Pulsatile interaction between the macro-vasculature and micro-vasculature: proof-of-concept among patients with type 2 diabetes.

PURPOSE: It is widely thought that excess pulsatile pressure from increased stiffness of large central arteries (macro-vasculature) is transmitted to capillary networks (micro-vasculature) and causes target organ damage. However, this hypothesis has never been tested. We sought to examine the association between macro- and micro-vasculature waveform features in patients with type 2 diabetes (i.e., those with elevated stiffness; T2D) compared with non-diabetic controls. METHODS: Among 13 T2D (68 ± 6 years, 39% male) and 15 controls (58 ± 11 years, 40% male) macro-vascular stiffness was determined via aortic pulse wave velocity (aPWV) and macro-vascular waveforms were measured using radial tonometry. Forearm micro-vascular waveforms were measured simultaneously with macro-vascular waveforms via low power laser Doppler fluxmetry. Augmentation index (AIx) was derived on macro- and micro-vascular waveforms. Target organ damage was assessed by estimated glomerular filtration rate (eGFR) and central retinal artery equivalent (CRAE). RESULTS: aPWV was higher among T2D (9.3 ± 2.5 vs 7.5 ± 1.4 m/s, p = 0.046). There was an obvious pulsatile micro-vascular waveform with qualitative features similar to macro-vasculature pressure waveforms. In all subjects, macro- and micro-vasculature AIx were significantly related (r = 0.43, p = 0.005). In T2D alone, micro-vasculature AIx was associated with eGFR (r = - 0.63, p = 0.037), whereas in controls, macro-vasculature AIx and AP were associated with CRAE (r = - 0.58, p = 0.025 and r = - 0.61, p = 0.015). CONCLUSIONS: Macro- and micro-vasculature waveform features are related; however, micro-vasculature features are more closely related to markers of target organ damage in T2D. These findings are suggestive of a possible interaction between the macro- and micro-circulation.

Association of Change in Cardiovascular Risk Factors With Incident Cardiovascular Events.

Importance: There is consistent evidence of the association between ideal cardiovascular health and lower incident cardiovascular disease (CVD); however, most studies used a single measure of cardiovascular health. Objective: To examine how cardiovascular health changes over time and whether these changes are associated with incident CVD. Design, Setting, and Participants: Prospective cohort study in a UK general community (Whitehall II), with examinations of cardiovascular health from 1985/1988 (baseline) and every 5 years thereafter until 2015/2016 and follow-up for incident CVD until March 2017. Exposures: Using the 7 metrics of the American Heart Association (nonsmoking; and ideal levels of body mass index, physical activity, diet, blood pressure, fasting blood glucose, and total cholesterol), participants with 0 to 2, 3 to 4, and 5 to 7 ideal metrics were categorized as having low, moderate, and high cardiovascular health. Change in cardiovascular health over 10 years between 1985/1988 and 1997/1999 was considered. Main Outcome and Measure: Incident CVD (coronary heart disease and stroke). Results: The study population included 9256 participants without prior CVD (mean [SD] age at baseline, 44.8 [6.0] years; 2941 [32%] women), of whom 6326 had data about cardiovascular health change. Over a median follow-up of 18.9 years after 1997/1999, 1114 incident CVD events occurred. In multivariable analysis and compared with individuals with persistently low cardiovascular health (consistently low group, 13.5% of participants; CVD incident rate per 1000 person-years, 9.6 [95% CI, 8.4-10.9]), there was no significant association with CVD risk in the low to moderate group (6.8% of participants; absolute rate difference per 1000 person-years, -1.9 [95% CI, -3.9 to 0.1]; HR, 0.84 [95% CI, 0.66-1.08]), the low to high group, (0.3% of participants; absolute rate difference per 1000 person-years, -7.7 [95% CI, -11.5 to -3.9]; HR, 0.19 [95% CI, 0.03-1.35]), and the moderate to low group (18.0% of participants; absolute rate difference per 1000 person-years, -1.3 [95% CI, -3.0 to 0.3]; HR, 0.96 [95% CI, 0.80-1.15]). A lower CVD risk was observed in the consistently moderate group (38.9% of participants; absolute rate difference per 1000 person-years, -4.2 [95% CI, -5.5 to -2.8]; HR, 0.62 [95% CI, 0.53-0.74]), the moderate to high group (5.8% of participants; absolute rate difference per 1000 person-years, -6.4 [95% CI, -8.0 to -4.7]; HR, 0.39 [95% CI, 0.27-0.56]), the high to low group (1.9% of participants; absolute rate difference per 1000 person-years, -5.3 [95% CI, -7.8 to -2.8]; HR, 0.49 [95% CI, 0.29-0.83]), the high to moderate group (9.3% of participants; absolute rate difference per 1000 person-years, -4.5 [95% CI, -6.2 to -2.9]; HR, 0.66 [95% CI, 0.51-0.85]), and the consistently high group (5.5% of participants; absolute rate difference per 1000 person-years, -5.6 [95% CI, -7.4 to -3.9]; HR, 0.57 [95% CI, 0.40-0.80]). Conclusions and Relevance: Among a group of participants without CVD who received follow-up over a median 18.9 years, there was no consistent relationship between direction of change in category of a composite metric of cardiovascular health and risk of CVD.

Exercise excess pressure and exercise-induced albuminuria in patients with type 2 diabetes mellitus.

Exercise-induced albuminuria is common in patients with type 2 diabetes mellitus (T2DM) in response to maximal exercise, but the response to light-moderate exercise is unclear. Patients with T2DM have abnormal central hemodynamics and greater propensity for exercise hypertension. This study sought to determine the relationship between light-moderate exercise central hemodynamics (including aortic reservoir and excess pressure) and exercise-induced albuminuria. Thirty-nine T2DM (62 ± 9 yr; 49% male) and 39 nondiabetic controls (53 ± 9 yr; 51% male) were examined at rest and during 20 min of light-moderate cycle exercise (30 W; 50 revolutions/min). Albuminuria was assessed by the albumin-creatinine ratio (ACR) at rest and 30 min postexercise. Hemodynamics recorded included brachial and central blood pressure (BP), aortic stiffness, augmented pressure (AP), aortic reservoir pressure, and excess pressure integral (Pexcess). There was no difference in ACR between groups before exercise (P > 0.05). Exercise induced a significant rise in ACR in T2DM but not controls (1.73 ± 1.43 vs. 0.53 ± 1.0 mg/mol, P = 0.002). All central hemodynamic variables were significantly higher during exercise in T2DM (i.e., Pexcess, systolic BP and AP; P < 0.01 all). In T2DM (but not controls), exercise Pexcess was associated with postexercise ACR (r = 0.51, P = 0.002), and this relationship was independent of age, sex, body mass index, heart rate, aortic stiffness, antihypertensive medication, and ambulatory daytime systolic BP (ß = 0.003, P = 0.003). Light-moderate exercise induced a significant rise in ACR in T2DM, and this was independently associated with Pexcess, a potential marker of vascular dysfunction. These novel findings suggest that Pexcess could be important for appropriate renal function in T2DM.

Aortic reservoir characteristics and brain structure in people with type 2 diabetes mellitus; a cross sectional study.

BACKGROUND: Central hemodynamics help to maintain appropriate cerebral and other end-organ perfusion, and may be altered with ageing and type 2 diabetes mellitus (T2DM). We aimed to determine the associations between central hemodynamics and brain structure at rest and during exercise in people with and without T2DM. METHODS: In a sample of people with T2DM and healthy controls, resting and exercise measures of aortic reservoir characteristics (including excess pressure integral [P(excess)]) and other central hemodynamics (including augmentation index [AIx] and aortic pulse wave velocity [aPWV]) were recorded. Brain volumes (including gray matter volume [GMV] and white matter lesions [WML]) were derived from magnetic resonance imaging (MRI) scans. Multivariable linear regression was used to study the associations of hemodynamic variables with brain structure in the two groups adjusting for age, sex, daytime systolic BP (SBP) and heart rate. RESULTS: There were 37 T2DM (63 ± 9 years; 47% male) and 37 healthy individuals (52 ± 8 years; 51% male). In T2DM, resting aPWV was inversely associated with GMV (standardized ß = -0.47, p = 0.036). In healthy participants, resting P(excess) was inversely associated with GMV (ß = -0.23, p = 0.043) and AIx was associated with WML volume (ß = 0.52, p = 0.021). There were no associations between exercise hemodynamics and brain volumes in either group. CONCLUSIONS: Brain atrophy is associated with resting aortic stiffness in T2DM, and resting P(excess) in healthy individuals. Central vascular mechanisms underlying structural brain changes may differ between healthy individuals and T2DM.

Is the number of ideal cardiovascular health metrics in midlife associated with lower risk of cancer? Evidence from 3 European prospective cohorts.

BACKGROUND: Primordial prevention may be a relevant strategy for the prevention of cancer. Given the commonality of risk factors and mechanisms between cancer and cardiovascular disease, we examined the associations between the number of ideal cardiovascular health metrics in midlife and incident cancer. METHODS: In 3 European cohorts (NutriNet-Santé and GAZEL, France; Whitehall II, United Kingdom), the number of ideal cardiovascular health metrics was determined at baseline (range 0-7). Follow-up for cancer events was until October 2020 (NutriNet-Santé), March 2017 (Whitehall II) and December 2015 (GAZEL). Cox regression was conducted in each cohort, and results were thereafter pooled using a random-effects model. RESULTS: Data were available on 39 718 participants. A total of 16 237 were from NutriNet-Santé (mean age 51.3 yr; 28% men), 9418 were from Whitehall II (mean age 44.8 yr; 68% men) and 14 063 were from GAZEL (mean age 45.2 yr; 75% men). The median follow-up was 8.1 years in NutriNet-Santé, 29.6 years in Whitehall II and 24.8 years in GAZEL, and yielded a total of 4889 cancer events. A greater number of ideal cardiovascular health metrics was associated with a lower overall cancer risk in each cohort, with an aggregate hazard ratio (HR) per 1 increment in number of ideal metrics of 0.91 (95% confidence interval [CI] 0.88-0.93). This association remained after removal of the smoking metric (aggregate HR per unit increment in number of ideal metrics: 0.94, 95% CI 0.90-0.97), and site-specific analysis demonstrated a significant association with lung cancer. INTERPRETATION: A greater number of ideal cardiovascular health metrics in midlife was associated with lower cancer risk, notably lung cancer. Primordial prevention of cardiovascular risk factors in midlife may be a complementary strategy to prevent the onset of cancer.

Longitudinal Changes in Excess Pressure Independently Predict Declining Renal Function Among Healthy Individuals-A Pilot Study.

BACKGROUND: Aortic reservoir function independently predicts end-organ damage in cross-sectional analyses. However, longitudinal associations are more important regarding causation, but this has never been examined at rest or in response to light-moderate intensity exercise. The aim of this study was to determine the association between the change in aortic reservoir characteristics, in particular excess pressure integral (Pexcess) at rest and in response to exercise and the change in kidney function among healthy individuals followed over time. METHODS: Aortic reservoir function (Pexcess and reservoir pressure), aortic stiffness, brachial and central blood pressure (BP), and renal function (estimated glomerular filtration rate [eGFR]) were recorded among 33 healthy individuals (57 ± 9 years; 55% male) at baseline and after an average 3.0 ± 0.3 years. RESULTS: Over the follow up period, there was a significant increase in resting brachial BP, central BP, Pexcess, and aortic stiffness (P < 0.05 all). The change over time in resting Pexcess (but not aortic stiffness) was significantly related to the change in eGFR (r = -0.38, P = 0.038) and remained independent of age at follow up, change in 24-hour ambulatory systolic BP and body mass index (ß = -0.0300, P = 0.043). There was no association between the change in aortic pulse wave velocity and the change eGFR (P = 0.46) nor were there any associations with exercising hemodynamics. CONCLUSIONS: Pexcess is independently associated with a decline in renal function among healthy people followed over 3 years. These novel findings indicate the need to determine the underlying physiological determinants of aortic reservoir function.

Aortic-to-brachial stiffness gradient and kidney function in type 2 diabetes.

OBJECTIVES: A reversed aortic-to-brachial stiffness gradient (ab-SG), defined as aortic pulse wave velocity (aPWV) greater than brachial PWV (bPWV), was recently shown to predict mortality independent of aPWV in dialysis patients. Patients with type 2 diabetes mellitus (T2DM) have increased risk of renal damage and exhibit haemodynamic abnormalities at rest and during exercise that may alter the ab-SG. This study aimed to examine ab-SG in patients with T2DM by comparison with nondiabetic controls during rest and exercise, and to determine associations between ab-SG, aPWV, and kidney function. METHODS: Study participants were 60 patients with T2DM and 60 age and sex-matched nondiabetic controls (58 ±â€Š8 years, 55% male both). ab-SG was defined as the quotient of bPWV (carotid-to-radial) and aPWV (carotid-to-femoral) recorded via applanation tonometry. Kidney function was assessed using estimated glomerular filtration rate (eGFR). The exercise substudy was undertaken in 21 patients with T2DM and 21 matched nondiabetic controls during semirecumbent exercise. RESULTS: ab-SG was significantly lower in patients with T2DM (0.99 ±â€Š0.2 vs. 1.2 ±â€Š0.3, P < 0.001) and aPWV, but not bPWV, was significantly higher (P < 0.001 and P = 0.25). A total of 58% of patients with T2DM vs. 27% of nondiabetic controls (χ = 11.0, P < 0.001) had a reversed ab-SG (aPWV ≥ bPWV). ab-SG predicted eGFR independent of age, sex, T2DM status, and cardiovascular risk factors (ß = 13.2, P = 0.024), whereas aPWV did not (ß = -0.88, P = 0.30). Exercise ab-SG was significantly lower in patients with T2DM (0.97 ±â€Š0.2 vs. 1.2 ±â€Š0.2, P < 0.001), but did not predict eGFR. CONCLUSIONS: Patients with T2DM have a reversed ab-SG during rest and exercise. Resting ab-SG predicts kidney function independent of aPWV, implying a reversed ab-SG may have a pathophysiological function.

Brachial-to-radial SBP amplification: implications of age and estimated central blood pressure from radial tonometry.

OBJECTIVES: The reference standard for noninvasive estimation of central blood pressure (BP) is radial tonometry calibrated using brachial SBP and DBP. Brachial-to-radial-SBP amplification (B-R-SBPAmp) may introduce error into central BP estimation, but the magnitude of such amplification is uncertain. This study aimed to determine the magnitude and effect of ageing on B-R-SBPAmp; the effect of B-R-SBPAmp on radial tonometry estimated central SBP; and correlates of B-R-SBPAmp. METHODS: Forty young (28 ±â€Š5 years) and 20 older (60 ±â€Š8 years) healthy participants underwent brachial and radial artery ultrasound to identify SBP from the first Doppler flow inflection during BP cuff deflation (first Korotkoff sound). Impedance cardiography, ultrasound, tonometry and anthropometric data were collected to explore B-R-SBPAmp correlates. RESULTS: Radial SBP was significantly higher than brachial SBP in younger (118 ±â€Š12 versus 110 ±â€Š10  mmHg; P < 0.001) and older (135 ±â€Š12 versus 121 ±â€Š11  mmHg; P < 0.001) participants. The magnitude of B-R-SBPAmp (radial minus brachial SBP) was higher in older than younger participants (14 ±â€Š7 versus 8 ±â€Š7  mmHg; P = 0.002), independent of sex and heart rate. Estimated central SBP was higher in both age groups when radial waveforms were recalibrated using radial (versus brachial) SBP (P < 0.001). The central SBP change relative to B-R-SBPAmp was associated with augmentation index (r = 0.739, P < 0.001), independent of age, sex and heart rate. Age, male sex and high-density lipoprotein each positively related to B-R-SBPAmp in multiple regression analysis (P < 0.05). CONCLUSION: Major B-R-SBPAmp occurs in healthy people and is higher with increasing age. Furthermore, B-R-SBPAmp contributes to underestimation of radial tonometry derived central SBP.

Abdominal Obesity and Brain Atrophy in Type 2 Diabetes Mellitus.

AIM: Type 2 diabetes mellitus (T2D) is associated with gray matter atrophy. Adiposity and physical inactivity are risk factors for T2D and brain atrophy. We studied whether the associations of T2D with total gray matter volume (GMV) and hippocampal volume (HV) are dependent on obesity and physical activity. MATERIALS AND METHODS: In this cross-sectional study, we measured waist-hip ratio (WHR), body mass index (BMI), mean steps/day and brain volumes in a community dwelling cohort of people with and without T2D. Using multivariable linear regression, we examined whether WHR, BMI and physical activity mediated or modified the association between T2D, GMV and HV. RESULTS: There were 258 participants with (mean age 67 ± 7 years) and 302 without (mean age 72 ± 7 years) T2D. Adjusting for age, sex and intracranial volume, T2D was independently associated with lower total GMV (p = 0.001) and HV (p<0.001), greater WHR (p<0.001) and BMI (p<0.001), and lower mean steps/day (p = 0.002). After adjusting for covariates, the inclusion of BMI and mean steps/day did not significantly affect the T2D-GMV association, but WHR attenuated it by 32% while remaining independently associated with lower GMV (p<0.01). The T2D-HV association was minimally changed by the addition of BMI, steps/day or WHR in the model. No statistical interactions were observed between T2D and measures of obesity and physical activity in explaining brain volumes. CONCLUSIONS: Abdominal obesity or its downstream effects may partially mediate the adverse effect of T2D on brain atrophy. This requires confirmation in longitudinal studies.

Validity and reliability of central blood pressure estimated by upper arm oscillometric cuff pressure.

BACKGROUND: Noninvasive central blood pressure (BP) independently predicts mortality, but current methods are operator-dependent, requiring skill to obtain quality recordings. The aims of this study were first, to determine the validity of an automatic, upper arm oscillometric cuff method for estimating central BP (O(CBP)) by comparison with the noninvasive reference standard of radial tonometry (T(CBP)). Second, we determined the intratest and intertest reliability of O(CBP). METHODS: To assess validity, central BP was estimated by O(CBP) (Pulsecor R6.5B monitor) and compared with T(CBP) (SphygmoCor) in 47 participants free from cardiovascular disease (aged 57 ± 9 years) in supine, seated, and standing positions. Brachial mean arterial pressure (MAP) and diastolic BP (DBP) from the O(CBP) device were used to calibrate in both devices. Duplicate measures were recorded in each position on the same day to assess intratest reliability, and participants returned within 10 ± 7 days for repeat measurements to assess intertest reliability. RESULTS: There was a strong intraclass correlation (ICC = 0.987, P < 0.001) and small mean difference (1.2 ± 2.2 mm Hg) for central systolic BP (SBP) determined by O(CBP) compared with T(CBP). Ninety-six percent of all comparisons (n = 495 acceptable recordings) were within 5 mm Hg. With respect to reliability, there were strong correlations but higher limits of agreement for the intratest (ICC = 0.975, P < 0.001, mean difference 0.6 ± 4.5 mm Hg) and intertest (ICC = 0.895, P < 0.001, mean difference 4.3 ± 8.0 mm Hg) comparisons. CONCLUSIONS: Estimation of central SBP using cuff oscillometry is comparable to radial tonometry and has good reproducibility. As a noninvasive, relatively operator-independent method, O(CBP) may be as useful as T(CBP) for estimating central BP in clinical practice.