Abstract
Background: Excess transmission of pressure pulsatility caused by increased arterial stiffness may incur microcirculatory damage in end organs (target organ damage [TOD]) and, in turn, elevate risk for cardiovascular disease (CVD) events. Methods and Results: We related arterial stiffness measures (carotid-femoral pulse wave velocity, mean arterial pressure, central pulse pressure) to the prevalence and incidence of TOD (defined as albuminuria and/or echocardiographic left ventricular hypertrophy) in up to 6203 Framingham Study participants (mean age 50±15 years, 54% women). We then related presence of TOD to incident CVD in multivariable Cox regression models without and with adjustment for arterial stiffness measures. Cross-sectionally, greater arterial stiffness was associated with a higher prevalence of TOD (adjusted odds ratios ranging from 1.23 to 1.54 per SD increment in arterial stiffness measure, P<0.01). Prospectively, increased carotid-femoral pulse wave velocity was associated with incident albuminuria (odds ratio per SD 1.28, 95% CI, 1.02–1.61; P<0.05), whereas higher mean arterial pressure and central pulse pressure were associated with incident left ventricular hypertrophy (odds ratio per SD 1.37 and 1.45, respectively; P<0.01). On follow-up, 297 of 5803 participants experienced a first CVD event. Presence of TOD was associated with a 33% greater hazard of incident CVD (95% CI, 0–77%; P<0.05), which was attenuated upon adjustment for baseline arterial stiffness measures by 5–21%. Conclusions: Elevated arterial stiffness is associated with presence of TOD and may partially mediate the relations of TOD with incident CVD. Our observations in a large community-based sample suggest that mitigating arterial stiffness may lower the burden of TOD and, in turn, clinical CVD.
| Original language | English (US) |
|---|---|
| Article number | e012141 |
| Journal | Journal of the American Heart Association |
| Volume | 8 |
| Issue number | 14 |
| DOIs | |
| State | Published - 2019 |
Keywords
- arterial stiffness
- cardiovascular disease
- epidemiology
- pulse wave velocity
- target organ damage
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Interrelations Between Arterial Stiffness, Target Organ Damage, and Cardiovascular Disease Outcomes'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
Interrelations Between Arterial Stiffness, Target Organ Damage, and Cardiovascular Disease Outcomes. / Vasan, Ramachandran S.; Short, Meghan I.; Niiranen, Teemu J.; Xanthakis, Vanessa; DeCarli, Charles; Cheng, Susan; Seshadri, Sudha; Mitchell, Gary F.
In: Journal of the American Heart Association, Vol. 8, No. 14, e012141, 2019.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Interrelations Between Arterial Stiffness, Target Organ Damage, and Cardiovascular Disease Outcomes
AU - Vasan, Ramachandran S.
AU - Short, Meghan I.
AU - Niiranen, Teemu J.
AU - Xanthakis, Vanessa
AU - DeCarli, Charles
AU - Cheng, Susan
AU - Seshadri, Sudha
AU - Mitchell, Gary F.
N1 - Funding Information: This work was supported by the National Heart, Lung, and?Blood Institute's FHS (National Institutes of Health [NIH] contracts N01-HC-25195, HHSN268201500001I and 75N92019D00031) and NIH grants HL080124, HL071039, HL077447, HL107385, 1R01HL126136, 5R01HL107385, 1R01HL60040, 1RO1HL70100, R01HL131532, and R01HL134168. Dr Vasan is supported in part by the Evans Medical Foundation and the Jay and Louis Coffman Endowment from the Department of Medicine, Boston University School of Medicine. The design and selection criteria of FHS (Framingham Heart Study) cohorts have been previously described. Beginning in 1948, approximately two thirds of the households in Framingham, MA, were enrolled in the Original Cohort (n=5209). Their offspring (and their spouses) and the children of the offspring were enrolled in the Offspring Cohort and the Generation 3 Cohort in 1971 and 2002, respectively, as detailed elsewhere. In addition, 2 Omni cohorts (combined n=916) were recruited in 1994 and 2003 to reflect the increasingly diverse population of Framingham. These cohorts specifically targeted residents of Hispanic, Asian, Indian, African American, Pacific Islander, and Native American descent. The study protocol was approved by the institutional review board at the Boston Medical Center and all participants provided written informed consent. All data and materials have been made publicly available at the National Heart, Lung, and Blood Institute's data repository BioLINCC.24,25. For the current investigation (Figure), we considered 7927 FHS participants who took part in Offspring Cohort examination 8 (2005?2008), Third Generation Cohort examination 1 (2002?2005), First Omni Cohort examination 3 (2007?2008), Second Omni Cohort examination 1 (2003?2005), or New Offspring Spouse examination 1 (2003?2005). These examinations are referred to as the baseline for the present analyses. Overall, 6203 individuals had data available for covariates, central hemodynamics, LVH, and albuminuria, and were included in analyses relating central hemodynamics with albuminuria and LVH (Figure). Of these participants, 3144 underwent brain magnetic resonance imaging (MRI) and were included in analyses relating hemodynamic measures with all types of organ damage (Figure). In total, 5803 individuals without history of CVD had no missing data for covariates, albuminuria, LVH, or central hemodynamics and were included in analyses on the association of albuminuria and LVH with incident cardiovascular outcomes (Figure). A subsample of 4215 individuals free of albuminuria (Offspring and Third Generation Cohort participants) and 1111 free of echocardiographic LVH (Offspring Cohort) attended the subsequent examination at which incidence of albuminuria and echocardiographic LVH was reassessed. The design and selection criteria of FHS (Framingham Heart Study) cohorts have been previously described. Beginning in 1948, approximately two thirds of the households in Framingham, MA, were enrolled in the Original Cohort (n=5209). Their offspring (and their spouses) and the children of the offspring were enrolled in the Offspring Cohort and the Generation 3 Cohort in 1971 and 2002, respectively, as detailed elsewhere. In addition, 2 Omni cohorts (combined n=916) were recruited in 1994 and 2003 to reflect the increasingly diverse population of Framingham. These cohorts specifically targeted residents of Hispanic, Asian, Indian, African American, Pacific Islander, and Native American descent. The study protocol was approved by the institutional review board at the Boston Medical Center and all participants provided written informed consent. All data and materials have been made publicly available at the National Heart, Lung, and Blood Institute's data repository BioLINCC.24,25. For the current investigation (Figure), we considered 7927 FHS participants who took part in Offspring Cohort examination 8 (2005?2008), Third Generation Cohort examination 1 (2002?2005), First Omni Cohort examination 3 (2007?2008), Second Omni Cohort examination 1 (2003?2005), or New Offspring Spouse examination 1 (2003?2005). These examinations are referred to as the baseline for the present analyses. Overall, 6203 individuals had data available for covariates, central hemodynamics, LVH, and albuminuria, and were included in analyses relating central hemodynamics with albuminuria and LVH (Figure). Of these participants, 3144 underwent brain magnetic resonance imaging (MRI) and were included in analyses relating hemodynamic measures with all types of organ damage (Figure). In total, 5803 individuals without history of CVD had no missing data for covariates, albuminuria, LVH, or central hemodynamics and were included in analyses on the association of albuminuria and LVH with incident cardiovascular outcomes (Figure). A subsample of 4215 individuals free of albuminuria (Offspring and Third Generation Cohort participants) and 1111 free of echocardiographic LVH (Offspring Cohort) attended the subsequent examination at which incidence of albuminuria and echocardiographic LVH was reassessed. Supine brachial systolic and diastolic BPs were obtained using an auscultatory device. Vascular stiffness was assessed using arterial applanation tonometry as previously described. Briefly, arterial tonometry with simultaneous ECG recordings was performed on the brachial, femoral, and carotid arteries on the right side of the body of participants. Transit distances for arterial pulse waves were assessed by body surface measurements from the suprasternal notch to the pulse-recording sites. MAP was derived from integration of the brachial waveform, which was calibrated by using systolic and diastolic auscultatory BP at the time of tonometry. Diastolic BP and integrated MAP were used to calibrate carotid pressure tracings from which central aortic pressure was calculated. Details of signal analyses and data processing have been published. In our experience at FHS, MAP derived from applanation tonometry of the brachial artery is very highly correlated with that derived from a similarly calibrated and integrated signal-averaged oscillometric brachial pressure waveform (r exceeds 0.96). For the present investigation, we assessed 3 primary measures of arterial stiffness and central hemodynamics: (1) CFPWV, the current reference standard for aortic stiffness; (2) central PP (CPP), ie, the BP amplitude in the proximal aorta; and (3) central MAP, reflecting steady state pressure in the large arteries. Transthoracic echocardiography with Doppler color flow imaging was performed at the index FHS examinations using a standardized protocol. All echocardiograms were evaluated by an experienced sonographer or cardiologist and measured using a standardized reading protocol. Cardiac dimensions were quantified using digital images and the leading-edge technique as recommended by the American Society of Echocardiography. LV mass was calculated according to American Society of Echocardiography guidelines. We defined LVH as LV mass index >95?g/m and >115?g/m for women and men, respectively. A subsequent measure of LV mass (obtained using the same imaging and measurement protocol) was available in the Offspring Cohort at their ninth examination cycle (2011?2014). Urinary albumin-creatinine ratio (UACR) was measured from spot morning urine samples obtained from participants during their FHS examinations. UACR is a reliable measure of urinary albumin excretion, and is highly correlated with albumin excretion rates obtained from 24-hour collection. Urinary albumin concentration was measured using an immunoturbidimetry assay. Urinary creatinine was assessed using a modified Jaff? method. Albuminuria was defined using the sex-specific cut points of UACR ?17?mg/g (men) or ?25?mg/g (women). Follow-up measurements of UACR were available at the subsequent examination in a majority of the participants (see Figure). Brain MRI was performed on a subset of FHS participants using methods that have been previously described. The MRI markers of TOD were covert brain infarcts (CBIs) (ie, in the absence of a clinical stroke event or transient ischemic attack), and large white matter hyperintensities (WMHs). MRI acquisition, measurement techniques, and interrater reliability have been previously described. Operators blinded to participants? demographic, clinical, and biomarker data rated the images of interest. We determined the volume of WMH according to previously published methods, and defined extensive WMH where the natural log of the ratio of WMH volume to total cranial volume was >1 SD above the age-adjusted mean value for this cohort. We manually characterized CBIs based on their size, location, and imaging characteristics, as previously described. All FHS participants are under continuous surveillance for the incidence of CVD events and death. We obtained medical records for all hospitalizations and physician visits related to new-onset CVD during follow-up, which were reviewed by an adjudication panel consisting of 3 physician investigators using standardized criteria. For the present investigation, CVD was comprised of a composite of cardiovascular death, fatal or nonfatal myocardial infarction, stroke, angina pectoris, unstable angina (prolonged ischemic episode with documented reversible ST-segment changes), transient ischemic attack, heart failure, and intermittent claudication. Criteria for these CVD events have been previously described. The 5 different study samples (Figure) contributed to different sets of analyses. We used the largest sample (sample 1, N=6203) for cross-sectional analyses relating each of the 3 arterial stiffness/hemodynamic measures (separate analyses for each measure) to the presence of TOD (echocardiographic LVH and albuminuria, modeled individually and conjointly) (Figure; a). A smaller sample (sample 2, N=3144) was used for relating arterial stiffness measures to?prevalence of TOD as evidenced by brain MRI (CBI and WMH, modeled individually and conjointly with echocardiographic LVH and albuminuria). We used multivariable logistic regression to evaluate the cross-sectional associations, with CFPWV, CPP, and MAP as the independent variables and TOD (albuminuria, LVH, CBI, and WMH) as the dependent variables, and fitting separate models for each combination of arterial stiffness measure and TOD. We also fit a model with presence versus absence of any TOD as the binary dependent variable. Regression models adjusted for age, sex, body mass index, diabetes mellitus, antihypertensive treatment, smoking, prevalent CVD, total cholesterol/high-density lipoprotein cholesterol ratio, triglycerides, lipid-lowering medications, heart rate, and estimated glomerular filtration rate. Given the correlation among the 3 arterial stiffness variables (see Results section below), they were not mutually adjusted for one another in the regression models in primary analyses. In secondary analyses, we modeled LV mass and UACR as continuous variables using linear regression models adjusting for the covariates noted above. For all analyses, CFPWV was transformed by taking the inverse to reduce skewness of the distribution of the data, and multiplied by ?1000 to retain the directionality of the variable, in which larger values are associated with worse outcomes. In prospective analyses, we related each arterial stiffness measure individually to the incidence of TOD on follow-up among individuals free of TOD at baseline using multivariable logistic regression models. Separate analyses were performed for incident albuminuria (sample 3, N=4215 participants free of baseline albuminuria who attended the next follow-up examination) and incident echocardiographic LVH (sample 4, N=1111 individuals free of LVH at baseline who had repeated echocardiographic examination at the next follow-up examination). Models were adjusted for the covariates listed above. In additional prospective analyses, we related the presence of TOD at the baseline examination to the incidence of CVD in 5803 individuals without prevalent CVD (sample 5, N=5803) using Cox regression models after confirming that the assumption of proportionality of hazards was met. The models were adjusted for the aforementioned covariates besides prevalent CVD. In addition, to describe how associations between TOD and incident CVD may be mediated by arterial stiffness measures, we evaluated associations of TOD with CVD after adjusting for CFPWV, CPP, and MAP (in separate models) to assess the extent of attenuation of associations (Figure; b/b?). Since the relations of TOD and arterial stiffness may be bidirectional, we performed additional analyses in which we related the 3 arterial stiffness measures individually to CVD incidence (sample 5, N=5803) using multivariable-adjusted Cox regression models. We evaluated these relations with and without adjusting for presence versus absence of TOD (Figure; c/c?). We considered a 2-sided P<0.05 statistically significant across all analyses. The variance in all models was adjusted for familial structure, using generalized estimating equations for linear and logistic models, and the robust sandwich estimator for Cox proportional hazards models. We performed statistical analyses using SAS software version 9.4 (SAS Institute, Inc). Dr Vasan had access to all of the study data and takes responsibility for its integrity and that of the data analyses. Publisher Copyright: © 2019 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2019
Y1 - 2019
N2 - Background: Excess transmission of pressure pulsatility caused by increased arterial stiffness may incur microcirculatory damage in end organs (target organ damage [TOD]) and, in turn, elevate risk for cardiovascular disease (CVD) events. Methods and Results: We related arterial stiffness measures (carotid-femoral pulse wave velocity, mean arterial pressure, central pulse pressure) to the prevalence and incidence of TOD (defined as albuminuria and/or echocardiographic left ventricular hypertrophy) in up to 6203 Framingham Study participants (mean age 50±15 years, 54% women). We then related presence of TOD to incident CVD in multivariable Cox regression models without and with adjustment for arterial stiffness measures. Cross-sectionally, greater arterial stiffness was associated with a higher prevalence of TOD (adjusted odds ratios ranging from 1.23 to 1.54 per SD increment in arterial stiffness measure, P<0.01). Prospectively, increased carotid-femoral pulse wave velocity was associated with incident albuminuria (odds ratio per SD 1.28, 95% CI, 1.02–1.61; P<0.05), whereas higher mean arterial pressure and central pulse pressure were associated with incident left ventricular hypertrophy (odds ratio per SD 1.37 and 1.45, respectively; P<0.01). On follow-up, 297 of 5803 participants experienced a first CVD event. Presence of TOD was associated with a 33% greater hazard of incident CVD (95% CI, 0–77%; P<0.05), which was attenuated upon adjustment for baseline arterial stiffness measures by 5–21%. Conclusions: Elevated arterial stiffness is associated with presence of TOD and may partially mediate the relations of TOD with incident CVD. Our observations in a large community-based sample suggest that mitigating arterial stiffness may lower the burden of TOD and, in turn, clinical CVD.
AB - Background: Excess transmission of pressure pulsatility caused by increased arterial stiffness may incur microcirculatory damage in end organs (target organ damage [TOD]) and, in turn, elevate risk for cardiovascular disease (CVD) events. Methods and Results: We related arterial stiffness measures (carotid-femoral pulse wave velocity, mean arterial pressure, central pulse pressure) to the prevalence and incidence of TOD (defined as albuminuria and/or echocardiographic left ventricular hypertrophy) in up to 6203 Framingham Study participants (mean age 50±15 years, 54% women). We then related presence of TOD to incident CVD in multivariable Cox regression models without and with adjustment for arterial stiffness measures. Cross-sectionally, greater arterial stiffness was associated with a higher prevalence of TOD (adjusted odds ratios ranging from 1.23 to 1.54 per SD increment in arterial stiffness measure, P<0.01). Prospectively, increased carotid-femoral pulse wave velocity was associated with incident albuminuria (odds ratio per SD 1.28, 95% CI, 1.02–1.61; P<0.05), whereas higher mean arterial pressure and central pulse pressure were associated with incident left ventricular hypertrophy (odds ratio per SD 1.37 and 1.45, respectively; P<0.01). On follow-up, 297 of 5803 participants experienced a first CVD event. Presence of TOD was associated with a 33% greater hazard of incident CVD (95% CI, 0–77%; P<0.05), which was attenuated upon adjustment for baseline arterial stiffness measures by 5–21%. Conclusions: Elevated arterial stiffness is associated with presence of TOD and may partially mediate the relations of TOD with incident CVD. Our observations in a large community-based sample suggest that mitigating arterial stiffness may lower the burden of TOD and, in turn, clinical CVD.
KW - arterial stiffness
KW - cardiovascular disease
KW - epidemiology
KW - pulse wave velocity
KW - target organ damage
UR - http://www.scopus.com/inward/record.url?scp=85069807357&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85069807357&partnerID=8YFLogxK
U2 - 10.1161/JAHA.119.012141
DO - 10.1161/JAHA.119.012141
M3 - Article
C2 - 31303106
AN - SCOPUS:85069807357
VL - 8
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
SN - 2047-9980
IS - 14
M1 - e012141
ER -