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Cardiovascular maladaptation to exercise in young hypertensive patients
Cardiovascular maladaptation to exercise in young hypertensive patients Maurizio Cusm`a Piccione, Concetta Zito, Bijoy Khandheria, Antonio Madaffari, Alessandra Oteri, Gabriella Falanga, DomenicaDonato, Myriam D’Angelo, Maria Ludovica Carerj, Gianluca Di Bella, Egidio Imbalzano, Pietro Pugliatti, Scipione Carerj PII: DOI: Reference:
S0167-5273(17)30023-2 doi:10.1016/j.ijcard.2017.01.004 IJCA 24369
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
28 June 2016 27 December 2016 3 January 2017
Please cite this article as: Piccione Maurizio Cusm`a, Zito Concetta, Khandheria Bijoy, Madaffari Antonio, Oteri Alessandra, Falanga Gabriella, DomenicaDonato, D’Angelo Myriam, Carerj Maria Ludovica, Di Bella Gianluca, Imbalzano Egidio, Pugliatti Pietro, Carerj Scipione, Cardiovascular maladaptation to exercise in young hypertensive patients, International Journal of Cardiology (2017), doi:10.1016/j.ijcard.2017.01.004
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ACCEPTED MANUSCRIPT Original Research
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Cardiovascular maladaptation to exercise in young hypertensive patients
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Maurizio Cusmà Piccionea, Concetta Zitoa, Bijoy Khandheriab*, Antonio Madaffaria, Alessandra Oteria, Gabriella Falangaa, DomenicaDonatoa, Myriam D‟Angeloa, Maria Ludovica Carerja, Gianluca Di Bellaa, Egidio Imbalzanoa, Pietro Pugliattia, Scipione Carerja a
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Department of Clinical-Experimental Medicine and Pharmacology, Cardiology Division, University of Messina, Via Consolare Valeria, Messina, ME 98122, Italy b
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Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke‟s Medical Centers, 2801 W. Kinnickinnic River Parkway, Ste. 840, Milwaukee, Wisconsin 53215,USA
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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Short Title: Maladaptation to exercise in systemic hypertension Conflicts of Interest: None. Funding: None. Word Count: 6,377 (including references, legends and tables) Keywords: Strain, Exercise echocardiography, Echo-tracking, Longitudinal function, Stiffness
*Corresponding author: Bijoy K. Khandheria, MD Aurora St. Luke‟s Medical Center 2801 W. Kinnickinnic River Parkway, Ste. 840 Milwaukee, WI 53215 Phone: +1 414 649 3909 Fax: +1 414 649 3578 Email: [email protected] 1
ACCEPTED MANUSCRIPT ABSTRACT
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Background: Impairment of the adaptive mechanisms that increase cardiac output during exercise can translate to a reduced functional capacity. We investigated cardiovascular
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adaptation to exertion in asymptomatic hypertensive patients, aiming to identify the early
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signs of cardiac and vascular dysfunction.
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Methods and Results: We enrolled 54 subjects: 30 patients (45.1±11.9 years, 19 males) and 24 age-matched healthy controls (44.4±9.6 years, 14 males). Speckle-tracking
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echocardiography (STE) and echo-tracking were performed at rest and during exertion to assess myocardial deformation and arterial stiffness.
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Results: E/E‟ increased from rest to peak exercise more in patients than in controls (peak
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stage: p = 0.024). Global longitudinal strain increased significantly from rest to peak stage in
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controls (p=0.011) whereas it remained unchanged in patients (p = 0.777). Left atrial (LA) reservoir was significantly increased throughout the exercise only in controls (p = 0.001) whereas it was almost unchanged in patients (p = 0.293). LA stiffness was significantly higher in patients than in controls both at rest (p=0.023) and during exercise (p < 0.001). Beta index and pulse wave velocity (PWV) increased during exercise in both groups, showing higher values in patients in each step. Conclusions: Our study showed a more pronounced maladaptation during exercise, with respect to rest, of the cardiovascular system with impaired cardiac-vessel coupling in hypertensive patients compared to healthy subjects. Exercise echocardiography implemented by STE and echo-tracking is invaluable in the early detection of these cardiovascular abnormalities. 2
ACCEPTED MANUSCRIPT 1. Introduction The ability of the left ventricle to adequately fill and empty in less time during
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exertion, without increased filling pressures, represents a key mechanism of the
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cardiovascular system in responding to greater peripheral metabolic demand [1]. This
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adaptive mechanism, relying on the increase of venous return, myocardial contractility, and heart rate, has been found to be impaired in various heart diseases and arterial
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hypertension even in the absence of clinically apparent structural changes, translating into
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reduced exercise tolerance [2-4]. In this regard, the assessment of cardiovascular adaptation to exercise in hypertensive patients may be useful in identifying early
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abnormalities preceding the occurrence of overt heart failure. More sensitive diagnostic
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tools that allow accurate analysis of myocardial function may be required because
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conventional echocardiography, as widely reported [5], can detect abnormalities of cardiac function only in advanced stages of hypertensive disease. In this respect, speckletracking echocardiography(STE), which is proving to be sensitive in the early detection of systolic and diastolic dysfunction in various diseases, as well the study of left atrial (LA) reserve, may be particularly valuable [6-9]. Recently, Hensel et al. showed, by means of STE, lower values of LV deformation (circumferential and longitudinal strain, longitudinal strain rate) at rest and, particularly, during exercise in hypertensive patients with normal left ventricular function,[10].Similarly, the measurement of arterial wall distensibility, in addition to the evaluation of carotid intima-media thickness, is increasingly being performed to detect early vascular abnormalities in arterial hypertension and several other conditions [11,12]. Therefore, the analysis of arterial 3
ACCEPTED MANUSCRIPT stiffness, at rest and during exercise, which can be accomplished using the echo-tracking technique, may be of particular interest for a comprehensive evaluation of cardiovascular
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system efficiency. The main aim of our study is to investigate, after evaluating LV and
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LA myocardial deformation parameters and vascular functional parameters, the cardiac
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and vascular adaptation to exertion in patients affected by systemic hypertension.
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2. Methods
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We prospectively enrolled 54 young subjects, including 30 patients with isolated essential hypertension (45.1±11.9 years, 19 males) and 24 age-matched, healthy controls
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(44.4±9.6 years, 14 males). Clinical examination and cardiovascular ultrasonographic
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study were performed in each subject. All patients were on a single anti-hypertensive
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drug, such as an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, Ca2+-blocker, or beta-blocker. Overall, blood pressure values were well controlled by medical therapy, as confirmed by the 24-hour blood pressure monitoring that was an essential criterion of eligibility for all patients. Inclusion criteria were the absence of symptoms, the ability to perform adequate exercise, and an LV ejection fraction ≥55%. Exclusion criteria were the presence of other cardiovascular risk factors (e.g., diabetes mellitus, dyslipidemia, cigarette smoking and obesity), comorbidities (i.e., systemic disorders, renal insufficiency, etc.), a systolic blood pressure at rest >200 mmHg, the presence of LV wall motion abnormalities, or more-than-mild heart valve disease. Each subject underwent exercise testing by using an upright cycloergometer according to an incremental step protocol with an increase of 25 watts every 3minutes. 4
ACCEPTED MANUSCRIPT The exercise test was interrupted after reaching a predetermined workload of 100 watts or because of exhaustion. This specific maximal workload was chosen because our aim was
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to evaluate cardiovascular adaptation to exercise, not to perform a test for inducible
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myocardial ischemia; furthermore, the accuracy of 2-dimensional (2D) strain and arterial
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stiffness analyses could have been limited by a higher heart rate at a greater workload. Ultrasonographic study was performed using a GE Vivid 7 echocardiography machine
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(Horten, Norway). Images and videoclips of the parasternal long- and short-axis views at
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basal, mid and apical levels, and of the apical four-, two-, and three-chamber views were acquired at rest, peak (100 watts), and recovery steps. A frame rate >70 frames per
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second was employed, as widely established. LV end-diastolic and end-systolic volumes,
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Simpson‟s biplane ejection fraction, and myocardial mass according to Devereux‟s
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formula from M-mode images of the mid-ventricular short-axis view were calculated [13]. Mitral inflow measurements were obtained from the four-chamber apical view by placing the sample volume at the mitral leaflet tips, and peak velocities of E and A waves, E/A ratio, and E-wave deceleration time were measured. E/E‟ was calculated as the ratio between the peak velocities of E and E‟ waves, the latter having been obtained from tissue Doppler imaging at the septal corner of the mitral annulus. LV stroke volume was calculated, using continuity equation, by measuring LV outflow tract diameter, from parasternal long axis view, and velocity time integral after placing the sample volume, at the same level, from 5-chamber apical view. For each subject, strain analysis was performed offline using a dedicated software package (Echopac V. 8.0.0 GE, Horten, Norway). The endocardial border was traced 5
ACCEPTED MANUSCRIPT manually from apical views, automatically obtaining the calculation of a region of interest comprising the area between endocardial and epicardial layers. Tracking quality
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was verified for each segment, and low-quality images were excluded from strain
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analysis (about 4% of myocardial segments at rest, 15% at peak exercise, 5% at
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recovery). Global values of longitudinal strain derived from each apical view were calculated through automated function imaging analysis. In addition, LV twist was
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measured as the net difference between basal and apical rotations; LV untwist was
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derived from the early-diastolic peak of the untwisting rate of the ventricle. Finally, LA reservoir and booster were measured by using the same software for the study of LV
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strain, respectively evaluating the maximal positive and negative deformations of LA
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walls at end-systole and pre-systole (at the beginning of T wave and at the end of P wave
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on electrocardiogram)[14]. LA stiffness was calculated, as previously established, as the ratio between E/E‟ and LA reservoir peak values [15]. Two independent observers who were unaware of the clinical conditions of the patients evaluated the recordings and calculated the echocardiographic parameters. Each subject was studied by use of a color Doppler echocardiography machine (Prosound α 10, Aloka, Tokyo, Japan) equipped with a 7.5 MHz linear array probe and a high-resolution echo-tracking system using radio-frequency signals and allowing accurate measurement of changes in the diameter of the carotid artery. Stiffness parameters (stiffness index [β], pulse wave velocity [PWV]) were obtained from the right and left common carotid arteries at about 1 cm proximal to the bulb region. Intima-media thickness was measured at the same site, in the far wall, as the distance 6
ACCEPTED MANUSCRIPT between the first and second echogenic lines from the lumen [16]. Time-related pressure waveforms were obtained from systolic and diastolic changes of arterial
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diameter after calibration for blood pressure measured with a cuff-type manometer
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applied to the right upper arm. β was automatically calculated as a mean of 5 beats,
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according to the established formula β= ln (Ps/Pd)/(Ds − Dd/Dd), where Ps and Pd represent, respectively, systolic and diastolic blood pressure values andDs and Dd the
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common carotid artery maximal and minimal diameters, respectively [17]. PWV,
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derived from β, was obtained from the on-line „„one-point‟‟ measurement, calculated from the following equation: PWV = (βP/2)1/2 where P is diastolic pressure and is
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blood density (1050 Kg m3)[18]. For each parameter, an average of the values of the
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right and left sides was used. Systemic vascular resistance (SVR) was calculated from
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the formula SVR = (80*mean systolic blood pressure)/cardiac output, neglecting to consider right atrial pressure, which has been postulated to be around zero. Data were expressed as mean ± standard deviation (SD). Statistical analysis was performed using SPSS statistical software (SPSS v.17 for Windows, SPSS. Inc., Chicago, IL, USA). Independent t-test was used for comparison of continuous variables between groups, and chi-square was used for comparison of categorical variables between groups. Pearson‟s and Spearman‟s coefficients were used to study the correlation between variables. Repeated measures one-way analysis of variance (ANOVA), including tests of within-subjects and between-subjects effects, was used to evaluate whether significant changes of variables could be found, from rest to recovery, in each subject and whether these changes were different between groups. P ≤ 0.05 was considered significant. 7
ACCEPTED MANUSCRIPT Informed consent was obtained from each patient; the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by
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the institution‟s human research committee.
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Inter-rater reliability
The agreement of two measurements performed by a single observer or two
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different observers was estimated by using Bland-Altman analysis. As shown in Figs. 1
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and 2, a good intra-observer and inter-observer agreement between different measurements, with regard to LV GLS, twist, untwist, LA reservoir, beta index and
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3. Results
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PWV, was found.
Clinical and echocardiographic parameters at rest are listed in Table 1. As shown, hypertensive patients had greater wall thickness (p < 0.001) and lower LV diameter than healthy controls (end-diastolic diameter: p = 0.001). None of the patients had LV hypertrophy, and a few of them were showing only LV concentric remodeling (RWT > 0.42). There was no difference in LV ejection fraction between the groups, whereas E/A ratio was lower and mitral deceleration time was greater in patients than in controls (p = 0.001 and p = 0.048, respectively). Other systolic and diastolic parameters, calculated from tissue Doppler imaging and 2D strain analysis, were comparable between groups, with the only exception being higher E/E‟ values in patients than in controls (p = 0.035) (Table 2). Concerning vascular function, hypertensive patients showed higher values of 8
ACCEPTED MANUSCRIPT beta index and PWV than healthy subjects (6.1±2.1 vs 4.8±1.9, p = 0.046, and 5.7±1.1 vs 4.7±0.8, p = 0.001, respectively), suggesting an increased arterial stiffness in basal
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condition; carotid intima-media thickness was comparable between patients and controls
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(0.9 ± 0.2 mm vs 0.8 ± 0.1 mm, p = 0.078).
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Patients and controls, respectively, reached a maximal workload of 90.3±16.2 W and 113.6±17.4 W (p = 0.023). The results from echocardiographic and vascular analysis
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during exercise at different steps are reported in Table 3. First, there was a greater
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increase of E/E‟ from rest to peak stage in patients (from 9.3±2.6 to 12.1±5.1, p = 0.014) than in controls (from 7.5±1.4 to 8.8±1.7, p = 0.003) (Fig.3), with a significant difference
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between peak values when comparing the two groups (p = 0.024). With regard to
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myocardial deformation, global longitudinal strain (GLS) was found to be substantially
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unchanged from rest to peak stage in hypertensive patients (from -17.5±8.5% to 17.3±9.5%, p = 0.777) and significantly increased in controls (from -19.6±3.1% to 21.5±2.4%, p = 0.011), with a significant difference between the groups only at peak stage (p = 0.042) (Figs.3 and 4). The differences between peak exercise and resting values of GLS (∆GLS) were -2.2±2.2 vs-0.2±4.2, p = 0.049, in healthy subjects and patients, respectively, indicating a lesser increase of GLS in response to exercise in patients when compared with controls. Similarly, LV twist showed opposite changes in patients and controls, decreasing in the former and increasing in the latter; however, these changes did not reach statistical significance (from 13.8±6.1 to 12.9±3.2, p = 0.693, and from 12.5±4.7 to 15.6±7.8, p = 0.140, respectively) (Fig.3). LV untwist increased during exercise in both groups (from 9
ACCEPTED MANUSCRIPT 69±30 to -107±34, p = 0.031, and from -51±12 to -135±17, p = 0.015, in patients and controls, respectively), with a more minor increase in patients than in controls (p = 0.029
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between groups, at peak stage) (Fig.3).
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LA reservoir significantly increased throughout exercise only in controls (from
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40.1±4.4% to 53.4±9.1%, p = 0.001) whereas it remained almost unchanged in patients (from 37.1±8.4% to 39.6±6.7%, p = 0.293); moreover, there was significant difference in
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LA reservoir values during peak exercise between the groups (p < 0.001) (Figs.5and 6).
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The difference between the values of LA reservoir from rest to exercise (∆RES) was 13.8±9.1 vs 1.9±7.3, p=0.001, in healthy subjects and patients, respectively. Furthermore,
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LA stiffness was significantly greater in patients than in controls both at rest (0.26±0.08
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vs 0.19±0.08, p=0.023) and during exercise (0.29±0.13 vs 0.17±0.04, p < 0.001), with an
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opposite trend from rest to peak exercise in the two groups (Fig.5). LA booster showed a decrease, from rest to peak exercise, in both groups, with a more pronounced and mildly significant change only in patients (from -12.8±1.5% to -8.8±1.6%, p = 0.043). Concerning vascular parameters, PWV increased during exercise in patients group (p = 0.003, from rest to peak exercise) showing, as well as beta index, higher values in hypertensive patients in each step (at peak stage: 6.6±2.2 vs 6.3±1.2, p = 0.658for beta index and 6.3±0.9 vs 5.6±0.4, p = 0.010 for PWV; recovery: 6.8±2.2 vs 5.1±1.5, p = 0.004 for beta index and 5.8±1.1 vs 4.6±0.7, p < 0.001 for PWV) (Fig.5). Differently from carotid stiffness parameters, SVR decreased, either in patients or in controls, from rest to peak exercise (p < 0.001 in both groups); although higher values of SVR were found in patients at each step, these were not significantly different between groups. 10
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4. Discussion
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Our study shows that a cardiovascular maladaptation to exercise occurs in
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asymptomatic hypertensive patients with only mild cardiac morphological and functional
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abnormalities (i.e. LV concentric remodeling and early diastolic dysfunction) in comparison to healthy subjects. This finding, caused by the impairment of multiple
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cardiovascular compensatory mechanisms leading to inefficient performance on exertion,
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may be responsible for the lower functional capacity of these patients. In particular, we found: 1) lower LV longitudinal strain and LA reservoir in
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hypertensive patients compared to controls, at rest and, particularly, during exercise with
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significantly impaired LV and LA strain reserve; 2) a lesser increase, from rest to peak
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exercise, of LV untwisting rate in hypertensive patients than in controls; 3) higher LA stiffness, at rest and on exercise, in hypertensive patients than in controls; 4) higher increase of LV filling pressures , as estimated by E/E‟, in patients than in controls; 5) an increase of arterial stiffness, both at rest and during exercise, in hypertensive patients than in healthy subjects. In a healthy cardiovascular system, the increase of cardiac output, needed to adequately respond to peripheral oxygen demand, relies on multiple factors including venous return, atrial walls distensibility, LV diastolic filling and systolic performance; all these deal with the ability of the arterial system to efficiently deliver blood flow to peripheral tissues. We found, in our study, that these mechanisms are partially deficient in hypertensive patients, who, conversely, accomplish the needed increase of cardiac 11
ACCEPTED MANUSCRIPT output on exertion at the expense of higher LV filling pressures due to impaired LA walls distensibility at reservoir, blunted LV longitudinal myocardial deformation (“longitudinal
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reserve”), reduced LV twist/untwist (“torsional reserve”) and stiffer arterial system. This
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may explain the absence of symptoms at rest and the occurrence of symptoms only
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during physical effort.
Multiple subclinical LV myocardial abnormalities have been repeatedly found in
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hypertensive patients, at baseline. In particular, lower GLS combined with greater LV
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twist, both strictly related to diastolic blood pressure values on ambulatory blood pressure monitoring, has been found in young hypertensive patients without LV hypertrophy [19].
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Similarly, impaired LV longitudinal deformation, as assessed by tissue Doppler imaging
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and speckle-tracking echocardiography, combined with increased LV circumferential
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strain and twist, has been seen in hypertensive patients with LV hypertrophy compared with patients without LV hypertrophy and healthy subjects[20]. A close relationship between impaired LV mechanics, particularly LV longitudinal and “rotational” function, and cardiovascular performance at rest and during exercise has increasingly emerged. In this regard, a direct association between LV systolic longitudinal function assessed by GLS and LV filling pressures estimated by E/E‟ ratio has been pointed out, suggesting that LV diastolic performance may be independently associated with LV longitudinal systolic function [21]. A close relationship between LV untwisting rate and peak oxygen uptake also has been shown in hypertensive patients [22]. In accordance with previous findings, we found several subclinical LV myocardial 12
ACCEPTED MANUSCRIPT abnormalities, especially involving LV longitudinal deformation and untwist, in our patients. In particular, we observed in these patients a blunted cardiac functional reserve,
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characterized by a lesser increase of LV longitudinal deformation and LV untwist, both
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associated with higher E/E‟ values, during exercise. These abnormalities, already
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previously pointed out in patients with heart failure with preserved ejection fraction, were detectable only by performing exercise echocardiography and using 2D strain analysis,
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indicative of early impairment of LV systolic and diastolic properties despite apparently
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normal standard echocardiographic parameters. In these regards, impairment of LV functional reserve may have relevant implications for the functional capacity and the
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increase of LV filling pressures during exertion, as pointed out in our study. This
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accounts for the unique clinical features of these patients, such as the occurrence of
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symptoms resulting in limitation of functional capacity only during exertion [23]. On one hand, these abnormalities may be partially dependent on increased afterload due to higher blood pressure values, as occurs in hypertension; on the other hand, the early development of myocardial fibrosis associated with hypertensive heart disease may be particularly involved in the determinism of impaired longitudinal function relying, as known, on longitudinally oriented subendocardial fibers. These are the most vulnerable to myocardial ischemia resulting from excessive LV intracavitary pressures and/or microvascular dysfunction in hypertensive disease. In recent years, the role of LA function in cardiovascular performance, both at rest and particularly during exercise, has been increasingly highlighted, especially in patients with heart failure with preserved ejection fraction (HFPEF). In these patients, impaired 13
ACCEPTED MANUSCRIPT LA reservoir, conduit and booster function have been linked to higher prevalence of heart failure hospitalizations, atrial fibrillation, worse LV systolic function and greater LV
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mass and LA volume [24]. In particular, LA reservoir has been related to exercise
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capacity and E/E‟ ratio in patients with (HFPEF), [25]. Similar abnormalities regarding
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LA reservoir and stiffness also have been shown in hypertensive asymptomatic patients [26,27];
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In our study, accordingly with previous results, we found impaired LA function
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occurring from rest to exercise in hypertensive patients, . In particular, we observed, during exercise, a lesser increase of LA reservoir combined with a greater LA stiffness,
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which reflects increased E/E‟ ratio. Along with these findings, we observed in both
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groups a decrease of LA booster from rest to peak exercise. This could be explained by
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considering that, during exercise, LV diastolic filling likely occurs mostly in early diastole, due to shortening of diastolic time and to greater blood volume from venous return, which increases atrioventricular pressure gradient at this stage; this occurs at the expense of late-diastolic filling. As a consequence, increase of LA reservoir and, conversely, decrease of LA booster can be observed at peak exercise in each subject. With particular regard to LA booster, this showed higher values at rest in hypertensive patients, likely due to more delayed LV active relaxation favoring LV late-diastolic filling, whereas LA booster had near the same values at peak exercise in both groups. These results may explain why we found a statistically significant difference between values of LA booster from rest to peak exercise only in hypertensive patients. The abnormal LA function, likely caused by progressive LA enlargement and/or 14
ACCEPTED MANUSCRIPT fibrosis driven by hypertensive disease, may contribute to reduced functional capacity of these patients. This may be particularly relevant during exercise, since impaired LA
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reservoir, matching with greater blood volume, leads to greater upstream pressures and a
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lesser increase in LV diastolic filling and, subsequently, lesser stroke volume. As an
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additional finding of our study, we observed greater arterial stiffness in hypertensive patients compared to healthy controls, both at rest and, to a greater extent, during
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exercise. These abnormalities could have been unmasked by directly evaluating arterial
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wall distensibility and after measuring SVR, which was higher in our patients at each step. In this respect, SVR decreased in both groups, from rest to peak exercise, since,
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usually, Cardiac Output increases more markedly than BP during aerobic/isotonic
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exercise. Our results suggest that impaired elastic properties of the arterial vessels, likely
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due to endothelial dysfunction and/or early arterial wall structural changes, can be found in hypertensive patients, contributing to the maladaptive changes observed during exercise and increased LV filling pressures. Decreased arterial compliance during exercise that resulted in impaired vasodilator reserve recently was found in female hypertensive patients with an inability to increase cardiac stroke volume (“stroke volume reserve”) on exertion [28]. Moreover, antihypertensive therapy has been shown to reduce arterial and ventricular stiffness and, hence, enhance ventricular-arterial coupling and LV systolic/diastolic function in these patients [29].In our study, we highlighted the usefulness of measuring stiffness parameters through exertion, since the impairment of arterial elastic properties may occur or become apparent only during physical effort, influencing LV performance and 15
ACCEPTED MANUSCRIPT functional capacity. Echo-tracking technique, allowing a simple and reproducible calculation of the stiffness parameters in this particular setting, appears to be well suited
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for routine evaluation of arterial elastic properties in these patients.
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5. Limitations
The main limitation of our study is the small size of the population; this implies
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that our findings need to be confirmed in a larger cohort study. As a further limitation, we
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did not investigate other relevant parameters such as NT-proBNP and the markers of collagen synthesis, i.e., transforming growth factor (TGFβ-1) and metalloproteinase-9
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(MMP-9). In addition, we could not evaluate systolic pulmonary artery pressure either at
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rest or during exercise in our study‟s population because of inadequate acoustic window.
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Moreover, our patients were submitted to exercise testing without discontinuation of therapy, so we couldn‟t investigate how this may have affected our results. In this respect, we can only hypothesize that therapy may have improved the adaptation to effort among hypertensive patients. Furthermore, we could not submit our patients to cardiac magnetic resonance imaging to detect LV and LA fibrosis; however, lower values of 2D strain have been repeatedly associated with fibrosis detected on cardiac magnetic resonance imaging. However, 2D strain values also are partially influenced by LV afterload; this has to be considered when interpreting the results of 2D strain analysis in case of particularly elevated values of blood pressure. In our study, nevertheless, our patients showed only mildly elevated values of blood pressure. 6. Conclusions 16
ACCEPTED MANUSCRIPT Although only mild morphostructural and functional cardiovascular abnormalities can be found in asymptomatic hypertensive patients using conventional techniques, more
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accurate assessment through speckle-tracking echocardiography and carotid echo-
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tracking during exercise can unmask multiple maladaptive changes to exertion in these
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patients, accounting for reduced exercise tolerance. In this respect, impaired “longitudinal” ventricular deformation and atrial reserve coupled with increased arterial
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stiffness may explain the observed cardiovascular maladaptation during exercise in these
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patients.
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Conflict of interest
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The authors declare no conflicts of interest.
Acknowledgments
The authors gratefully acknowledge Jennifer Pfaff and Susan Nord of Aurora Cardiovascular Services for editorial preparation of the manuscript and Brian Miller and Brian Schurrer of Aurora Research Institute for help with the figures.
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cardiovascular risk factors. Int. J. Cardiol. 152(2011)225-230.
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13. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography‟s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J. Am. Soc. Echocardiogr. 18 (2005)1440-1463. 14.Longobardo L, Todaro MC, Zito C, et al. Role of imaging in assessment of atrial fibrosis in patients with atrial fibrillation: state-of-the-art review. Eur. Heart J.Cardiovasc. Imaging15(2014)1-5. 15. Di Bella G, Minutoli F, Madaffari A, et al. Left atrial function in cardiac amyloidosis. J. Cardiovasc. Med. (Hagerstown).17(2016)113-121.
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ACCEPTED MANUSCRIPT 16. Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus
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statement from the American Society of Echocardiography Carotid Intima-Media
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Thickness Task Force. Endorsed by the Society for Vascular Medicine. J. Am. Soc.
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Echocardiogr. 21(2008)93-111; quiz 189-190. Erratum in: J. Am. Soc. Echocardiogr. 21(2008)376.
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17.Antonini-Canterin F, Carerj S, Di Bello V, et al. Arterial stiffness and ventricular
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stiffness: a couple of diseases or a coupling disease? A review from the cardiologist‟s point of view. Eur. J. Echocardiogr. 10(2009)36-43.
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18. Harada A, Okada T, Niki K, et al. On-line noninvasive one-point measurements of
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pulse wave velocity. Heart Vessels 17 (2002) 61-68.
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19. Shin SM, Shim WJ, Park SM. Early changes of left ventricular function in young adults with never-treated hypertension and no left ventricular hypertrophy: relationships to ambulatory blood pressure monitoring. Clin. Exp.Hypertens.36(2014)517-523. 20.Imbalzano E, Zito C, Carerj S, et al. Left ventricular function in hypertension: new insight by speckle tracking echocardiography. Echocardiography28(2011)649-657. 21.Ballo P, Nistri S, Cameli M, et al. Association of left ventricular longitudinal and circumferential systolic dysfunction with diastolic function in hypertension: a non linear analysis focused on the interplay with left ventricular geometry. J. Card. Fail.20(2014)110-120.
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ACCEPTED MANUSCRIPT 22.Celic V, Tadic M, Suzic-Lazic J, et al. Two- and three-dimensional speckle tracking analysis of the relation between myocardial deformation and functional capacity in
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patients with systemic hypertension. Am. J. Cardiol. 113(2014)832-839.
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23. Phan TT, Abozguia K, Shivu GN, et al. Myocardial contractile inefficiency and
J. Am. Soc. Echocardiogr. 23(2010)201-206.
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dyssynchrony in heart failure with preserved ejection fraction and narrow QRS complex.
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24. Santos AB, Kraigher-Krainer E, Gupta DK, et al. Impaired left atrial function in heart
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failure with preserved ejection fraction. Eur. J. Heart Fail. 16 (2014) 1096-1103. 25.Kusunose K, Motoki H, Popovic ZB, Thomas JD, Klein AL, Marwick TH.
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Independent association of left atrial function with exercise capacity inpatients with
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preserved ejection fraction. Heart 98 (2012)1311-1317.
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26. Liu Y, Wang K, Su D, et al. Noninvasive assessment of left atrial phasic function in patients with hypertension and diabetes using two-dimensional speckle tracking and volumetric parameters. Echocardiography31(2014)727-735. 27. Miyoshi H, Oishi Y, Mizuguchi Y, et al. Association of left atrial reservoir function with left atrial structural remodeling related to left ventricular dysfunction in asymptomatic patients with hypertension: evaluation by two-dimensional speckletracking echocardiography. Clin. Exp. Hypertens. 37(2015)155-165. 28.Sahlén A, Abdula G, Norman M, et al. Arterial vasodilatory and ventricular diastolic reserves determine the stroke volume response to exercise in elderly female hypertensive patients. Am. J. Physiol. Heart Circ. Physiol. 301(2011)H2433-41.
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ACCEPTED MANUSCRIPT 29. Lam CS, Shah AM, Borlaug BA, et al. Effect of antihypertensive therapy on
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ventricular-arterial mechanics, coupling, and efficiency. Eur. Heart J. 34(2013)676-683.
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ACCEPTED MANUSCRIPT FIGURE LEGENDS Fig. 1. Bland-Altman graphs showing intra-observer (panels A, B, and C) and inter-observer
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(panels D, E, and F) variability in the measurement of left ventricular global longitudinal strain
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(LV GLS) (panels A and D), LV twist (panels B and E) and LV untwist (panels C and F).
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Fig. 2. Bland-Altman graphs showing intra-observer (panels A, B, and C) and inter-observer (panels D, E, and F) variability in the measurement of left atrial (LA) reservoir (panels A and D),
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beta index (panels B and E) and pulse wave velocity (PWV) (panels C and F). Fig.3.Box and whisker graphs showing left ventricular (LV) global longitudinal strain (upper left
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panel), E/E‟ (upper right panel), LV twist (lower left panel), and LV untwist (lower right panel) in patients (green lines) and controls (blue lines) at rest, peak exercise, and recovery. Significant
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p-values are reported as: black type – values between groups at each step, green type – values between rest and peak exercise in hypertensive patients and blue type – values between rest and
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peak exercise in healthy subjects.
Fig. 4. Examples of left ventricular global longitudinal strain (GLS), obtained from GE Automated Function Imaging, in a healthy subject (panels A and B) and a hypertensive patient (panels C and D), at rest (panels A and C) and peak exercise (panels B and D). Fig.5.Box and whisker graphs showing left atrial reservoir (upper left panel), left atrial stiffness (upper right panel), beta index (lower left panel), and pulse wave velocity (lower right panel) in patients (green lines) and controls (blue lines) at rest, peak exercise, and recovery. Significant pvalues are reported as: black type – values between groups at each step, green type – values between rest and peak exercise in hypertensive patients and blue type – values between rest and peak exercise in healthy subjects.
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ACCEPTED MANUSCRIPT Fig.6.Examples of left atrial reservoir evaluated as positive peak average of myocardial deformation at end-systole, in a healthy subject (panels A and B) and a hypertensive patient
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(panels C and D), at rest (panels A and C) and peak exercise (panels B and D).
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Controls
(n=30)
(n=24)
Age, years
45.1±11.9
44.4±9.6
Men
19(63%)
Systolic blood pressure, mmHg
142±19
119±15
0.005
Diastolic blood pressure, mmHg
88±8
73±9
<0.001
Maximal workload, watts
90.3±16.2
113.6±17.4
0.023
Angiotensin converting enzyme
14(46%)
-
-
7(23%)
-
-
9(30%)
-
-
Interventricular septum thickness, mm
10.1±1.1
8.27±0.76
<0.001
Posterior wall thickness,mm
8.54±1.09
7.09±1.01
<0.001
End-diastolic diameter, mm
46.5±3.9
50.1±4.6
0.001
End-systolic diameter, mm
29.8±6.5
32.3±4.1
0.101
Relative wall thickness
0.36 ± 0.06
0.28±0.03
0.308
Left ventricular mass, g/m2
71.1±11.7
69.5±12.8
0.488
End-diastolic volume, mL
94.5±19.3
95.1±16.9
0.942
End-systolic volume, mL
34.1±7.7
33.6±11.1
0.892
Ejection fraction, %
64.1±4.7
63.1±4.8
0.409
E/A
1.2±0.41
1.8±0.58
0.001
Mitral deceleration time, msec
186.3 ± 9.4
166.4 ± 8.9
0.048
14(58%)
0.059
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0.647
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p value
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Patients
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Table 1Clinical and standard echocardiographic features at rest.
inhibitors/angiotensin receptor blockers
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Beta-blockers
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26.3±7.3
24.7±6.3
0.549
Carotid intima-media thickness
0.9 ± 0.2
0.8 ± 0.1
0.786
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Values reported as mean ± standard deviation, or number, percentage. Bold denotes statistical
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significance.
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ACCEPTED MANUSCRIPT Table 2TissueDoppler imaging, speckle-tracking echocardiography and echo-tracking parameters at rest. Controls
(n=30)
(n=24)
9.3±2.1
E/E‟
9.3±2.6
Global longitudinal strain,%
-17.5±8.5
Left ventricular twist, º Left ventricular untwist, º/s
0.035
-19.6±3.1
0.253
13.8±6.1
12.5±4.7
0.674
-69±30
-51±12
0.135
37.1±8.4
40.1±4.4
0.640
-12.8±1.5
-10.6±2.7
0.074
0.26±0.08
0.19±0.08
0.023
6.1±2.1
4.8±1.9
0.046
5.7±1.1
4.7±0.8
0.001
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7.5±1.4
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Pulse wave velocity, m/s
0.127
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Left atrial booster, %
Beta index
9.8±1.7
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Left atrial reservoir, %
Left atrial stiffness
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Septal S‟, cm/s
p value
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Patients
Values reported as mean± standard deviation. Bold denotes statistical significance.
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ACCEPTED MANUSCRIPT Table 3Step-by-step clinical, echocardiographic and vascular parameters.
Peak
Recovery
142±19
181±21*
146±30†
88 ± 8
99 ± 17*
85 ± 13†
105.9 ± 9.4
126.9 ± 6.6*
106.1 ± 18.3†
<0.001*; <0.001†
Heart rate, bpm
74.2 ± 7.8
131.1±12.3*
82.5 ± 6.9†
<0.001*; <0.001†
Stroke volume, ml
94.7± 21.3
117± 32*
93.1± 23.5†
<0.001*; <0.001†
Systemic vascular
1211±40.1
677.2±23.7*
1114.8±32.5†
<0.001*; <0.001†
9.3 ± 2.6
12.1 ± 5.1*
8.6 ± 2.1
0.014*
-17.5 ± 8.5
-17.3 ± 9.5
-18.3 ± 9.6†
0.036†
Left ventricular twist, º
13.8 ± 6.1
12.9 ± 3.2
13.6 ± 4.7
ns
Left ventricular
-69 ± 30
-107 ± 34*
-88 ± 32†
0.031*; 0.038†
Left atrial reservoir, %
37.1 ± 8.4
39.6 ± 6.7
38.9 ± 9.1
ns
Left atrial booster, %
-12.8±1.5
-8.8±1.6*
-12±2.1†
*0.043; †0.008
Left atrial stiffness
0.26 ± 0.08
0.29 ± 0.13
0.23 ± 0.09
ns
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Systolic blood pressure,
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Rest
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Patients (n = 30)
Diastolic blood
Mean arterial pressure,
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resistance,
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mmHg
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pressure, mmHg
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mmHg
p value <0.001*; <0.001†
0.005*; 0.001†
dyne*s/cm5 E/E‟
Global longitudinal strain, %
untwist, º/s
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6.1±2.1
6.2±2.2
6.8±2.2
ns
Pulse wave velocity,
5.7±1.1
6.3±0.9*
5.8±1.1†
0.003*;0.013†
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m/s
Rest
Peak
Recovery
p value
119 ± 15
159 ± 18*
117 ± 13†
0.001*; <0.001†
73 ± 9
82 ± 7
Diastolic blood
Mean arterial pressure,
90.5±8.2
0.007†
88.7±4.8†
<0.001*; <0.001†
125.7± 11.9*
79.2 ± 7.5†
<0.001*; <0.001†
128.8±20.2*
94.4±14.8†
<0.001*; <0.001†
108.1±8.8*
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mmHg
70 ± 8†
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pressure, mmHg
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mmHg
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Systolic blood pressure,
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Controls (n = 24)
71.2 ± 8.6
Stroke volume, ml
95.8±13.4
Systemic vascular
1063±17.6
537.1±8.8*
948.7±19.2†
<0.001*; <0.001†
E/E‟
7.5 ± 1.4
8.8 ± 1.7*
7.2 ± 1.4†
0.003*; 0.041†
Global longitudinal
-19.6 ± 3.1
-21.5 ± 2.4*
-19.9 ± 2.9†
0.011*; <0.001†
Left ventricular twist, º
12.5 ± 4.7
15.6 ± 7.8
13.9 ± 5.6
ns
Left ventricular
-51 ± 12
-135 ± 17*
-90 ± 19†
0.015*; 0.029†
40.1 ± 4.4
53.4 ± 9.1*
45.9 ± 11.1
0.001*
resistance,
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Heart rate, bpm
dyne*s/cm5
strain, %
untwist, º/s Left atrial reservoir, %
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-10.6±2.7
-8.9±2.0
-10.5±3.2
ns
Left atrial stiffness
0.19 ± 0.08
0.17 ± 0.04
0.16 ± 0.05
ns
Beta
4.8 ± 1.9
6.3 ± 1.2*
5.1 ± 1.5†
Pulse wave velocity,
4.7 ± 0.8
5.6 ± 0.4
4.6 ± 0.7
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ns
vs peak
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Values are reported as mean ± standard deviation.
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* vs rest †
<0.001*; 0.001†
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m/s
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Left atrial booster, %
30
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Fig. 2
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Fig. 3
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Fig. 4
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Fig. 5
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Fig. 6
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S0167-5273(17)30023-2 doi:10.1016/j.ijcard.2017.01.004 IJCA 24369
To appear in:
International Journal of Cardiology
Received date: Revised date: Accepted date:
28 June 2016 27 December 2016 3 January 2017
Please cite this article as: Piccione Maurizio Cusm`a, Zito Concetta, Khandheria Bijoy, Madaffari Antonio, Oteri Alessandra, Falanga Gabriella, DomenicaDonato, D’Angelo Myriam, Carerj Maria Ludovica, Di Bella Gianluca, Imbalzano Egidio, Pugliatti Pietro, Carerj Scipione, Cardiovascular maladaptation to exercise in young hypertensive patients, International Journal of Cardiology (2017), doi:10.1016/j.ijcard.2017.01.004
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ACCEPTED MANUSCRIPT Original Research
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Cardiovascular maladaptation to exercise in young hypertensive patients
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Maurizio Cusmà Piccionea, Concetta Zitoa, Bijoy Khandheriab*, Antonio Madaffaria, Alessandra Oteria, Gabriella Falangaa, DomenicaDonatoa, Myriam D‟Angeloa, Maria Ludovica Carerja, Gianluca Di Bellaa, Egidio Imbalzanoa, Pietro Pugliattia, Scipione Carerja a
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Department of Clinical-Experimental Medicine and Pharmacology, Cardiology Division, University of Messina, Via Consolare Valeria, Messina, ME 98122, Italy b
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Aurora Cardiovascular Services, Aurora Sinai/Aurora St. Luke‟s Medical Centers, 2801 W. Kinnickinnic River Parkway, Ste. 840, Milwaukee, Wisconsin 53215,USA
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All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Short Title: Maladaptation to exercise in systemic hypertension Conflicts of Interest: None. Funding: None. Word Count: 6,377 (including references, legends and tables) Keywords: Strain, Exercise echocardiography, Echo-tracking, Longitudinal function, Stiffness
*Corresponding author: Bijoy K. Khandheria, MD Aurora St. Luke‟s Medical Center 2801 W. Kinnickinnic River Parkway, Ste. 840 Milwaukee, WI 53215 Phone: +1 414 649 3909 Fax: +1 414 649 3578 Email: [email protected] 1
ACCEPTED MANUSCRIPT ABSTRACT
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Background: Impairment of the adaptive mechanisms that increase cardiac output during exercise can translate to a reduced functional capacity. We investigated cardiovascular
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adaptation to exertion in asymptomatic hypertensive patients, aiming to identify the early
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signs of cardiac and vascular dysfunction.
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Methods and Results: We enrolled 54 subjects: 30 patients (45.1±11.9 years, 19 males) and 24 age-matched healthy controls (44.4±9.6 years, 14 males). Speckle-tracking
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echocardiography (STE) and echo-tracking were performed at rest and during exertion to assess myocardial deformation and arterial stiffness.
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Results: E/E‟ increased from rest to peak exercise more in patients than in controls (peak
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stage: p = 0.024). Global longitudinal strain increased significantly from rest to peak stage in
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controls (p=0.011) whereas it remained unchanged in patients (p = 0.777). Left atrial (LA) reservoir was significantly increased throughout the exercise only in controls (p = 0.001) whereas it was almost unchanged in patients (p = 0.293). LA stiffness was significantly higher in patients than in controls both at rest (p=0.023) and during exercise (p < 0.001). Beta index and pulse wave velocity (PWV) increased during exercise in both groups, showing higher values in patients in each step. Conclusions: Our study showed a more pronounced maladaptation during exercise, with respect to rest, of the cardiovascular system with impaired cardiac-vessel coupling in hypertensive patients compared to healthy subjects. Exercise echocardiography implemented by STE and echo-tracking is invaluable in the early detection of these cardiovascular abnormalities. 2
ACCEPTED MANUSCRIPT 1. Introduction The ability of the left ventricle to adequately fill and empty in less time during
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exertion, without increased filling pressures, represents a key mechanism of the
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cardiovascular system in responding to greater peripheral metabolic demand [1]. This
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adaptive mechanism, relying on the increase of venous return, myocardial contractility, and heart rate, has been found to be impaired in various heart diseases and arterial
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hypertension even in the absence of clinically apparent structural changes, translating into
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reduced exercise tolerance [2-4]. In this regard, the assessment of cardiovascular adaptation to exercise in hypertensive patients may be useful in identifying early
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abnormalities preceding the occurrence of overt heart failure. More sensitive diagnostic
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tools that allow accurate analysis of myocardial function may be required because
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conventional echocardiography, as widely reported [5], can detect abnormalities of cardiac function only in advanced stages of hypertensive disease. In this respect, speckletracking echocardiography(STE), which is proving to be sensitive in the early detection of systolic and diastolic dysfunction in various diseases, as well the study of left atrial (LA) reserve, may be particularly valuable [6-9]. Recently, Hensel et al. showed, by means of STE, lower values of LV deformation (circumferential and longitudinal strain, longitudinal strain rate) at rest and, particularly, during exercise in hypertensive patients with normal left ventricular function,[10].Similarly, the measurement of arterial wall distensibility, in addition to the evaluation of carotid intima-media thickness, is increasingly being performed to detect early vascular abnormalities in arterial hypertension and several other conditions [11,12]. Therefore, the analysis of arterial 3
ACCEPTED MANUSCRIPT stiffness, at rest and during exercise, which can be accomplished using the echo-tracking technique, may be of particular interest for a comprehensive evaluation of cardiovascular
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system efficiency. The main aim of our study is to investigate, after evaluating LV and
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LA myocardial deformation parameters and vascular functional parameters, the cardiac
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and vascular adaptation to exertion in patients affected by systemic hypertension.
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2. Methods
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We prospectively enrolled 54 young subjects, including 30 patients with isolated essential hypertension (45.1±11.9 years, 19 males) and 24 age-matched, healthy controls
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(44.4±9.6 years, 14 males). Clinical examination and cardiovascular ultrasonographic
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study were performed in each subject. All patients were on a single anti-hypertensive
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drug, such as an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, Ca2+-blocker, or beta-blocker. Overall, blood pressure values were well controlled by medical therapy, as confirmed by the 24-hour blood pressure monitoring that was an essential criterion of eligibility for all patients. Inclusion criteria were the absence of symptoms, the ability to perform adequate exercise, and an LV ejection fraction ≥55%. Exclusion criteria were the presence of other cardiovascular risk factors (e.g., diabetes mellitus, dyslipidemia, cigarette smoking and obesity), comorbidities (i.e., systemic disorders, renal insufficiency, etc.), a systolic blood pressure at rest >200 mmHg, the presence of LV wall motion abnormalities, or more-than-mild heart valve disease. Each subject underwent exercise testing by using an upright cycloergometer according to an incremental step protocol with an increase of 25 watts every 3minutes. 4
ACCEPTED MANUSCRIPT The exercise test was interrupted after reaching a predetermined workload of 100 watts or because of exhaustion. This specific maximal workload was chosen because our aim was
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to evaluate cardiovascular adaptation to exercise, not to perform a test for inducible
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myocardial ischemia; furthermore, the accuracy of 2-dimensional (2D) strain and arterial
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stiffness analyses could have been limited by a higher heart rate at a greater workload. Ultrasonographic study was performed using a GE Vivid 7 echocardiography machine
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(Horten, Norway). Images and videoclips of the parasternal long- and short-axis views at
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basal, mid and apical levels, and of the apical four-, two-, and three-chamber views were acquired at rest, peak (100 watts), and recovery steps. A frame rate >70 frames per
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second was employed, as widely established. LV end-diastolic and end-systolic volumes,
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Simpson‟s biplane ejection fraction, and myocardial mass according to Devereux‟s
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formula from M-mode images of the mid-ventricular short-axis view were calculated [13]. Mitral inflow measurements were obtained from the four-chamber apical view by placing the sample volume at the mitral leaflet tips, and peak velocities of E and A waves, E/A ratio, and E-wave deceleration time were measured. E/E‟ was calculated as the ratio between the peak velocities of E and E‟ waves, the latter having been obtained from tissue Doppler imaging at the septal corner of the mitral annulus. LV stroke volume was calculated, using continuity equation, by measuring LV outflow tract diameter, from parasternal long axis view, and velocity time integral after placing the sample volume, at the same level, from 5-chamber apical view. For each subject, strain analysis was performed offline using a dedicated software package (Echopac V. 8.0.0 GE, Horten, Norway). The endocardial border was traced 5
ACCEPTED MANUSCRIPT manually from apical views, automatically obtaining the calculation of a region of interest comprising the area between endocardial and epicardial layers. Tracking quality
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was verified for each segment, and low-quality images were excluded from strain
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analysis (about 4% of myocardial segments at rest, 15% at peak exercise, 5% at
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recovery). Global values of longitudinal strain derived from each apical view were calculated through automated function imaging analysis. In addition, LV twist was
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measured as the net difference between basal and apical rotations; LV untwist was
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derived from the early-diastolic peak of the untwisting rate of the ventricle. Finally, LA reservoir and booster were measured by using the same software for the study of LV
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strain, respectively evaluating the maximal positive and negative deformations of LA
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walls at end-systole and pre-systole (at the beginning of T wave and at the end of P wave
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on electrocardiogram)[14]. LA stiffness was calculated, as previously established, as the ratio between E/E‟ and LA reservoir peak values [15]. Two independent observers who were unaware of the clinical conditions of the patients evaluated the recordings and calculated the echocardiographic parameters. Each subject was studied by use of a color Doppler echocardiography machine (Prosound α 10, Aloka, Tokyo, Japan) equipped with a 7.5 MHz linear array probe and a high-resolution echo-tracking system using radio-frequency signals and allowing accurate measurement of changes in the diameter of the carotid artery. Stiffness parameters (stiffness index [β], pulse wave velocity [PWV]) were obtained from the right and left common carotid arteries at about 1 cm proximal to the bulb region. Intima-media thickness was measured at the same site, in the far wall, as the distance 6
ACCEPTED MANUSCRIPT between the first and second echogenic lines from the lumen [16]. Time-related pressure waveforms were obtained from systolic and diastolic changes of arterial
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diameter after calibration for blood pressure measured with a cuff-type manometer
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applied to the right upper arm. β was automatically calculated as a mean of 5 beats,
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according to the established formula β= ln (Ps/Pd)/(Ds − Dd/Dd), where Ps and Pd represent, respectively, systolic and diastolic blood pressure values andDs and Dd the
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common carotid artery maximal and minimal diameters, respectively [17]. PWV,
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derived from β, was obtained from the on-line „„one-point‟‟ measurement, calculated from the following equation: PWV = (βP/2)1/2 where P is diastolic pressure and is
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blood density (1050 Kg m3)[18]. For each parameter, an average of the values of the
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right and left sides was used. Systemic vascular resistance (SVR) was calculated from
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the formula SVR = (80*mean systolic blood pressure)/cardiac output, neglecting to consider right atrial pressure, which has been postulated to be around zero. Data were expressed as mean ± standard deviation (SD). Statistical analysis was performed using SPSS statistical software (SPSS v.17 for Windows, SPSS. Inc., Chicago, IL, USA). Independent t-test was used for comparison of continuous variables between groups, and chi-square was used for comparison of categorical variables between groups. Pearson‟s and Spearman‟s coefficients were used to study the correlation between variables. Repeated measures one-way analysis of variance (ANOVA), including tests of within-subjects and between-subjects effects, was used to evaluate whether significant changes of variables could be found, from rest to recovery, in each subject and whether these changes were different between groups. P ≤ 0.05 was considered significant. 7
ACCEPTED MANUSCRIPT Informed consent was obtained from each patient; the study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by
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the institution‟s human research committee.
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Inter-rater reliability
The agreement of two measurements performed by a single observer or two
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different observers was estimated by using Bland-Altman analysis. As shown in Figs. 1
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and 2, a good intra-observer and inter-observer agreement between different measurements, with regard to LV GLS, twist, untwist, LA reservoir, beta index and
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3. Results
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PWV, was found.
Clinical and echocardiographic parameters at rest are listed in Table 1. As shown, hypertensive patients had greater wall thickness (p < 0.001) and lower LV diameter than healthy controls (end-diastolic diameter: p = 0.001). None of the patients had LV hypertrophy, and a few of them were showing only LV concentric remodeling (RWT > 0.42). There was no difference in LV ejection fraction between the groups, whereas E/A ratio was lower and mitral deceleration time was greater in patients than in controls (p = 0.001 and p = 0.048, respectively). Other systolic and diastolic parameters, calculated from tissue Doppler imaging and 2D strain analysis, were comparable between groups, with the only exception being higher E/E‟ values in patients than in controls (p = 0.035) (Table 2). Concerning vascular function, hypertensive patients showed higher values of 8
ACCEPTED MANUSCRIPT beta index and PWV than healthy subjects (6.1±2.1 vs 4.8±1.9, p = 0.046, and 5.7±1.1 vs 4.7±0.8, p = 0.001, respectively), suggesting an increased arterial stiffness in basal
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condition; carotid intima-media thickness was comparable between patients and controls
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(0.9 ± 0.2 mm vs 0.8 ± 0.1 mm, p = 0.078).
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Patients and controls, respectively, reached a maximal workload of 90.3±16.2 W and 113.6±17.4 W (p = 0.023). The results from echocardiographic and vascular analysis
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during exercise at different steps are reported in Table 3. First, there was a greater
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increase of E/E‟ from rest to peak stage in patients (from 9.3±2.6 to 12.1±5.1, p = 0.014) than in controls (from 7.5±1.4 to 8.8±1.7, p = 0.003) (Fig.3), with a significant difference
D
between peak values when comparing the two groups (p = 0.024). With regard to
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myocardial deformation, global longitudinal strain (GLS) was found to be substantially
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unchanged from rest to peak stage in hypertensive patients (from -17.5±8.5% to 17.3±9.5%, p = 0.777) and significantly increased in controls (from -19.6±3.1% to 21.5±2.4%, p = 0.011), with a significant difference between the groups only at peak stage (p = 0.042) (Figs.3 and 4). The differences between peak exercise and resting values of GLS (∆GLS) were -2.2±2.2 vs-0.2±4.2, p = 0.049, in healthy subjects and patients, respectively, indicating a lesser increase of GLS in response to exercise in patients when compared with controls. Similarly, LV twist showed opposite changes in patients and controls, decreasing in the former and increasing in the latter; however, these changes did not reach statistical significance (from 13.8±6.1 to 12.9±3.2, p = 0.693, and from 12.5±4.7 to 15.6±7.8, p = 0.140, respectively) (Fig.3). LV untwist increased during exercise in both groups (from 9
ACCEPTED MANUSCRIPT 69±30 to -107±34, p = 0.031, and from -51±12 to -135±17, p = 0.015, in patients and controls, respectively), with a more minor increase in patients than in controls (p = 0.029
PT
between groups, at peak stage) (Fig.3).
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LA reservoir significantly increased throughout exercise only in controls (from
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40.1±4.4% to 53.4±9.1%, p = 0.001) whereas it remained almost unchanged in patients (from 37.1±8.4% to 39.6±6.7%, p = 0.293); moreover, there was significant difference in
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LA reservoir values during peak exercise between the groups (p < 0.001) (Figs.5and 6).
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The difference between the values of LA reservoir from rest to exercise (∆RES) was 13.8±9.1 vs 1.9±7.3, p=0.001, in healthy subjects and patients, respectively. Furthermore,
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LA stiffness was significantly greater in patients than in controls both at rest (0.26±0.08
TE
vs 0.19±0.08, p=0.023) and during exercise (0.29±0.13 vs 0.17±0.04, p < 0.001), with an
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opposite trend from rest to peak exercise in the two groups (Fig.5). LA booster showed a decrease, from rest to peak exercise, in both groups, with a more pronounced and mildly significant change only in patients (from -12.8±1.5% to -8.8±1.6%, p = 0.043). Concerning vascular parameters, PWV increased during exercise in patients group (p = 0.003, from rest to peak exercise) showing, as well as beta index, higher values in hypertensive patients in each step (at peak stage: 6.6±2.2 vs 6.3±1.2, p = 0.658for beta index and 6.3±0.9 vs 5.6±0.4, p = 0.010 for PWV; recovery: 6.8±2.2 vs 5.1±1.5, p = 0.004 for beta index and 5.8±1.1 vs 4.6±0.7, p < 0.001 for PWV) (Fig.5). Differently from carotid stiffness parameters, SVR decreased, either in patients or in controls, from rest to peak exercise (p < 0.001 in both groups); although higher values of SVR were found in patients at each step, these were not significantly different between groups. 10
ACCEPTED MANUSCRIPT
4. Discussion
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Our study shows that a cardiovascular maladaptation to exercise occurs in
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asymptomatic hypertensive patients with only mild cardiac morphological and functional
SC
abnormalities (i.e. LV concentric remodeling and early diastolic dysfunction) in comparison to healthy subjects. This finding, caused by the impairment of multiple
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cardiovascular compensatory mechanisms leading to inefficient performance on exertion,
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may be responsible for the lower functional capacity of these patients. In particular, we found: 1) lower LV longitudinal strain and LA reservoir in
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hypertensive patients compared to controls, at rest and, particularly, during exercise with
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significantly impaired LV and LA strain reserve; 2) a lesser increase, from rest to peak
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exercise, of LV untwisting rate in hypertensive patients than in controls; 3) higher LA stiffness, at rest and on exercise, in hypertensive patients than in controls; 4) higher increase of LV filling pressures , as estimated by E/E‟, in patients than in controls; 5) an increase of arterial stiffness, both at rest and during exercise, in hypertensive patients than in healthy subjects. In a healthy cardiovascular system, the increase of cardiac output, needed to adequately respond to peripheral oxygen demand, relies on multiple factors including venous return, atrial walls distensibility, LV diastolic filling and systolic performance; all these deal with the ability of the arterial system to efficiently deliver blood flow to peripheral tissues. We found, in our study, that these mechanisms are partially deficient in hypertensive patients, who, conversely, accomplish the needed increase of cardiac 11
ACCEPTED MANUSCRIPT output on exertion at the expense of higher LV filling pressures due to impaired LA walls distensibility at reservoir, blunted LV longitudinal myocardial deformation (“longitudinal
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reserve”), reduced LV twist/untwist (“torsional reserve”) and stiffer arterial system. This
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may explain the absence of symptoms at rest and the occurrence of symptoms only
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during physical effort.
Multiple subclinical LV myocardial abnormalities have been repeatedly found in
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hypertensive patients, at baseline. In particular, lower GLS combined with greater LV
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twist, both strictly related to diastolic blood pressure values on ambulatory blood pressure monitoring, has been found in young hypertensive patients without LV hypertrophy [19].
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Similarly, impaired LV longitudinal deformation, as assessed by tissue Doppler imaging
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and speckle-tracking echocardiography, combined with increased LV circumferential
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strain and twist, has been seen in hypertensive patients with LV hypertrophy compared with patients without LV hypertrophy and healthy subjects[20]. A close relationship between impaired LV mechanics, particularly LV longitudinal and “rotational” function, and cardiovascular performance at rest and during exercise has increasingly emerged. In this regard, a direct association between LV systolic longitudinal function assessed by GLS and LV filling pressures estimated by E/E‟ ratio has been pointed out, suggesting that LV diastolic performance may be independently associated with LV longitudinal systolic function [21]. A close relationship between LV untwisting rate and peak oxygen uptake also has been shown in hypertensive patients [22]. In accordance with previous findings, we found several subclinical LV myocardial 12
ACCEPTED MANUSCRIPT abnormalities, especially involving LV longitudinal deformation and untwist, in our patients. In particular, we observed in these patients a blunted cardiac functional reserve,
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characterized by a lesser increase of LV longitudinal deformation and LV untwist, both
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associated with higher E/E‟ values, during exercise. These abnormalities, already
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previously pointed out in patients with heart failure with preserved ejection fraction, were detectable only by performing exercise echocardiography and using 2D strain analysis,
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indicative of early impairment of LV systolic and diastolic properties despite apparently
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normal standard echocardiographic parameters. In these regards, impairment of LV functional reserve may have relevant implications for the functional capacity and the
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increase of LV filling pressures during exertion, as pointed out in our study. This
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accounts for the unique clinical features of these patients, such as the occurrence of
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symptoms resulting in limitation of functional capacity only during exertion [23]. On one hand, these abnormalities may be partially dependent on increased afterload due to higher blood pressure values, as occurs in hypertension; on the other hand, the early development of myocardial fibrosis associated with hypertensive heart disease may be particularly involved in the determinism of impaired longitudinal function relying, as known, on longitudinally oriented subendocardial fibers. These are the most vulnerable to myocardial ischemia resulting from excessive LV intracavitary pressures and/or microvascular dysfunction in hypertensive disease. In recent years, the role of LA function in cardiovascular performance, both at rest and particularly during exercise, has been increasingly highlighted, especially in patients with heart failure with preserved ejection fraction (HFPEF). In these patients, impaired 13
ACCEPTED MANUSCRIPT LA reservoir, conduit and booster function have been linked to higher prevalence of heart failure hospitalizations, atrial fibrillation, worse LV systolic function and greater LV
PT
mass and LA volume [24]. In particular, LA reservoir has been related to exercise
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capacity and E/E‟ ratio in patients with (HFPEF), [25]. Similar abnormalities regarding
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LA reservoir and stiffness also have been shown in hypertensive asymptomatic patients [26,27];
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In our study, accordingly with previous results, we found impaired LA function
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occurring from rest to exercise in hypertensive patients, . In particular, we observed, during exercise, a lesser increase of LA reservoir combined with a greater LA stiffness,
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which reflects increased E/E‟ ratio. Along with these findings, we observed in both
TE
groups a decrease of LA booster from rest to peak exercise. This could be explained by
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considering that, during exercise, LV diastolic filling likely occurs mostly in early diastole, due to shortening of diastolic time and to greater blood volume from venous return, which increases atrioventricular pressure gradient at this stage; this occurs at the expense of late-diastolic filling. As a consequence, increase of LA reservoir and, conversely, decrease of LA booster can be observed at peak exercise in each subject. With particular regard to LA booster, this showed higher values at rest in hypertensive patients, likely due to more delayed LV active relaxation favoring LV late-diastolic filling, whereas LA booster had near the same values at peak exercise in both groups. These results may explain why we found a statistically significant difference between values of LA booster from rest to peak exercise only in hypertensive patients. The abnormal LA function, likely caused by progressive LA enlargement and/or 14
ACCEPTED MANUSCRIPT fibrosis driven by hypertensive disease, may contribute to reduced functional capacity of these patients. This may be particularly relevant during exercise, since impaired LA
PT
reservoir, matching with greater blood volume, leads to greater upstream pressures and a
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lesser increase in LV diastolic filling and, subsequently, lesser stroke volume. As an
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additional finding of our study, we observed greater arterial stiffness in hypertensive patients compared to healthy controls, both at rest and, to a greater extent, during
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exercise. These abnormalities could have been unmasked by directly evaluating arterial
MA
wall distensibility and after measuring SVR, which was higher in our patients at each step. In this respect, SVR decreased in both groups, from rest to peak exercise, since,
D
usually, Cardiac Output increases more markedly than BP during aerobic/isotonic
TE
exercise. Our results suggest that impaired elastic properties of the arterial vessels, likely
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due to endothelial dysfunction and/or early arterial wall structural changes, can be found in hypertensive patients, contributing to the maladaptive changes observed during exercise and increased LV filling pressures. Decreased arterial compliance during exercise that resulted in impaired vasodilator reserve recently was found in female hypertensive patients with an inability to increase cardiac stroke volume (“stroke volume reserve”) on exertion [28]. Moreover, antihypertensive therapy has been shown to reduce arterial and ventricular stiffness and, hence, enhance ventricular-arterial coupling and LV systolic/diastolic function in these patients [29].In our study, we highlighted the usefulness of measuring stiffness parameters through exertion, since the impairment of arterial elastic properties may occur or become apparent only during physical effort, influencing LV performance and 15
ACCEPTED MANUSCRIPT functional capacity. Echo-tracking technique, allowing a simple and reproducible calculation of the stiffness parameters in this particular setting, appears to be well suited
RI
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for routine evaluation of arterial elastic properties in these patients.
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5. Limitations
The main limitation of our study is the small size of the population; this implies
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that our findings need to be confirmed in a larger cohort study. As a further limitation, we
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did not investigate other relevant parameters such as NT-proBNP and the markers of collagen synthesis, i.e., transforming growth factor (TGFβ-1) and metalloproteinase-9
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(MMP-9). In addition, we could not evaluate systolic pulmonary artery pressure either at
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rest or during exercise in our study‟s population because of inadequate acoustic window.
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Moreover, our patients were submitted to exercise testing without discontinuation of therapy, so we couldn‟t investigate how this may have affected our results. In this respect, we can only hypothesize that therapy may have improved the adaptation to effort among hypertensive patients. Furthermore, we could not submit our patients to cardiac magnetic resonance imaging to detect LV and LA fibrosis; however, lower values of 2D strain have been repeatedly associated with fibrosis detected on cardiac magnetic resonance imaging. However, 2D strain values also are partially influenced by LV afterload; this has to be considered when interpreting the results of 2D strain analysis in case of particularly elevated values of blood pressure. In our study, nevertheless, our patients showed only mildly elevated values of blood pressure. 6. Conclusions 16
ACCEPTED MANUSCRIPT Although only mild morphostructural and functional cardiovascular abnormalities can be found in asymptomatic hypertensive patients using conventional techniques, more
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accurate assessment through speckle-tracking echocardiography and carotid echo-
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tracking during exercise can unmask multiple maladaptive changes to exertion in these
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patients, accounting for reduced exercise tolerance. In this respect, impaired “longitudinal” ventricular deformation and atrial reserve coupled with increased arterial
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stiffness may explain the observed cardiovascular maladaptation during exercise in these
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patients.
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Conflict of interest
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The authors declare no conflicts of interest.
Acknowledgments
The authors gratefully acknowledge Jennifer Pfaff and Susan Nord of Aurora Cardiovascular Services for editorial preparation of the manuscript and Brian Miller and Brian Schurrer of Aurora Research Institute for help with the figures.
17
ACCEPTED MANUSCRIPT References 1.Nonogi H, Hess OM, Ritter M, Krayenbuehl HP. Diastolic properties of the normal left
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2. Higginbotham MB, Morris KG, Williams RS, McHale PA, Coleman RE, Cobb FR.
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Regulation of stroke volume during submaximal and maximal upright exercise in normal man. Circ. Res.58(1986)281-291.
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3.Kitzman DW, Higginbotham MB, Cobb FR, Sheikh KH, Sullivan MJ. Exercise
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4. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise
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hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction.
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Circ. Heart Fail. 3(2010)588-595.
5. Hensel KO, Jenke A, Leischik R. Speckle-tracking and tissue-Doppler stress echocardiography in arterial hypertension: a sensitive tool for detection of subclinical LV impairment. Biomed. Res. Int. 2014 (2014) 472562. 6.Mondillo S, Galderisi M, Mele D, et al. Speckle-tracking echocardiography: a new technique for assessing myocardial function. J. Ultrasound Med. 30(2011)71-83. 7. Cusmà Piccione M, Piraino B, Zito C, et al. Early identification of cardiovascular involvement in patients with β-thalassemia major. Am. J.Cardiol.112(2013)1246-1251. 8. Cusmà Piccione M, Zito C, Bagnato G, et al. Role of 2D strain in the early identification of left ventricular dysfunction and in the risk stratification of systemic sclerosis patients. Cardiovasc. Ultrasound.11 (2013) 6. 18
ACCEPTED MANUSCRIPT 9. Todaro MC, Carerj S, Khandheria B, et al. Usefulness of atrial function for risk stratification in asymptomatic aortic stenosis. J Cardiol 67 (2016) 71-79.
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10. Hensel KO, Jenke A, Leischik R. Speckle-tracking and tissue-Doppler stress
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11. Mohammed M, Zito C, Cusmà-Piccione M, et al. Arterial stiffness changes inpatients
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D
mediated dilation to global arterial load: impact of hypertension and additional
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cardiovascular risk factors. Int. J. Cardiol. 152(2011)225-230.
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13. Lang RM, Bierig M, Devereux RB, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography‟s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J. Am. Soc. Echocardiogr. 18 (2005)1440-1463. 14.Longobardo L, Todaro MC, Zito C, et al. Role of imaging in assessment of atrial fibrosis in patients with atrial fibrillation: state-of-the-art review. Eur. Heart J.Cardiovasc. Imaging15(2014)1-5. 15. Di Bella G, Minutoli F, Madaffari A, et al. Left atrial function in cardiac amyloidosis. J. Cardiovasc. Med. (Hagerstown).17(2016)113-121.
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ACCEPTED MANUSCRIPT 16. Stein JH, Korcarz CE, Hurst RT, et al. Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus
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statement from the American Society of Echocardiography Carotid Intima-Media
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Echocardiogr. 21(2008)93-111; quiz 189-190. Erratum in: J. Am. Soc. Echocardiogr. 21(2008)376.
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17.Antonini-Canterin F, Carerj S, Di Bello V, et al. Arterial stiffness and ventricular
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stiffness: a couple of diseases or a coupling disease? A review from the cardiologist‟s point of view. Eur. J. Echocardiogr. 10(2009)36-43.
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18. Harada A, Okada T, Niki K, et al. On-line noninvasive one-point measurements of
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pulse wave velocity. Heart Vessels 17 (2002) 61-68.
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19. Shin SM, Shim WJ, Park SM. Early changes of left ventricular function in young adults with never-treated hypertension and no left ventricular hypertrophy: relationships to ambulatory blood pressure monitoring. Clin. Exp.Hypertens.36(2014)517-523. 20.Imbalzano E, Zito C, Carerj S, et al. Left ventricular function in hypertension: new insight by speckle tracking echocardiography. Echocardiography28(2011)649-657. 21.Ballo P, Nistri S, Cameli M, et al. Association of left ventricular longitudinal and circumferential systolic dysfunction with diastolic function in hypertension: a non linear analysis focused on the interplay with left ventricular geometry. J. Card. Fail.20(2014)110-120.
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ACCEPTED MANUSCRIPT 22.Celic V, Tadic M, Suzic-Lazic J, et al. Two- and three-dimensional speckle tracking analysis of the relation between myocardial deformation and functional capacity in
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patients with systemic hypertension. Am. J. Cardiol. 113(2014)832-839.
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23. Phan TT, Abozguia K, Shivu GN, et al. Myocardial contractile inefficiency and
J. Am. Soc. Echocardiogr. 23(2010)201-206.
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dyssynchrony in heart failure with preserved ejection fraction and narrow QRS complex.
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24. Santos AB, Kraigher-Krainer E, Gupta DK, et al. Impaired left atrial function in heart
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failure with preserved ejection fraction. Eur. J. Heart Fail. 16 (2014) 1096-1103. 25.Kusunose K, Motoki H, Popovic ZB, Thomas JD, Klein AL, Marwick TH.
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Independent association of left atrial function with exercise capacity inpatients with
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preserved ejection fraction. Heart 98 (2012)1311-1317.
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26. Liu Y, Wang K, Su D, et al. Noninvasive assessment of left atrial phasic function in patients with hypertension and diabetes using two-dimensional speckle tracking and volumetric parameters. Echocardiography31(2014)727-735. 27. Miyoshi H, Oishi Y, Mizuguchi Y, et al. Association of left atrial reservoir function with left atrial structural remodeling related to left ventricular dysfunction in asymptomatic patients with hypertension: evaluation by two-dimensional speckletracking echocardiography. Clin. Exp. Hypertens. 37(2015)155-165. 28.Sahlén A, Abdula G, Norman M, et al. Arterial vasodilatory and ventricular diastolic reserves determine the stroke volume response to exercise in elderly female hypertensive patients. Am. J. Physiol. Heart Circ. Physiol. 301(2011)H2433-41.
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ACCEPTED MANUSCRIPT 29. Lam CS, Shah AM, Borlaug BA, et al. Effect of antihypertensive therapy on
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ventricular-arterial mechanics, coupling, and efficiency. Eur. Heart J. 34(2013)676-683.
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ACCEPTED MANUSCRIPT FIGURE LEGENDS Fig. 1. Bland-Altman graphs showing intra-observer (panels A, B, and C) and inter-observer
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(panels D, E, and F) variability in the measurement of left ventricular global longitudinal strain
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(LV GLS) (panels A and D), LV twist (panels B and E) and LV untwist (panels C and F).
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Fig. 2. Bland-Altman graphs showing intra-observer (panels A, B, and C) and inter-observer (panels D, E, and F) variability in the measurement of left atrial (LA) reservoir (panels A and D),
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beta index (panels B and E) and pulse wave velocity (PWV) (panels C and F). Fig.3.Box and whisker graphs showing left ventricular (LV) global longitudinal strain (upper left
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panel), E/E‟ (upper right panel), LV twist (lower left panel), and LV untwist (lower right panel) in patients (green lines) and controls (blue lines) at rest, peak exercise, and recovery. Significant
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D
p-values are reported as: black type – values between groups at each step, green type – values between rest and peak exercise in hypertensive patients and blue type – values between rest and
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peak exercise in healthy subjects.
Fig. 4. Examples of left ventricular global longitudinal strain (GLS), obtained from GE Automated Function Imaging, in a healthy subject (panels A and B) and a hypertensive patient (panels C and D), at rest (panels A and C) and peak exercise (panels B and D). Fig.5.Box and whisker graphs showing left atrial reservoir (upper left panel), left atrial stiffness (upper right panel), beta index (lower left panel), and pulse wave velocity (lower right panel) in patients (green lines) and controls (blue lines) at rest, peak exercise, and recovery. Significant pvalues are reported as: black type – values between groups at each step, green type – values between rest and peak exercise in hypertensive patients and blue type – values between rest and peak exercise in healthy subjects.
23
ACCEPTED MANUSCRIPT Fig.6.Examples of left atrial reservoir evaluated as positive peak average of myocardial deformation at end-systole, in a healthy subject (panels A and B) and a hypertensive patient
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TE
D
MA
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SC
RI
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(panels C and D), at rest (panels A and C) and peak exercise (panels B and D).
24
ACCEPTED MANUSCRIPT
Controls
(n=30)
(n=24)
Age, years
45.1±11.9
44.4±9.6
Men
19(63%)
Systolic blood pressure, mmHg
142±19
119±15
0.005
Diastolic blood pressure, mmHg
88±8
73±9
<0.001
Maximal workload, watts
90.3±16.2
113.6±17.4
0.023
Angiotensin converting enzyme
14(46%)
-
-
7(23%)
-
-
9(30%)
-
-
Interventricular septum thickness, mm
10.1±1.1
8.27±0.76
<0.001
Posterior wall thickness,mm
8.54±1.09
7.09±1.01
<0.001
End-diastolic diameter, mm
46.5±3.9
50.1±4.6
0.001
End-systolic diameter, mm
29.8±6.5
32.3±4.1
0.101
Relative wall thickness
0.36 ± 0.06
0.28±0.03
0.308
Left ventricular mass, g/m2
71.1±11.7
69.5±12.8
0.488
End-diastolic volume, mL
94.5±19.3
95.1±16.9
0.942
End-systolic volume, mL
34.1±7.7
33.6±11.1
0.892
Ejection fraction, %
64.1±4.7
63.1±4.8
0.409
E/A
1.2±0.41
1.8±0.58
0.001
Mitral deceleration time, msec
186.3 ± 9.4
166.4 ± 8.9
0.048
14(58%)
0.059
RI
0.647
SC
MA
p value
PT
Patients
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Table 1Clinical and standard echocardiographic features at rest.
inhibitors/angiotensin receptor blockers
TE
D
Ca2+-blockers
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Beta-blockers
25
ACCEPTED MANUSCRIPT Left atrial volume, mL/m2
26.3±7.3
24.7±6.3
0.549
Carotid intima-media thickness
0.9 ± 0.2
0.8 ± 0.1
0.786
PT
Values reported as mean ± standard deviation, or number, percentage. Bold denotes statistical
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TE
D
MA
NU
SC
RI
significance.
26
ACCEPTED MANUSCRIPT Table 2TissueDoppler imaging, speckle-tracking echocardiography and echo-tracking parameters at rest. Controls
(n=30)
(n=24)
9.3±2.1
E/E‟
9.3±2.6
Global longitudinal strain,%
-17.5±8.5
Left ventricular twist, º Left ventricular untwist, º/s
0.035
-19.6±3.1
0.253
13.8±6.1
12.5±4.7
0.674
-69±30
-51±12
0.135
37.1±8.4
40.1±4.4
0.640
-12.8±1.5
-10.6±2.7
0.074
0.26±0.08
0.19±0.08
0.023
6.1±2.1
4.8±1.9
0.046
5.7±1.1
4.7±0.8
0.001
SC
7.5±1.4
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TE
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Pulse wave velocity, m/s
0.127
D
Left atrial booster, %
Beta index
9.8±1.7
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Left atrial reservoir, %
Left atrial stiffness
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Septal S‟, cm/s
p value
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Patients
Values reported as mean± standard deviation. Bold denotes statistical significance.
27
ACCEPTED MANUSCRIPT Table 3Step-by-step clinical, echocardiographic and vascular parameters.
Peak
Recovery
142±19
181±21*
146±30†
88 ± 8
99 ± 17*
85 ± 13†
105.9 ± 9.4
126.9 ± 6.6*
106.1 ± 18.3†
<0.001*; <0.001†
Heart rate, bpm
74.2 ± 7.8
131.1±12.3*
82.5 ± 6.9†
<0.001*; <0.001†
Stroke volume, ml
94.7± 21.3
117± 32*
93.1± 23.5†
<0.001*; <0.001†
Systemic vascular
1211±40.1
677.2±23.7*
1114.8±32.5†
<0.001*; <0.001†
9.3 ± 2.6
12.1 ± 5.1*
8.6 ± 2.1
0.014*
-17.5 ± 8.5
-17.3 ± 9.5
-18.3 ± 9.6†
0.036†
Left ventricular twist, º
13.8 ± 6.1
12.9 ± 3.2
13.6 ± 4.7
ns
Left ventricular
-69 ± 30
-107 ± 34*
-88 ± 32†
0.031*; 0.038†
Left atrial reservoir, %
37.1 ± 8.4
39.6 ± 6.7
38.9 ± 9.1
ns
Left atrial booster, %
-12.8±1.5
-8.8±1.6*
-12±2.1†
*0.043; †0.008
Left atrial stiffness
0.26 ± 0.08
0.29 ± 0.13
0.23 ± 0.09
ns
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Systolic blood pressure,
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Rest
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Patients (n = 30)
Diastolic blood
Mean arterial pressure,
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resistance,
D
mmHg
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pressure, mmHg
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mmHg
p value <0.001*; <0.001†
0.005*; 0.001†
dyne*s/cm5 E/E‟
Global longitudinal strain, %
untwist, º/s
28
ACCEPTED MANUSCRIPT Beta
6.1±2.1
6.2±2.2
6.8±2.2
ns
Pulse wave velocity,
5.7±1.1
6.3±0.9*
5.8±1.1†
0.003*;0.013†
PT
m/s
Rest
Peak
Recovery
p value
119 ± 15
159 ± 18*
117 ± 13†
0.001*; <0.001†
73 ± 9
82 ± 7
Diastolic blood
Mean arterial pressure,
90.5±8.2
0.007†
88.7±4.8†
<0.001*; <0.001†
125.7± 11.9*
79.2 ± 7.5†
<0.001*; <0.001†
128.8±20.2*
94.4±14.8†
<0.001*; <0.001†
108.1±8.8*
TE
D
mmHg
70 ± 8†
MA
pressure, mmHg
NU
mmHg
SC
Systolic blood pressure,
RI
Controls (n = 24)
71.2 ± 8.6
Stroke volume, ml
95.8±13.4
Systemic vascular
1063±17.6
537.1±8.8*
948.7±19.2†
<0.001*; <0.001†
E/E‟
7.5 ± 1.4
8.8 ± 1.7*
7.2 ± 1.4†
0.003*; 0.041†
Global longitudinal
-19.6 ± 3.1
-21.5 ± 2.4*
-19.9 ± 2.9†
0.011*; <0.001†
Left ventricular twist, º
12.5 ± 4.7
15.6 ± 7.8
13.9 ± 5.6
ns
Left ventricular
-51 ± 12
-135 ± 17*
-90 ± 19†
0.015*; 0.029†
40.1 ± 4.4
53.4 ± 9.1*
45.9 ± 11.1
0.001*
resistance,
AC CE P
Heart rate, bpm
dyne*s/cm5
strain, %
untwist, º/s Left atrial reservoir, %
29
ACCEPTED MANUSCRIPT
-10.6±2.7
-8.9±2.0
-10.5±3.2
ns
Left atrial stiffness
0.19 ± 0.08
0.17 ± 0.04
0.16 ± 0.05
ns
Beta
4.8 ± 1.9
6.3 ± 1.2*
5.1 ± 1.5†
Pulse wave velocity,
4.7 ± 0.8
5.6 ± 0.4
4.6 ± 0.7
RI
ns
vs peak
AC CE P
TE
D
MA
Values are reported as mean ± standard deviation.
NU
* vs rest †
<0.001*; 0.001†
SC
m/s
PT
Left atrial booster, %
30
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
AC CE P
TE
D
Fig. 1
31
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
AC CE P
TE
D
Fig. 2
32
Fig. 3
AC CE P
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
33
Fig. 4
AC CE P
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
34
Fig. 5
AC CE P
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
35
Fig. 6
AC CE P
TE
D
MA
NU
SC
RI
PT
ACCEPTED MANUSCRIPT
36