysis: which parameter to measure to predict cardiovascular mortality? Kidney Blood Press Res. 2009;32: doi: / Bursztyn M, Norton GR, Ben-Dov IZ, Booysen HL, Sibiya MJ, Sareli P, Woodiwiss AJ. Aortic pulse pressure amplification imputed from simple clinical measures adds to the ability of brachial pressure to predict survival. Am J Hypertens. 2016;29: doi: /ajh/hpv Jain S, Khera R, Corrales-Medina VF, Townsend RR, Chirinos JA. Inflammation and arterial stiffness in humans. Atherosclerosis. 2014;237: doi: /j.atherosclerosis Schillaci G, Bartoloni E, Pucci G, Pirro M, Settimi L, Alunno A, Gerli R, Mannarino E. Aortic stiffness is increased in polymyalgia rheumatica and improves after steroid treatment. Ann Rheum Dis. 2012;71: doi: /annrheumdis Mäki-Petäjä KM, Elkhawad M, Cheriyan J, Joshi FR, Ostör AJ, Hall FC, Rudd JH, Wilkinson IB. Anti-tumor necrosis factor-α therapy reduces aortic inflammation and stiffness in patients with rheumatoid arthritis. Circulation. 2012;126: doi: / CIRCULATIONAHA Aïssou L, Meune C, Avouac J, Meunier M, Elhaï M, Sorbets E, Kahan A, Allanore Y. Small, medium but not large arteries are involved in digital ulcers associated with systemic sclerosis. Joint Bone Spine. 2016;83: doi: /j.jbspin Nordin A, Jensen-Urstad K, Björnådal L, Pettersson S, Larsson A, Svenungsson E. Ischemic arterial events and atherosclerosis in patients with systemic sclerosis: a population-based case-control study. Arthritis Res Ther. 2013;15:R87. doi: /ar Sacre K, Escoubet B, Pasquet B, Chauveheid MP, Zennaro MC, Tubach F, Papo T. Increased arterial stiffness in systemic lupus erythematosus (SLE) patients at low risk for cardiovascular disease: a cross-sectional controlled study. PLoS One. 2014;9:e doi: /journal.pone Boutouyrie P, Lacolley P, Briet M, Regnault V, Stanton A, Laurent S, Mahmud A. Pharmacological modulation of arterial stiffness. Drugs. 2011;71: doi: / Summary Evaluation of subclinical atherosclerosis by indirect measures of vascular aging and peripheral arterial resistance may be suggested in patients with systemic sclerosis, in particular in patients with limited cutaneous subset. What Is Relevant? Atherosclerotic involvement of small arteries precedes stiffening of larger arteries in patients with systemic sclerosis.