Chen Chi

Angiotensin System Blockade Combined With Calcium Channel Blockers Is Superior to Other Combinations in Cardiovascular Protection With Similar Blood Pressure Reduction: A Meta-Analysis in 20,451 Hypertensive Patients.

The authors aimed to investigate the superiority of angiotensin system blockade (angiotensin‐converting enzyme [ACE] inhibitor/angiotensin receptor blocker [ARB]) plus a calcium channel blocker (CCB) (A+C) over other combination therapies in antihypertensive treatment. A meta‐analysis in 20,451 hypertensive patients from eight randomized controlled trials was conducted to compare the A+C treatment with other combination therapies in terms of blood pressure (BP) reduction, clinical outcomes, and adverse events. The results showed that BP reduction did not differ significantly among the A+C therapy and other combination therapies in systolic and diastolic BP (P=.87 and P=.56, respectively). However, A+C therapy, compared with other combination therapies, achieved a significantly lower incidence of cardiovascular composite endpoints, including cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke (risk ratio [RR], 0.80; 95% confidence interval [CI], 0.70–0.91; P<.001), but similar all‐cause mortality (RR, 0.90; 95% CI, 0.77–1.04; P=.15) and stroke rates (RR, 0.90; 95% CI, 0.77–1.04; P=.09). Moreover, A+C therapy yielded a 4.21 mL/min/1.73 m2 lower estimated glomerular filtration rate reduction than other combinations (P<.001). Finally, A+C therapy showed a similar incidence of adverse events as other combination therapies (P=.34) but presented a significantly lower incidence of serious adverse events (RR, 0.85; 95% CI, 0.73–0.98; P=.03). In conclusion, A+C therapy is superior to other combinations of antihypertensive treatment as it shows a lower incidence of cardiovascular events and adverse events, while it has similar effects in lowering BP and preserving renal function.

Northern Shanghai Study: cardiovascular risk and its associated factors in the Chinese elderly—a study protocol of a prospective study design

Introduction Cardiovascular (CV) diseases are the leading cause of death and disability in the world. Increasing lifespans and ageing populations also contribute to an increasing CV burden. However, in China, there were few well-designed cohort studies focusing on the elderly population, let alone an established CV risk score. The objective of this study is to establish a CV risk score based on a community-dwelling Chinese elderly population, determining the profile of the associated CV risk factors and target organ damages (TODs), so as to guide the later intervention. Methods and analysis The Northern Shanghai Study is an ongoing prospective community-based study. After enrolment, clinical examination, anthropometric measurement and a questionnaire will be administered to each participant at baseline and after every 2 years in the follow-up. Our tests and examinations include: blood/urine sample and biochemical measurements, office blood pressure recording, carotid ultrasonograph, echocardiograph, pulse wave velocity, pulse wave analysis, 4-limb blood pressure recording, body mass index, etc. Baseline measurement will also include the assessments on TODs and the conventional CV risk factors. In the follow-up, the incidence of CV events and mortality will be recorded. The Northern Shanghai Risk Score will be calculated, with considerations on CV risk factors and TODs. Ethics and dissemination This study was approved by the Shanghai Tenth Peoples Hospital Institutional Review Board. All participants signed a written consent form. Trial registration number NCT02368938; Pre-results.

Comparison of Carotid‐Femoral and Brachial‐Ankle Pulse‐Wave Velocity in Association With Target Organ Damage in the Community‐Dwelling Elderly Chinese: The Northern Shanghai Study

Background Carotid‐femoral pulse‐wave velocity (cf‐PWV) and brachial‐ankle PWV (ba‐PWV) are the 2 most frequently applied PWV measurements. However, little is known about the comparison of hypertensive target organ damage (TOD) with cf‐PWV and ba‐PWV. Methods and Results A total of 1599 community‐dwelling elderly subjects (age >65 years) in northern Shanghai were recruited from June 2014 to August 2015. Both cf‐PWV and ba‐PWV were measured using SphygmoCor and VP1000 systems, respectively. Within the framework of comprehensive cardiovascular examinations, risk factors were assessed, and asymptomatic TOD, including left ventricular mass index, peak transmitral pulsed Doppler velocity/early diastolic tissue Doppler velocity (E/Ea), carotid intima‐media thickness, arterial plaque, creatinine clearance rate, and urinary albumin‐creatinine ratio were all evaluated. Both PWVs were significantly associated with male sex, age, waist/hip circumference, fasting plasma glucose, and systolic blood pressure, and ba‐PWV was also significantly related to body mass index. Both PWVs were significantly correlated with most TOD. When cf‐PWV and ba‐PWV were both or separately put into the stepwise linear regression model together with cardiovascular risk factors and treatment, only cf‐PWV, but not ba‐PWV, was significantly associated with carotid intima‐media thickness and creatinine clearance rate (P<0.05). When cf‐PWV and ba‐PWV were both or separately put into the same full‐mode model after adjustment for confounders, only cf‐PWV, but not ba‐PWV, showed significant association with carotid intima‐media thickness and creatinine clearance rate (P<0.05). Similar results were observed in logistic regression analysis. Conclusions Taken together, in the community‐dwelling elderly Chinese, cf‐PWV seems to be more closely associated with hypertensive TOD, especially vascular and renal TOD, as compared with ba‐PWV. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02368938.

2A.04: WHETHER ACE INHIBITOR/ARB COMBINED WITH CCB IS SUPERIOR TO OTHER COMBINATIONS? A META-ANALYSIS IN 20,669 HYPERTENSIVES.

Objective: Current clinical evidence and latest guidelines recommended the combination antihypertensive therapy with angiotensin-converting enzyme (ACE) inhibitor / angiotensin receptor blocker (ARB) and calcium channel blocker (CCB) in patients with grade 2 to 3 hypertension. However, data are scarce in the comparison between the ACE inhibitor / ARB + CCB (A+C) therapy and other combinations. We therefore conducted a meta-analysis to see if ACE inhibitor/ARB combined with CCB is superior to other combinations. Figure. No caption available. Design and method: A meta-analysis was conducted in 20,669 hypertensives from 9 randomized controlled trials and we compared the A+C therapy with other combinations, in terms of blood pressure (BP) reduction, clinical outcomes and adverse effects. Results: BP reduction did not differ significantly between the A+C therapy and other combination therapies, neither in systolic nor in diastolic BP, with P = 0.43 and P = 0.41, respectively. However, A+C strategy, compared with other combination therapies, achieved a significantly lower incidence of cardiovascular composite endpoints, including cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke (Risk ratio [RR] and 95% confidential interval [CI]: 0.80 [0.70, 0.91], P < 0.001, see as Figure), but similar all-cause mortality (0.90 [0.77, 1.04], P = 0.15) and stroke rate (0.90 [0.77, 1.04], P = 0.09). Moreover, A+C combination therapy exhibited a 3.10 ml/min/1.73m2 greater estimated glomerular filtration rate than other combinations (P = 0.01). Lastly, A+C therapy showed a similar incidence of adverse effects as other combinations (P = 0.34), but had a significantly lower incidence of severe adverse effects (0.85 [0.73, 0.98], P = 0.03). Conclusions: In summary, clinical evidences favor A+C therapy, which is superior to other combinations, in current anti-hypertensive strategy, with greater clinical benefit in cardiovascular outcome and reservation of renal function.

Phospholipase Cγ1 Mediates Intima Formation Through Akt‐Notch1 Signaling Independent of the Phospholipase Activity

Background Vascular smooth muscle cell proliferation, migration, and dedifferentiation are critical for vascular diseases. Recently, it was demonstrated that Notch receptors have opposing effects on intima formation after vessel injury. Therefore, it is important to investigate the specific regulatory pathways that activate the different Notch receptors. Methods and Results There was a time‐ and dose‐dependent activation of Notch1 by angiotensin II and platelet‐derived growth factor in vascular smooth muscle cells. When phospholipase Cγ1 (PLCγ1) expression was reduced by small interfering RNA, Notch1 activation and Hey2 expression (Notch target gene) induced by angiotensin II or platelet‐derived growth factor were remarkably inhibited, while Notch2 degradation was not affected. Mechanistically, we observed an association of PLCγ1 and Akt, which increased after angiotensin II or platelet‐derived growth factor stimulation. PLCγ1 knockdown significantly inhibited Akt activation. Importantly, PLCγ1 phospholipase site mutation (no phospholipase activity) did not affect Akt activation. Furthermore, PLCγ1 depletion inhibited platelet‐derived growth factor–induced vascular smooth muscle cell proliferation, migration, and dedifferentiation, while it increased apoptosis. In vivo, PLCγ1 and control small interfering RNA were delivered periadventitially in pluronic gel and complete carotid artery ligation was performed. Morphometric analysis 21 days after ligation demonstrated that PLCγ1 small interfering RNA robustly attenuated intima area and intima/media ratio compared with the control group. Conclusions PLCγ1‐Akt–mediated Notch1 signaling is crucial for intima formation. This effect is attributable to PLCγ1‐Akt interaction but not PLCγ1 phospholipase activity. Specific inhibition of the PLCγ1 and Akt interaction will be a promising therapeutic strategy for preventing vascular remodeling.

Measuring the Carotid to Femoral Pulse Wave Velocity (Cf-PWV) to Evaluate Arterial Stiffness

For the elderly, arterial stiffening is a good marker for aging evaluation and it is recommended that the arterial stiffness be determined noninvasively by the measurement of carotid to femoral pulse wave velocity (cf-PWV) (Class I; Level of Evidence A). In literature, numerous community-based or disease-specific studies have reported that higher cf-PWV is associated with increased cardiovascular risk. Here, we discuss strategies to evaluate arterial stiffness with cf-PWV. Following the well-defined steps detailed here, e.g., proper position operator, distance measurement, and tonometer position, we will obtain a standard cf-PWV value to evaluate arterial stiffness. In this paper, a detailed stepwise method to record a good quality PWV and pulse wave analysis (PWA) using a non-invasive tonometry-based device will be discussed.

VASCULAR AGEING AND PRECLINICAL TARGET ORGAN DAMAGE IN COMMUNITY-DWELLING ELDERLY: THE NORTHERN SHANGHAI STUDY

Objective: Vascular aging represents a mediating step between risk factors and cardiovascular (CV) events. And preclinical target organ damage (TOD) integrates the cumulative effects of CV risk factors with aging which can be detected before clinical events occur. This study is focusing on the relationships between healthy vascular aging (HVA) and preclinical TOD. Design and method: Cross-sectional data from the Northern Shanghai Study (NSS, Clinicaltrials.gov NCT02368938), prospectively recruited from June 2014 to June 2017 [n = 2098, 45.52% men, aged 71.3 ± 6.1 years]. Preclinical TODs were assessed in all the participants. Other clinical information was obtained by standard questionaire. HVA was defined as absence of hypertension and a relatively normal cf-PWV (presented per age decade and blood pressure category). We fitted logistic regression models to assess the probability of Non-HVA in association with all the preclinical TOD. Figure. No caption available. Results: In this analysis, 642 (30.6%) elderly participants had HVA, the prevalence of HVA decreased from 30.84% (aged 65–66) to 20.72% (aged over 75). Increased age, increased SBP, increased fasting glucose, increased BMI and family history of premature cardiovascular disease (CVD) were significantly associated with accelerated vascular aging (Non-HVA) (p = 0.005 to p < 0.001). After multivariate adjustments, accelerated vascular aging was associated with left ventricular diastolic dysfunction (LVDD) (OR (95%CI), 1.525 (1.171, 1.988), p = 0.003), left ventricular hypertrophy (LVH) (OR (95%CI), 1.858 (1.228, 2.811), p = 0.002) and micro-albuminuria (MAU) (OR (95%CI), 1.525 (1.171, 1.988), p = 0.002). Conclusions: Management of metabolic profile may help to prevent or delay vascular aging. And accelerated vascular aging is associated with LVH, LVDD and MAU, which provide a potential vascular target to reverse or terminate cardiac and renal TOD.

ASSOCIATION OF ASYMPTOMATIC TARGET ORGAN DAMAGES WITH SECRETED FRIZZLED RELATED PROTEIN 5 IN THE ELDERLY: THE NORTHERN SHANGHAI STUDY

Objective: Secreted frizzled related protein 5 (SFRP5) is a novel anti-inflammatory adipokine which is implicated in metabolic and cardiovascular disease (CVD). However, little is known about the relevance of SFRP5 with asymptomatic hypertensive target organ damages (TOD). We aimed to investigate the association between SFRP5 and TOD in a large population study. Figure. No caption available. Design and method: Associations between plasma SFRP5 and cardiovascular risk factors as well as TOD were investigated in 1745 participants from Northern Shanghai Study. Plasma SFRP5 level was measured by an enzyme-linked immunosorbent assay. Results: Plasma SFRP5 level was negatively associated with body mass index, waist/hip ratio and fasting blood glucose (all P < 0.001). Lower plasma SFRP5 level was observed in men than in women (4.19 vs 5.13 ng/ml, P < 0.001), in smokers than in nonsmokers (4.34 vs 4.78 ng/ml, P < 0.05). Additionally, plasma SFRP5 level was also lower in diabetes than those without diabetes (4.30 vs 4.81 ng/ml, P < 0.05). Further, an inverse association was observed between SFRP5 and pulse wave velocity as well as carotid intima-media thickness (both P < 0.05). Moreover, multivariate logistic regression analysis showed lower SFRP5 level was associated with increased arterial stiffness in the elderly (OR 0.83, 95% CI 0.71 to 0.99 per 1-SD increase, P < 0.05). Conclusions: Plasma SFRP5 level was inversely correlated with conventional cardiovascular risk factors and low plasma SFRP5 was also significantly associated with arterial stiffening in the elderly Chinese population.

COMPARISON OF ANKLE-BRACHIAL INDEX AND UPSTROKE TIME PER CARDIAC CYCLE IN ASSOCIATION WITH TARGET ORGAN DAMAGE IN ELDERLY CHINESE: THE NORTHERN SHANGHAI STUDY

Objective: Recent studies indicated that upstroke time per cardiac cycle (UTCC) in lower extremity is equivalent to ankle-brachial index (ABI) in diagnosing peripheral arterial disease and in predicting cardiovascular mortality. In the present study, we aim to compare ABI and UTCC in relation to target organ damage (TOD) Figure. No caption available. Design and method: 1841 elderly participants (mean age of 70 years) derived from the Northern Shanghai Study were included in the present study. ABI and UTCC were measured using VP-1000 device (Omron, Japan). TOD including left ventricular hypertrophy and diastolic dysfunction, carotid intima-media thickness and plaque, carotid-femoral pulse wave velocity (CF-PWV) and renal damage, were all evaluated. Results: ABI and UTCC both were significantly correlated with CF-PWV, carotid plaque and eGFR, but not with cardiac damage. Compared with ABI, UTCC showed stronger correlation with CF-PWV. When ABI and UTCC separately put into same multivariate full-mode logistic regression models, both ABI (Odds Ratio [OR]:2.273; 95% Confidence Interval [CI]:1.632–3.165) and UTCC (OR:1.627; 95%CI: 1.182–2.240) significantly associated with carotid plaque, but only UTCC significantly associated with increased CF-PWV (OR:1.664; 95%CI:1.147–2.416) and renal damage (OR:1.625; 95%CI:1.068–2.472). When ABI and UTCC both put into same multivariate stepwise logistic regression models, consistent results were observed. In ROC curve analysis, UTCC was better than ABI in discriminating increased CF-PWV (AUC:0.68 vs. 0.57; P < 0.001) and renal damage (AUC:0.67 vs. 0.60; P = 0.012). Conclusions: Compared with ABI, UTCC showed stronger association with vascular and renal damage in this elderly cohort. In combination with previous findings, UTCC may be a useful tool for diagnosing PAD and stratifying cardiovascular risk.

DETERMINANTS OF RENAL FUNCTIONAL IMPAIRMENT, THE IMPORTANCE OF FASTING PLASMA GLUCOSE CONTROL: THE NORTHERN SHANGHAI STUDY

Objective: Chronic kidney disease is a global health problem. However, the causes of renal functional impairment in the general elderly population remains unclear. The aim of this study was to investigate the determinants of renal functional impairment, within a framework of cardiovascular (CV) risk assessment in a community-dwelling elderly cohort. Design and method: From June 2014 to August 2015, a total of 912 community-dwelling elderly subjects (aged > = 65 years) from the northern Shanghai were recruited. CV risk factors were assessed, and renal function was evaluated by estimated glomerular filtration rate (e-GFR) at baseline and during 2-year follow-up. Rapid decline in e-GFR was defined as an e-GFR slope (decline in e-GFR) > 5 ml/min per 1.73 m2 per year. Results: The average decline in e-GFR was 0.104 ml/min/1.73m2 per year, while the increasing risk of having rapid decline in e-GFR was 1.25-fold every additional year. Decline in e-GFR was significantly different between diabetics and non-diabetics (p = 0.03). In full adjustment model, decline in e-GFR (p = 0.03) and rapid decline in e-GFR (OR 1.37, CI 1.07–1.75) were both significantly associated with fasting plasma glucose. Similar result of the association of rapid decline in e-GFR with fasting plasma glucose was obtained in the diabetes (full adjustment, OR 1.57, CI 1.05–2.34). Conclusions: In the community-dwelling elderly Chinese, the average decline in e-GFR was 0.104 ml/min/1.73m2 per year, and renal functional impairment was significantly associated with hyperglycemia in the old Chinese. Figure. No caption available.