Prediction Of Cerebrovascular/cardiovascular Disease Secondary To Metabolic Syndrome: Ultrasonographic Measures Of Vasodilator Response

Abstract: 

Background: End-stage renal failure is escalating due to the increased prevalence of renal damage (chronic kidney disease, CKD) secondary to arteriosclerosis resulting from metabolic syndrome (MetS). In congruence with the observed renal damage, the occurrence of cerebrovascular/cardiovascular disease (CCVD) affecting the patient's vital prognosis and quality of life also increases. Our previous study reported on surrogate markers utilized for the early diagnosis of CKD pathophysiologically based on MetS. In the present study, the vasodilator response is investigated for its potential diagnostic value in the early diagnosis of CCVD. Subjects and methods: The vasodilator responses (flow-mediated dilation [FMD] and nitroglycerin-induced dilation [NID]) to the right brachial artery were measured accordingly as efficient indicators to serve as surrogate markers for early diagnosis of CCVD in 208 Japanese males who are diagnosed with MetS. Before the analysis of FMD and NID data, the subjects were divided into groups according to the presence or absence of CCVD or the number of risk factors for MetS. Results: FMD values were generally extremely low and showed no significant differences between the two groups concerning the presence of CCVD or the number of MetS risk factors. In contrast, NID values were generally low but the decrease in NID values was significant and was more marked in the group with CCVD and in those with MetS risk factors compared to their respective pairing groups. Conclusion: Although FMD values already showed a decrease at the time of MetS diagnosis, NID values showed a delayed decrease, and this decrease in NID values was accompanied by the onset of CCVD. These findings suggest that FMD (lowered values) may serve as a surrogate marker for the early prediction of CCVD due to arteriosclerosis and that NID (lowered values) may serve as a surrogate marker for the diagnosis of a progressive pathophysiological change in CCVD.

Keywords: Metabolic syndrome, Arteriosclerosis, Metabolic syndrome nephropathy, Cerebrovascular/cardiovascular disease, Ultrasonic vasodilator responses

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Introduction 

Metabolic syndrome (MetS)1 ) causes organopathies through arteriosclerosis. Typical organopathies secondary to arteriosclerosis include chronic kidney disease (CKD) and cerebrovascular/cardiovascular disease (CCVD)2,3). Diabetic nephropathy (DN) and benign nephrosclerosis (BNS) which account for a large percentage of CKD cases are referred to as diabetic kidney disease (DKD)4) by extension. This confuses presumably due to the extensive involvement of recent lifestyle changes, aging, and various treatment effects, in addition to the lack of consideration for the pathophysiological background of DN and BNS. To clarify the misperception, we propose to consider the concept of "metabolic syndrome nephropathy (MetS-N)"5-8). This concept comprises the renal damage in patients with a pathophysiological background of MetS. Although the diagnosis of DKD is currently established by a combination of albuminuria (albumin-creatinine ratio [ACR]) and estimated glomerular filtration rate (eGFR), it has been reported that a combination of the renal interlobar arterial resistive index (RI) and estimated renal blood flow (RBF) permits a more accurate early diagnosis of MetS-N than the conventional method9). The objective of the present study was to examine whether flow-mediated dilatation (FMD) and nitroglycerin-induced dilatation (NID)―vasodilator responses of the brachial artery, measured by ultrasonography, can serve as surrogate markers for predictors/determinants of CCVD which frequently occurs with the progression of CKD as the pathophysiological basis of the Mets.

Methods

1. Subjects 

A total of 208 Japanese males (named as total [GT]) who met the definition of Japanese MetS1 and could contribute to a set of FMD and NID data during the 8 years between November 7, 2011, and October 28, 2019, were studied accordingly. The subjects were divided into four groups: (i) those with CCVD (group A: G-A, n=51) and those without CCVD (group B: G-B, n=157); and (ii) those with four MetS risk factors (group C: G-C, n=152) and those with three MetS risk factors (group D: G-D, n=58), according to the presence or absence of CCVD. The number of patients with obesity and other MetS risk factors (defined risk factors for MetS include obesity [requisite], elevated blood pressure, lipid abnormalities, and elevated blood glucose). The specification of the MetS risk factors was made according to the criteria of obesity (BMI  25 and/or visceral fat area [VFA]  100 cm2 ), elevated blood pressure ( 130 mmHg in systolic blood pressure [BPS] and/or -85 mm Hg in diastolic blood pressure [BPD]), lipid abnormalities (triglyceride [TG]  150 mg/dL and/or HDL cholesterol [HDLC] <40 mg/dL), elevated fasting glucose (HbA1c 6.2% and/ or fasting plasma glucose [FPG]  110 mg/d), and the use of antihypertensive medication, lipid-lowering medication, or diabetic medication.

2. Relationship between CKD and CCVD 

The study subjects (G-T) were evaluated for the incidence of CCVD after the CKD was classified, for its characterization, into six eGFR categories (G1 to G5 with G3 split into 3a and 3b) according to renal function. 

3. Evaluation Parameters 

The data was analyzed (mean ± standard deviation [SD]) according to 13 parameters which included the subject's age, MetS-related factors (BMI, BPS, BPD, TG, HDL-C, HbA1c, and FPG), LDL-C, renal function (creatinine [Cr], eGFR, and ACR), and uric acid (UA). The age data were obtained at the time the vasodilator response examination was conducted while the other characteristic data adopted in G-T indicated the worst values obtained throughout the study, and similar char characteristic data adopted in G-A, G-B, G-C, and G-D indicated the values obtained immediately before the examination. 

4. Procedure for FMD/NID 

Measurements FMD and NID measurements were performed by the following procedures. 1) Pretreatment: Each subject had breakfast regularly at 8:00 a.m. They were allowed to take their respective pre-scribed medications, if any. Smoking was prohibited and a minimal amount of water intakes were allowed until 2:00 p.m. In a favorable environment (silent and dark conditions at around 25°C with 50% relative humidity), the blood pressure was measured after the subject had rested in the supine position for 10 minutes. 2) FMD/NID measurement: UNEXEF38G (UNEX Corp., Aichi, Japan) the ultrasound equipment utilized for the vascular function study. 3) FMD measurement: After the resting diameter was measured at the right brachial artery, an inflatable cuff for blood pressure measurement was placed around the right arm and inflated to a systolic blood pressure plus 50 mmHg. After 5 minutes of cuff inflation for blood expulsion, blood flow was restored. The brachial artery diameter was measured for 2 minutes when the maximum brachial diameter was reached after blood flow restoration to evaluate the vasodilator response of the brachial artery (FMD value). FMD (%) was calculated using the following equation: FMD (%) = (maximum diameter - resting diameter)/(resting diameter) × 100. 4) After the completion of FMD measurement, each subject was placed on bed rest for 15 minutes and nitroglycerin (0.3 mg) was sprayed sublingually to measure the maximum brachial artery for a 5-minute vasodilator response for NID measurement (NID value). NID (%) was calculated using the following equation: NID (%) = (maximum diameter - resting diameter)/(resting diameter) × 100. 5) Cutoff value setting: Although statistics on normal cut-off values for FMD and NID in healthy Japanese individuals have not been reported, they have recently been published as 7.1% for FMD and 15.6% for NID by Maruhashi et al10). Taking these published data into consideration, we formed a comparison among G-T, G-A, and G-B and a comparison among G-T, G-C, and G-D. Incidentally, a cut-off value of 4%, the original value reported by UNEX Corporation, was used for the comparison of the FMD data across subdivision groups.

CCVD is defined as ischemic heart disease (angina pectoris and cardiac infarction) or cerebral stroke (cerebral hemorrhage and cerebral infarction) that occurred during the entire clinical follow-up period before baseline measurement. Statistical processing (non-paired t-test) was performed using the statistical analysis software Excel Statistics (Bell Curve for Excel; Social Survey Research Information Co., Ltd., Tokyo, Japan). FMD and NID measurements and other tests were performed within the limits of the medical service fees (no consultation with the clinic's ethics committee was required). The chi-square test was used to examine the relationship between the renal function-based classification (G1 to G5 with G3 split into 3a and 3b) of CKD and the incidence of CCVD. Statistical significance was set at p<0.05.

Figure 1. Percentage of subjects with CCVD by eGFR level Abbreviations: CCVD, cerebro-/cardiovascular disease; eGFR, estimated glomerular fi ltration rate.

Data are expressed as means±SD. Abbreviations: CCVD, Cerebro-/cardiovascular disease; MetS, metabolic syndrome; MetSRF, MetS risk factors; G-T, group total; G-A, a group with CCVD; G-B, a group without CCVD; G-C, a group with 4 MetSRF; G-D, a group with 3 MetSRF; BMI, body mass index; BPS, systolic blood pressure; BPD, diastolic blood pressure; TG, triglyceride; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; HbA1c, glycated hemoglobin; FPG, fasting plasma glucose; UA, uric acid; Cr, creatinine; eGFR, estimated glomerular filtration rate; ACR, albumin-creatinine ratio.