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Year : 2019  |  Volume : 9  |  Issue : 3  |  Page : 141-147

Determinants of microvascular dysfunction in normotensive offsprings of hypertensive parents

Department of Cardiology, Zagazig University Hospital, Zagazig, Egypt

Date of Web Publication3-Dec-2019

Correspondence Address:
Prof. Ragab A Mahfouz
Department of Cardiology, Zagazig University Hospital, Zagazig
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JICC.JICC_38_19

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Objective: Microvascular dysfunction usually precedes the onset of hypertension. We hypothesized that offspring of offsprings of hypertensive parents (OHP) would have coronary microvascular dysfunction. Yet, the determinants of microvascular dysfunction in OHP are not fully determined. We, therefore, studied coronary flow reserve (CFR) in OHP in relation to ambulatory blood pressure and lipid profiles. Subjects and Methods: One hundred and twenty-five healthy normotensive offsprings with family history of hypertension and 40 age- and sex-matched healthy normotensive offsprings without family history of hypertension (ONP) were enrolled for the study. All participates underwent transthoracic color Doppler echocardiography at rest and during adenosine (0.14 mg/kg) infusion. CFR was calculated as the ratio between hyperemic diastolic coronary flow to the resting diastolic coronary flow. All participates had ambulatory blood pressure monitoring. In addition, lipid profile was obtained, and triglycerides (TGs)/high-density lipoprotein cholesterol (HDL-C) was calculated. Results: CFR was significantly reduced among OHP compared with ONP (P < 0.001). Moreover, 61 of the OHP (49%) had CFR <2.0. OHP had an exaggerated morning blood pressure surge (MBPS) compared with ONP (P < 0.001). TG/HDL-C was significantly higher in OHP with reduced CFR compared with both OHP without reduced CFR and ONP (P < 0.001). TG/HDL-C was negatively correlated with CFR (P < 0.001). Furthermore, TG/HDL-C ratio was positively correlated with MBPS (P < 0.001). Multivariate analysis showed that BPMS and TG/HDL-C were independent predictors for reduced CFR in OHP (P < 0.001). Receiver-operating characteristic analysis showed that TG/HDL-c ratio ≥3.8 and MBPS ≥49 mmHg were the optimal cutoff values to predict reduced CFR among OHP, with (area under the curve = 0.91 and 0.92, respectively; P < 0.001). Conclusion: Our study suggests that microvascular function is significantly impaired in OHP. TG/HDL-C ratio and MBPS are independently associated with reduced CFR. These relationships could potentially reflect a subclinical precursor of cardiovascular risks and future hypertension, a premise that warrants close follow-up.

Keywords: Coronary flow, high-density lipoprotein, hypertension, offsprings, triglycerides

How to cite this article:
Mahfouz RA, Arab M, Ghareb MS. Determinants of microvascular dysfunction in normotensive offsprings of hypertensive parents. J Indian coll cardiol 2019;9:141-7

How to cite this URL:
Mahfouz RA, Arab M, Ghareb MS. Determinants of microvascular dysfunction in normotensive offsprings of hypertensive parents. J Indian coll cardiol [serial online] 2019 [cited 2020 Jun 5];9:141-7. Available from: http://www.joicc.org/text.asp?2019/9/3/141/272174

  Introduction Top

Hypertension is one of the most independent risk predictors for cardiovascular adverse outcomes and prevalent worldwide. Hence, early preventive intervention to individuals at increased risk for the development of hypertension, particularly those with a positive family history of hypertension is widely accepted recommendation.[1]

The development of hypertension is a multifactorial process. A considerable proportion of young person has hypertension. Obviously, family history of hypertension is a major risk predictor for developing hypertension in offspring of hypertensive parents (OHP).[2],[3] Studies found that children of parents with hypertension have higher blood pressure profiles compared with children of normotensive parents.[4],[5]

Wang et al.[6] demonstrated that parental hypertension has a strong independent relation with high blood pressure readings and incident hypertension along through adult life.

Furthermore, Greaney et al.[7] reported that young adults of hypertensive parents have a higher risk to develop hypertension and have an exaggerated sympathetic reactivity compared with those with a negative family history of hypertension.

Deyanov and Vangelova.[8] showed that individuals with a positive family history of hypertension had higher blood pressure response to exercise, blunted blood pressure recovery, and elevated total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) ratio.

Being at risk for hypertension, we hypothesized that, OHP have early subclinical atherosclerosis as well. Herein, we investigated the determinants of reduced coronary flow reserve (CFR) (as a marker of microvascular dysfunction) in OHP.

  Subjects and Methods Top

One hundred and twenty-five healthy normotensive OHP were followed up in hypertensive clinic of cardiology department. Forty normotensive offspring of healthy normotensive parents were enrolled to serve as a control group. A full medical and family history was obtained from all participates. Obese individuals and those with any history of chronic disease, anemia, diabetes, congenital heart disease, or other conditions requiring medical treatment were excluded. The study was approved by faculty ethical committee, and a written consent was obtained from all participants.

Blood pressure measurements and ambulatory blood pressure monitoring assessment

Office blood pressure was obtained and recorded from all participates after resting for at least 5 min in the sitting position. Individuals underwent a 24-h ambulatory blood pressure monitoring (ABPM) monitoring. Blood pressure and heart rate using a noninvasive, portable device (Spacelabs 90,217, Spacelabs Healthcare, Issaquah, WA, USA). The device was programmed to obtain and record blood pressure readings automatically every 20 min for the 24 h. The reported standard error margin for the system is ± 3 mmHg. Individuals were informed to take their ordinary activities at home or at work as usual. The following parameters were obtained: average 24 h blood pressure, average day blood pressure (mean 10 AM–10 PM), average night (mean 10 PM–6 AM), and average morning blood pressure (mean 6–10 AM). Morning blood pressure surge (MBPS) is obtained from subtracting the morning systolic blood pressure (SBP) (SBP for 2 h just after waking up) from the lowest nocturnal SBP during sleep. The nocturnal blood pressure fall (mmHg) was considered as the evening blood pressure minus the lowest blood pressure. Individuals who had a nocturnal fall of ≥10% in SBP were considered dippers.[9] The systolic pressures were used for all these calculations.

Echocardiographic study

All individuals underwent conventional echo-Doppler examination through a standard two-dimensional transducer device (Vingmed System Vivid 5; GE Vingmed Ultrasound, Horten, Norway). Left ventricular dimensions, mass, ejection fraction, left atrial dimension, and left atrial volume index were calculated according to the guidelines of the American Society of Echocardiography.[10]

For quantitative assessment of systolic and diastolic function, tissue Doppler imaging (TDI) was performed in the apical 4-chamber view to evaluate annular systolic and diastolic tissue velocities. The TDI sample volume was placed sequentially at septal and lateral regions of the mitral annulus (measurements were done at 50 m/s at the end of the expiration). The s' wave, early (e'), and late diastolic velocities (a') at septal and lateral wall were measured. The ratio of mitral flow E wave to mitral annular e′ wave (E/e' ratio, as a marker of the left ventricular filling pressure) for each of these annular velocities was obtained and averaged. The average of three consecutive cardiac cycles was taken for the measurement of each parameter.

Coronary flow reserve evaluation

Transthoracic echocardiographic, assessment of CFR was performed with the use of a high-frequency transducer (5–7 MHz). A modified apical two-chamber view was obtained. The baseline spectral Doppler velocity signals in mid-distal portion of the left anterior descending (LAD) artery at the anterior interventricular sulcus was recorded by placing a sample volume of 2 cm on the color signal in the LAD. The hyperemic spectral Doppler signals were recorded after an intravenous adenosine was administered (0.14 mg/kg/min). The baseline and hyperemic coronary flow velocities were measured and averaged over three cardiac cycles at baseline and peak hyperemia. The hyperemic to basal flow velocity ratio was calculated as an estimate of CFR. A value <2.0 was considered pathological.[11]

Laboratory investigations

Blood samples were analyzed for concentrations of fasting blood glucose, triglycerides (TG), TC, HDL-C, low-density lipoprotein cholesterol (LDL-C), serum creatinine, and high sensitive C-reactive protein. Serum lipids (enzymatic methods) and plasma glucose (glucose oxidase method) were assayed using the modular diagnostic oxidase-peroxidase procedure (DPP) automatic biochemistry analysis system (Roche, Rotkreuz, Switzerland). HDL-C and LDL-C were measured directly. In addition, the TG: HDL-C ratio was calculated.


The normal distribution of the data was analyzed assessed using K-S test. Quantitative and qualitative variables were compared using Chi-square test and t-test. Logistic regression test was used for multivariate analysis. The relationship between CFR and other variables was assessed by Spearman's correlation methods. Receiver-operating characteristic curve analysis was used to estimate the optimal cutoff TG/HDL-C and MBPS values or predicting reduced CFR. The SPSS 18.0 (Chicago, IL, USA) was used for statistical analysis.

  Results Top

[Table 1] represents the demographic data of all participates. OHP had a higher diastolic blood pressure (P< 0.05), an elevated TG/HDL-c (P< 0.001) [Figure 1] and hs-c reactive protein (P< 0.05) compared with those without family history of hypertension. In addition, during ABPM, OHP had an exaggerated MBPS (P< 0.001), while, other ABPM parameters were comparable. Coronary flow analysis shows that CFR was significantly reduced among individuals with hypertensive parents compared with those with normotensive parents (2.4 ± 0.3 vs. 3.6 ± 0.7, P < 0.001).
Table 1: Baseline characteristics of offsprings with and without family history hypertension

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Figure 1: The triglycerides to high-density lipoprotein in offsprings of hypertensive parents versus offsprings of normotensive parents

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Normotensive individuals with a family history of hypertension were stratified into two groups according to CFR value. Group with CFR <2.0 (n = 61) and the other with CFR ≥2.0 (n = 64). [Table 2] depicts a comparison between both groups. Diastolic blood pressure (P< 0.05), TG/HDL-c (P< 0.001), hs-c reactive protein (P< 0.05), and MBPS value (P< 0.001) were significantly higher in OHP with CFR < 2.0 furthermore, left ventricular mass (P< 0.05) and E/e' ratio (P< 0.03) were higher among OHP compared with offspring of normotensive parents.
Table 2: Characteristics of offsprings of hypertensive parents with coronary flow reserve <2.0 versus those with coronary flow reserve ≥2.0

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A correlation analysis was carried out to recognize the factors that may be associated with reduced CFR [Table 3]. Among OHP, there was an inverse correlation between CFR with MBPS values (P< 0.001) diastolic blood pressure (P< 0.05), TG/HDL-c ratio (P< 0.001), hs-c reactive protein (P< 0.01), and E/e' ratio (P< 0.05), while, there was a positive correlations with HDL-C value (<0.05). Furthermore, MBPS was significantly correlated with TG/HDL-c ratio (P< 0.001), [Figure 2].
Table 3: Correlation analysis of coronary flow reserve with other variables in offsprings of hypertensive parents

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Figure 2: Correlation analysis shows a significant association between blood pressure morning surge and triglycerides/high-density lipoprotein cholesterol ratio in offsprings of hypertensive parents

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Variables correlated with CFR in OHP were investigated with univariate and multivariate analysis as predictors for reduced CFR [Table 4]. MBPS and TG/HDL-C ratio were independent determinants of CFR (P< 0.001, for both).
Table 4: Univariable and multivariable predictors of reduced coronary flow reserve in offsprings of hypertensive parents

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With receiving operating curve analysis, our results show that MBPS ≥49 mmHg was the optimal cutoff value for predicting reduced CFR in OHP (area under the curve [AUC] = 0.83, with a sensitivity of 91% and a specificity of 79%). Furthermore, the optimal cutoff value for TG/HDL-C in predicting reduced CFR was ≥3.8 (AUC = 0.89, with a sensitivity of 93% and specificity of 81%) [Figure 3] and [Figure 4].
Figure 3: Receiver-operating characteristic analysis shows that triglycerides/high-density lipoprotein cholesterol ≥3.8 is the optimal cutoff value for predicting reduced coronary reserve in offsprings of hypertensive parents

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Figure 4: Receiver-operating characteristic analysis shows that morning blood pressure surge ≥49 mmHg is the optimal cutoff value for predicting reduced coronary reserve in offsprings of hypertensive parents

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  Discussion Top

The present study demonstrated the role of abnormal ambulatory blood pressure profile (exaggerated MBPS) in conjunction with disturbed lipid ratio TG/HDL-C (an important marker of inflammation) in the pathophysiology of microvascular dysfunction in OHP.

Our study revealed a variety of important findings in offsprings of hypertensive patients. (1) OHP had an exaggerated MBPS, higher TG/HDL-C, and elevated hs-C reactive protein compared with individuals without family history of hypertension, (2) a significant percentage (49%) among OHP had CFR < 2.0, (3) OHP with reduced CFR had an exaggerated of BPMS, elevated hs-C reactive protein, and higher TG/HDL-C ratio. (4) TG/HDL-C was significantly correlated MBPS, and (5) TG/HDL-C ≥3.8 and MBPS ≥49 mmHg were the optimal cutoff values for predicting reduced CFR in OHP, respectively.

Spite of being normal blood pressure range, we found that MBPS was significantly higher in offsprings with family history of hypertension while there were no significant differences in other ABPM parameters.

A previous investigations have reported that blood pressure readings were significantly higher among healthy young offsprings with a positive family history of hypertension.[12],[13],[14] These data revealed the significance of a positive family history of hypertension as a crucial risk factor for developing hypertension and early subclinical atherosclerosis.

Alpaydin et al.[15] demonstrated that MBPS carries a higher risk for cardiovascular events compared to the physiological blood pressure increase. They found a positive and significant relation with a higher inflammatory burden and increased carotid intima-media thickness in prehypertensive patients.

Caliskan et al.[16] found that an exaggerated MBPS was significantly associated with microvascular dysfunction in prehypertension patients and in those with Stage 1 hypertension, in the absence of obstructive coronary artery disease.

Pręgowska-Chwała et al.[17] demonstrated that patients with exaggerated MBPS had significantly higher deceleration time increased carotid intima-media thickness compared with those with lower MBPS, both in dippers and nondippers. They concluded that MBPS could have a significant link with markers of cardiovascular alterations.

Impaired microvascular function in patients with angiographically normal coronaries has increased interest, and CFR is a promising method to assess coronary microvascular dysfunction.[18],[11]

Borghi et al.[19] found a significant reduced vasodilatory capability during a handgrip isometric physical exercise at moderate intensity in normotensive OHP. Nevertheless, they did not study the determinants of this impaired vasodilator capacity. Hence, we tried in the current study to find out the possible contributing factors for impaired microvascular dysfunction in individuals with a family history of hypertension.

We found a close relation between CFR with MBPS, hs-C reactive protein, and TG/HDL-C among offsprings with family history for hypertension. Moreover, multivariate analysis showed that TG/HDL-C and MBPS were powerful independent predictors of reduced CFR in OHP, suggesting that BPMS and TG/HDL-C were important contributing factors for microvascular dysfunction in individuals with family history of hypertension.

Ding et al.[20] hypothesized that generalized impairment in microvascular function usually precedes the development of hypertension. Moreover, Wong et al.[21] reported that generalized arteriolar narrowing is a risk predictor for future hypertension. In addition, they demonstrated that each 20-μm decrease in retinal artery diameter was linked to 1.12 mmHg increase in SBP over 5 years.

Interestingly, we found a close association between higher TG/HDL-C ratio with exaggerated blood pressure morning surge among individuals with a family history of hypertension. The findings provide an atherogenic burden as a risk predictor for abnormal blood pressure profile and hence future hypertension.

Onat et al.[22] reported that the atherogenic index of plasma (“log10 TG/HDL-C”) is a crucial risk predictors for the future development of diabetes mellitus and hypertension.

Several studies have revealed that higher TG/HDL-C ratio is associated with the presence of remnant lipoproteins and low-density lipoprotein values and increased atherogenic burden.[23],[24],[25]

Studies have reported that insulin resistance might be the underlying pathophysiologic factor. Definitely, TG/HDL ratio might be a useful surrogate estimate of insulin action.[26],[27] The relation between TG/HDL-C and insulin resistance was clearly evident in diabetes mellitus and hypertension. Furthermore, Insulin resistance was significantly associated with accelerated atherosclerosis.[28] The relation of TG/HDL-C with reduced CFR and MBPS in our study may be explained in the context of insulin resistance.

These findings highlight the significance of addressing suspected microvascular dysfunction in normotensive healthy OHP and emphasis on the determinant risks for reduced CFR, related to blood pressure and lipids as MBPS and TG/HDL-C ratio.


Some limitations of the study were encountered. First, a limited sample size. Second, a single-center study. Third, we did not assess insulin resistance to investigate a possible link between TG/HDL-C and both CFR and MBPS. Finally, no follow-up evaluation was performed.

  Conclusion Top

Our study suggests that microvascular function is significantly impaired in OHP. TG/HDL-C ratio and MBPS are independently associated with reduced CFR. These relationships could potentially reflect a subclinical precursor of cardiovascular risks and future hypertension, a premise that warrants close follow-up.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

  [Table 1], [Table 2], [Table 3], [Table 4]


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