Genetic risk factors influence nighttime blood pressure and related cardiovascular complications in patients with coronary heart disease

ABSTRACT Genetic predisposition of elevated nighttime blood pressure (BP) in patients with coronary heart disease is unknown. We evaluated genetic predisposition and the relationship between

elevated nighttime BP and cardiovascular complications over a median of 8.6 years of observation of hypertensive subjects with coronary atherosclerosis confirmed by coronary angiography.

Genetic Risk Score (GRS19) was constructed to evaluate the additive effect of single-nucleotide polymorphisms for daytime and nighttime BP. The Receiver Operating Characteristic was used for

determination of cutoff points for daytime BP (systolic BP (SBP) 133 mm Hg and diastolic BP (DBP) 77 mm Hg) and nighttime BP (SBP 122 mm Hg and DBP 73 mm Hg). The curves of cumulative

incidence revealed an increased risk of major advanced cardiovascular events in subjects with elevated nighttime BP compared with those without elevated nighttime BP during the follow-up

period. Subjects with normal daytime and elevated nighttime BP exhibited increased GRS19 compared with those with normal daytime and nighttime BPs (8.6±3.0 _vs._ 7.9±3.0, _P_<0.01). After

adjustment for cardiovascular risk factors, GRS19 determined nighttime SBP (_β_ 0.4, 95% confidence interval (CI) 0.3–0.5, _P_<0.01). Our study confirmed that elevated nighttime SBP was

genetically determined and related to an increased risk of major adverse coronary events in patients with confirmed coronary atherosclerosis. SIMILAR CONTENT BEING VIEWED BY OTHERS NIGHTTIME

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LEVELS AND BLOOD PRESSURE AMONG HYPERTENSIVE PATIENTS BEYOND CONVENTIONAL MEASURES. AN OBSERVATIONAL STUDY Article Open access 23 June 2024 INTRODUCTION Several studies in different

populations have confirmed that nighttime blood pressure (BP) is a stronger predictor of cardiovascular events than daytime BP.1, 2, 3, 4 Previous studies have suggested that nighttime BP is

elevated in prediabetic and diabetic patients, patients with chronic kidney disease and those with lupus.5, 6, 7, 8 However, nighttime hypertension should be distinguished from a blunted

nighttime BP decrease (referred to as 'non-dipping status'), but nighttime hypertension is more common in non-dippers.9 From a pathophysiological point of view, there is a myriad

of nighttime BP control mechanisms, for example, arterial baroreceptors and chemoreceptors, autonomic and central nervous systems, the renin–angiotensin–aldosterone system and pressure

natriuresis.10 Recently, Obayashi _et al._11 confirmed that renal function is an essential parameter related to elevated nighttime BP in patients with prediabetes. Our recently published

study confirmed that non-dipping status is genetically determined in patients with coronary artery disease (CAD).12 A previously published meta-analysis concluded that nighttime BP is

superior to daytime BP in predicting cardiovascular events and total mortality.13 However, little information is known about the genetic determinants of elevated nighttime BP in this group

of patients. Therefore, we aim to investigate the relationship between genetic risk factors and elevated nighttime BP. METHODS SUBJECTS The present study recruited 1345 individuals (between

August 2003 and August 2006) with signs of myocardial ischemia identified by ECG stress test, dobutamine stress echocardiography or myocardial perfusion scintigraphy stress test. Subjects

with supraventricular and ventricular arrhythmias, NYHA class III or IV congestive heart failure, significant valvular heart disease (or valvular heart disease qualifying the patient for

cardiosurgery), renal insufficiency with a creatinine level ⩾2.0 mg dl−1, changes in pharmacotherapy of hypertension within 6 months before 24-h ambulatory BP monitoring and other chronic

diseases leading to limited life expectancy were excluded.12 BP MEASUREMENTS To avoid the influence on BP of either hospital conditions or the need for reduced physical activity, 24-h

ambulatory BP monitoring was obtained over a period of 2–4 weeks after coronary angiography (SpaceLabs 90210, SpaceLabs, Redmond, WA, USA) with BP readings set at 20-min intervals (0600–1800

hours) and at 30-min intervals (1800–0600 hours). The non-dominant arm was used for measurement with cuff size adjusted to arm circumference (adult cuff 27–34 cm or large adult cuff 35–44 

cm). All BP recordings were obtained on working days. Patients were instructed to maintain their usual activities but to refrain from strenuous exercise and emotional burden. Patients were

instructed to hold their arm still by their side during BP measurement and to return to the hospital 24 h later. Participants had no access to their ambulatory BP values. BP measurements

recorded between 0800 and 2200 hours were considered daytime BP values, and BP measurements recorded between 0000 and 0600 hours were considered as nighttime BP values. The percentage

decrease in mean systolic BP (SBP) during the nighttime period was calculated as 100 × (daytime SBP mean–nighttime SBP mean)/daytime SBP mean. Similarly, the percentage decrease in mean

diastolic BP (DBP) during the nighttime period was calculated as 100 × (daytime DBP mean–nighttime DBP mean)/daytime DBP mean. Using this percentage ratio, subjects were classified as

dippers or non-dippers (nighttime relative SBP or DBP decline ⩾ and <10%, respectively).14 This classification was performed for SBP and DBP for each included patient. Office BP

measurements were performed immediately before ambulatory BP measurements using a validated oscillometric device (OMRON 705 IT, OMRON, Greenspoint Parkway, IL, USA) with the cuff fitted to

arm circumference. BP was measured on the non-dominant arm.12 LABORATORY TESTS On admission day before a coronary angiography, fasting blood samples were collected to measure creatinine

level, fasting glucose level, total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglyceride levels. Additionally, blood samples were collected

to analyze DNA separation. SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) SELECTION AND GENOTYPING SNPs were selected from genome-wide association studies in which genome-wide association exceeded

the threshold of _P_<5 × 10−8. Selected SNPs were reported to be associated with CAD risk and are presented in Table 1.15, 16, 17, 18, 19, 20 DNA was obtained from whole blood. SNPs were

genotyped using an IPLEX reaction on a MassARRAY platform (Sequenom, San Diego, CA, USA) according to the manufacturer’s standard protocols at Lund University. Only SNPs with a genotyping

success rate >90% and minor allele frequency >5% were analyzed. Regarding quality control, we re-genotyped a random sample of 20% of the successfully genotyped samples for all

genotypes, and the concordance was 99.9%. GENETIC RISK SCORE Genetic Risk Score (GRS19) was constructed to evaluate the additive effect of 19 SNPs for elevated nighttime BP. This multilocus

score was created by summing the number of risk alleles (0/1/2) for each of the 19 SNPs (1 and 2 for heterozygous and homozygous risk allele, respectively, and 0 for homozygous non-risk

allele). GRS19 was assessed for each participant. ASSESSMENT OF CORONARY ATHEROSCLEROSIS Coronary angiography was performed in the Department of Invasive Cardiology, and angiograms were

evaluated independently by two experienced invasive cardiologists. Coronary angiography was used to confirm CAD. FOLLOW-UP PERIOD Subjects were observed from the date of coronary angiography

until 31 December 2013. Follow-up was performed during visits to the clinic. If patients were unable to attend, they were contacted by phone. Stroke diagnosis was performed according to

European Stroke Organization guidelines, and acute coronary syndromes were diagnosed according to European Society of Cardiology guidelines. Cardiovascular mortality involved events due to

acute coronary syndrome (myocardial infarction or unstable angina), heart failure and stroke. Major adverse coronary events included cardiovascular and total mortality and cardiovascular

events (stroke, acute coronary syndromes and new onset of heart failure). STATISTICAL ANALYSIS The main goal of the analysis was to create a relationship between SNPs and elevated nighttime

BP in coronary heart disease patients. A multiple regression model was used for this purpose. An analysis of the Receiver Operating Characteristic was used for predicting daytime and

nighttime SBP and DBP. To determine the ability of daytime and nighttime BPs, cutoff points used to correctly identify subjects with or without major adverse coronary events'

sensitivity and specificity across sites were compared. BP cutoff points were determined by interpolation from the point of intersection between the lines of specificity and sensitivity

(where sensitivity equaled specificity). The point of intersection between the lines of specificity and sensitivity identified the highest numbers of subjects with and without major adverse

coronary events. We also calculated positive and negative predictive values of BP cutoff points for major adverse coronary events. To compare continuous variables, Student's _t_-test or

Mann–Whitney _U_-test was used as appropriate. For categorical variables an χ2 test was used. Log-rank tests were used for comparison of the probability of major adverse coronary events in

the studied groups. Continuous variables were reported as the mean±s.d., and categorical variables were reported as percentages. _P_<0.05 was considered as the level of statistical

significance. Statistical analyses were performed using STATISTICA version 10 (STATISTICA, Tulsa, OK, USA) version 3.0.1. The study protocol was approved by the Ethics Committee of the

Medical University of Gdansk. RESULTS After considering the inclusion and exclusion criteria, 1345 subjects were included in the study. Daytime BP cutoff points that correctly identified the

greatest number of patients with major adverse coronary events were 133 mm Hg for SBP and 77 mm Hg for DBP. Nighttime BP cutoff points that correctly identified the greatest number of

patients with major adverse coronary events were 122 mm Hg for SBP and 73 mm Hg for DBP. According to daytime and nighttime BP cutoff points, patients were divided into four subgroups (Table

2). The baseline characteristics of the study group are summarized in Table 2. In patients with diabetes, we revealed a significant relationship between glycated hemoglobin and both

nighttime SBP (_r_=0.16, _P_<0.01) and nighttime DBP (_r_=0.10, _P_<0.01 ). However, there was no relationship between glycated hemoglobin and daytime SBP and daytime DBP. The BP

values and daytime–nighttime BP variability are presented in Table 3. Analysis of BP dipping revealed the following nighttime SBP drop in groups: daytime BP<133 and <77 mm Hg and

nighttime BP<122 and <73 mm Hg (7.0±5.8%), and daytime BP⩾133 and ⩾77 mm Hg and nighttime BP<122 and <73 mm Hg (13.0±4.8%), daytime BP<133 and <77 mm Hg and nighttime

BP⩾122 and ⩾73 mm Hg (3.0±5.3%), daytime BP⩾133 and ⩾77 mm Hg and nighttime BP⩾122 and ⩾73 mm Hg (4.1±6.6%). Analysis of BP dipping revealed the following nighttime DBP drop in groups:

daytime BP<133 and <77 mm Hg and nighttime BP<122 and <73 mm Hg (11.3±6.5%), daytime BP⩾133 and ⩾77 mm Hg and nighttime BP<122 and <73 mm Hg (17.5±5.5%), daytime BP<133

and <77 mm Hg and nighttime BP⩾122 and ⩾73 mm Hg (2.0±5.6%), and daytime BP⩾133 and ⩾77 mm Hg and nighttime BP⩾122 and ⩾73 mm Hg (8.1±6.6%). The relationships between daytime and

nighttime BPs and GRS19 are presented in Table 4. The median follow-up period was 8.6 years. During 11 567 person-years of follow-up, 245 participants died (2.1 per 1000 person-years),

including 114 of participants from cardiovascular causes (0.98 per 1000 person-years). After taking into consideration cardiovascular events during the follow-up period, 441 (32.7%) subjects

experienced major adverse coronary events. Patients with elevated nighttime and normal daytime BP exhibited an increased risk of major adverse coronary events compared with those with

normal nighttime and elevated daytime BP. The probability of major adverse coronary events in the studied subgroups of patients is presented in Figure 1. Significant differences were noted

between the probability of major adverse coronary events in patients with daytime BP⩾133 and ⩾77 mm Hg and nighttime BP⩾122 and ⩾73 mm Hg and patients with daytime BP⩾133 and ⩾77 mm Hg and

nighttime BP<122 and <73 mm Hg (_P_<0.03). We also observed significant differences between the probability of major adverse coronary events in patients with daytime BP⩾133 and ⩾77 

mm Hg and nighttime BP⩾122 and ⩾73 mm Hg and patients with daytime BP<133 and <77 mm Hg and nighttime BP<122 and <73 mm Hg (_P_<0.02). Significant differences were noted

between probability of major adverse coronary events in patients with daytime BP<133 and <77 mm Hg and nighttime BP⩾122 and ⩾73 mm Hg and patients with daytime BP⩾133 and ⩾77 mm Hg and

nighttime BP<122 and <73 mm Hg (_P_<0.05). We also observed significant differences between the probability of major adverse coronary events in patients with daytime BP<133 and

<77 mm Hg and nighttime BP⩾122 and ⩾73 mm Hg and patients with daytime BP<133 and <77 mm Hg and nighttime BP<122 and <73 mm Hg (_P_<0.04). DISCUSSION The main finding of

our study is the confirmation that elevated nighttime BP is genetically determined and nighttime DBP is related to GRS19 in CAD patients. We also found that elevated nighttime BP is

associated with risk of major adverse coronary events in CAD patients. Persuasive evidence suggests that nighttime BP is superior to daytime BP in predicting outcome.21 Given the limited

reproducibility of daytime BP levels due to the dependence of daily physical activity, cardiovascular risk assessment might be more accurate if based on nighttime BP. Therefore, it is

essential to understand the potential mechanisms that underlie BP regulation at night. The Georgia Cardiovascular Twin Study demonstrated that, apart from genes that also influence daytime

BP, specific genetic determinants explained 44% and 67% of nighttime SBP and DBP heritabilities, respectively.22 In addition to genes that influence both daytime and nighttime BP, a large

portion of heritability is explained by genes that specifically influence BP at night.23 In the present study, we detected and examined the relationship between nighttime BP and SNPs in

patients with CAD for the first time. Although a single SNP determines cardiovascular risk to a very small extent, Ripatti _et al._24 revealed that a GRS based on the additive effects of

SNPs is more associated with cardiovascular risk. Using the concept of the additive effect of SNPs, we constructed GRS based on 19 SNPs significantly associated with cardiovascular risk, and

we revealed that GRS19 was related to nighttime DBP. Moreover, we confirmed that elevated nighttime BP was related to an increased risk of major adverse coronary events. Therefore, GRS19

may be taken into consideration in cardiovascular risk assessment for patients with inappropriate daytime–nighttime BP variability. Leu _et al._25 confirmed genetic association with diurnal

BP changes among subjects with young-onset hypertension. In contrast to our study, Leu _et al._25 did not assess coronary atherosclerosis in coronary angiography. Previously performed

clinical trials confirmed that both elevated daytime BP and nighttime BP were related to cardiovascular risk in CAD patients.26 Moreover, blunted nighttime BP dipping was associated with

advanced CAD and cardiovascular complications that arise from this condition.27 Similarly, in a small group of men, Mousa _et al._28 confirmed the association between blunted nighttime BP

values and coronary atherosclerosis extent in coronary angiography. Brotman _et al._29 demonstrated that non-dipping status was a risk factor for all-cause mortality. Similar to the study by

Brotman _et al._,29 greater than half of the patients were non-dippers in our study. However, in the study by Brotman _et al._,29 non-dipping status was defined as a reduction in mean

nocturnal SBP<10% compared with mean daytime values. In our study, non-dipping status was defined as a reduction in mean SBP<10% and/or a reduction in mean DBP<10% compared with

respective daytime values. Pierdomenico _et al._30 confirmed that circadian BP changes were independently associated with increased cardiovascular risk in elderly subjects. In contrast to

our study, they did not take into consideration coexisting CAD confirmed by coronary angiography. Of note, in our study, elevated nighttime BPs were observed more often in patients with

diabetes, and glycemic control was worse in diabetics with elevated nighttime BPs. Diabetes mellitus is associated with markedly increased cardiovascular risk, and the predictive role of

nighttime BP has already been established in patients with diabetes.3, 31 Previously performed clinical trials confirmed that nocturnal hypertension is more frequent in diabetics, partially

due to autonomic dysfunction.32, 33 However, our study confirmed that elevated nighttime BP is more frequent in diabetics with less effectively controlled glycemia. Accordingly, diabetes,

especially when uncontrolled, may predispose a patient to elevated nighttime BP that may subsequently be related to high cardiovascular risk. A modification as simple and inexpensive as

switching the ingestion time of one or more hypertensive medications from morning to evening or bedtime may be the only action necessary to achieve proper control of nighttime BP. Recently

published results from the MAPEC study confirmed that elevated asleep BP was associated with cardiovascular morbidity and mortality, and a bedtime antihypertensive treatment strategy

significantly reduced cardiovascular risk.34 Our study confirmed that elevated nighttime BP was related to an increased probability of major adverse coronary events in patients with

confirmed CAD. Moreover, the highest risk of major adverse coronary events was observed in patients with elevated nighttime and daytime BPs, but patients with elevated nighttime BP and

normal daytime BP had increased risk of major adverse coronary events compared with subjects with normal nighttime BP and elevated daytime BP. To date, our studies have confirmed that

nighttime BP contribute to increased cardiovascular risk in patients with coronary atherosclerosis confirmed by coronary angiography.35 The systematic review by O'Flynn _et al._36

attempted to explain the reasons for high cardiovascular mortality related to isolated nighttime hypertension. However, analyzed data did not produce a clear answer concerning the

relationship between elevated nighttime BP and target organ damage associated with cardiovascular mortality.36 Haruhara _et al._37 suggested that isolated nocturnal hypertension was related

to renal interstitial fibrosis or tubular atrophy. Furthermore, in the RESIST-POL study, nighttime SBP was independently related to concentric heart hypertrophy.38 Sherwood _et al._39

confirmed that CAD and advanced age are accompanied by blunted nighttime BP dipping, which may increase the risk of adverse cardiovascular events. Some limitations of our study are worth

mentioning. Given that this study was retrospective, longitudinal assessment of hypertension control and changes in antihypertensive therapy were beyond the scope of the investigation. In

addition, multiple assessments of ambulatory BP were not performed, thereby eliminating our ability to determine whether BP values were stable over time or impacted by antihypertensive

treatment. Cutoff points of BP values were established on the basis of BP values measured over 24 h in patients with confirmed CAD. CONCLUSION In conclusion, our study confirmed an important

role of nighttime BP in the development of cardiovascular complications in CAD patients. Subjects with elevated nighttime BP and normal daytime BP exhibit an increased risk of

cardiovascular complications compared with those with normal nighttime and elevated daytime BP. Nighttime SBP is genetically determined and related to the additive effect of SNPs. Future

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Article  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pharmacology, Medical University of Gdansk, Gdansk, Poland Marcin Wirtwein *

Department of Clinical Sciences, Lund University, Malmö, Sweden Olle Melander & Marketa Sjőgren * Department of Hypertension and Diabetology, Medical University of Gdansk, Gdansk, Poland

Michal Hoffmann & Krzysztof Narkiewicz * I Department of Cardiology, Medical University of Gdansk, Gdansk, Poland Marcin Gruchala & Wojciech Sobiczewski Authors * Marcin Wirtwein

View author publications You can also search for this author inPubMed Google Scholar * Olle Melander View author publications You can also search for this author inPubMed Google Scholar *

Marketa Sjőgren View author publications You can also search for this author inPubMed Google Scholar * Michal Hoffmann View author publications You can also search for this author inPubMed 

Google Scholar * Krzysztof Narkiewicz View author publications You can also search for this author inPubMed Google Scholar * Marcin Gruchala View author publications You can also search for

this author inPubMed Google Scholar * Wojciech Sobiczewski View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Marcin

Wirtwein. ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wirtwein,

M., Melander, O., Sjőgren, M. _et al._ Genetic risk factors influence nighttime blood pressure and related cardiovascular complications in patients with coronary heart disease. _Hypertens

Res_ 41, 53–59 (2018). https://doi.org/10.1038/hr.2017.87 Download citation * Received: 07 January 2017 * Revised: 03 April 2017 * Accepted: 05 May 2017 * Published: 05 October 2017 * Issue

Date: January 2018 * DOI: https://doi.org/10.1038/hr.2017.87 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a

shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * coronary atherosclerosis *

coronary artery disease * dipping * DNA polymorphism * nighttime hypertension