Abstract
Objective
We investigated the relationship between D-dimer levels and long-term major adverse cardiovascular events (MACEs) in masked hypertension patients admitted to the cardiology outpatient clinic.
Methods
A total of 512 masked hypertension patients with a median 6 years of follow-up data who underwent serum D-dimer measurement in the hypertension outpatient clinic between April 2014 and June 2016 were retrospectively enrolled. The patients were stratified according to their D-dimer levels and were then divided into tertiles. Clinical outcomes were assessed for MACEs, which were defined as all-cause mortality, cardiovascular mortality, nonfatal myocardial infarction, and nonfatal stroke.
Results
The long-term incidence of MACE in masked hypertension patients was higher in the highest tertile of D-dimer. In multivariable analysis, D-dimer was an independent predictor of long-term MACE in masked hypertensive patients (OR: 1.006 [1.004–1.007]; p < 0.001). Compared to the lowest tertile, MACE was approximately 3 times higher in tertile 2 and approximately 10.5 times higher in the highest tertile. In addition, MACE was approximately 3.5 times more common in tertile 3 than in tertile 2. D-dimer was able to predict MACE in patients with masked hypertension (AUC for MACE 0.778; 95% CI: 0.724–0.832; p < 0.001) based on receiver operating characteristic curve analysis. In the Kaplan-Meier curve showing follow-up without MACE (MACE free) according to the D-dimer cutoff value, the long-term incidence of MACE was significantly higher in the high D-dimer group (p < 0.001).
Conclusions
D-dimer levels in patients with masked hypertension showed a significant association with increased long-term risk of MACE in this study.
Keywords: D-dimer, Masked hypertension, Major adverse cardiovascular events
Introduction
Hypertension is an important public health problem that imposes a heavy economic, social, and psychological burden due to its causal relationship with major adverse cardiovascular (CV) events (MACEs) [1–3]. However, a significant proportion of patients have been shown to have masked hypertension, defined as a mean 24-h ambulatory blood pressure (BP) (AMBP) >130 and 80 mm Hg, despite a clinical BP <140/90 mm Hg [4, 5]. The prevalence of masked hypertension in the general population can be as high as 10%. Still, data from various cross-sectional studies show that prevalence rates can increase to values as high as 50% [6]. Individuals with masked hypertension have been shown to have a higher risk of CV events than those with normotension, and this evidence suggests that screening and treatment of individuals with masked hypertension may be beneficial [7, 8]. To effectively estimate CV risks in individuals with masked hypertension, which is so common, it may be useful to use various risk scores. However, masked hypertension involves a broad spectrum of patients and patient groups in a variety of risk categories. Thus, the definition of markers with prognostic significance in patients with masked hypertension may contribute to risk stratification and help reduce the incidence of CV events.
D-dimer is a marker of thrombogenesis and hypercoagulability and is a degradation product of cross-linked fibrin formed during thrombus formation [9]. Adverse clinical outcomes including venous thromboembolism, stroke, pulmonary embolism, aortic dissection, tumors, and coronary artery disease have been associated with elevated D-dimer levels [10–15]. In addition, D-dimer levels are higher in people with high BP than in people with normal BP and have been shown to increase significantly with the severity of hypertension [16]. In masked hypertensive patients, however, no previous study has investigated the relationship between D-dimer levels and the long-term MACE. Therefore, in this study, we evaluated the relationship between D-dimer levels and long-term MACE in masked hypertension patients admitted to the cardiology outpatient clinic.
Subjects and Methods
Study Population
The study retrospectively included 512 masked hypertensive patients with long-term follow-up data undergoing serum D-dimer measurement at the hypertensive outpatient clinic of Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgeons Training and Research Hospital. Patients with clinical BP <140/90 mm Hg who were not taking any antihypertensive medication but had a mean 24-h AMBP >130 and 80 mm Hg were included. Exclusion criteria were documented hypertension, treatment with antihypertensive drugs, or clinical BP >140/90 mm Hg during the examination. In addition, patients with missing laboratory values, clinical data, and ABPM data were excluded. This study adhered to the tenets of the Declaration of Helsinki. The study had local Ethics Committee approval and all patients had informed consent.
Clinic and Ambulatory BP Measurements
Clinical BP measurements were performed according to the recommendation of the European Society of Cardiology (ESC) guidelines [1], and participants sat quietly for 10 min with the nondominant arm selected and placed at heart level. Three consecutive BP measurements were obtained at 1-min intervals at each reading, and the last 2 readings were averaged and defined as clinical BP (HEM7200, Omron Healthcare, Tokyo, Japan). All patients were followed up with ABPM for 24 h. BP was recorded oscillometrically with an automatic monitoring device (Mobil-O-Graph NG; I.E.M. GmbH, Stolberg, Germany) and analyzed using appropriate software (I.E.M. GmbH). The recordings were taken every 15 min between 08:00 and 23:00 during the day and every 30 min between 23:00 and 08:00 during the night. Masked hypertension was defined as clinic systolic and diastolic BP <140/90 mm Hg, with mean 24-h systolic BP >130 mm Hg and mean 24-h diastolic BP >80 mm Hg.
Data Collection
The echocardiographic mass of the left ventricle was estimated using the Devereux formula and indexed to the body surface area (left ventricular mass index). Left ventricular hypertrophy (LVH) was identified as a left ventricular mass index >115 g/m2 in men and >95 g/m2 in women. Biochemical parameters including fasting plasma glucose (FPG), glycosylated hemoglobin A1c (HbA1c), lipid profiles, and creatinine serum levels were measured using fasting venous blood. D-dimer levels were tested according to the manufacturer’s instructions (Instrumentation Laboratory, Lexington, MA, USA) using a HemosIL D-Dimer HS on an ACL TOP 550 automated coagulation analyzer. Patients were stratified into three groups on the basis of D-dimer levels as follows: tertile 1, <155.3 mg/dL; tertile 2, 155.3–256.7 mg/dL; and tertile 3, >256.7 mg/dL. Clinical, laboratory, and demographic information was collected from hospital records. National digital records were used to obtain patient survival data. Telephone calls with patients or their relatives were used to obtain information on MACE in survivors.
Definition
MACE was defined as nonfatal myocardial infarction (MI), nonfatal stroke, all-cause mortality, and CV mortality. CV mortality was specified as unexplained sudden death due to hemodynamically significant arrhythmia, acute heart failure, or acute STEMI. The fourth universal definition of MI guidelines [17] was used to define nonfatal MI. The stroke was considered an ischemic stroke with evidence of neurologic deficit requiring hospital admission, with clinical signs of lesions in computed tomography or magnetic resonance imaging of the brain.
Statistical Analysis
Statistical Package for Social Sciences, version 21 (IBM SPSS Statistics for Windows, version 21.0, IBM Corp., Armonk, NY, USA), was used for statistical analysis. To determine the normal distribution of variables, visual (histograms, probability plots) and analytical (Kolmogorov-Smirnov/Shapiro-Wilk tests) methods were used. Descriptive analyses are presented in terms of mean values and standard deviations. Numbers and percentages are used for categorical variables. Numerical variables were compared using one-way ANOVA and Kruskal-Wallis test. Chi-squared test was used to compare categorical data. Univariate and multivariate logistic regression analyses were used to identify independent predictors of MACE, and 95% confidence intervals (CIs) and odds ratios (ORs) were presented. Receiver operating characteristic (ROC) curves were used to show the predictive value of d-dimer for MACE. Kaplan-Meier curves were used to show survival without MACE. All tests were 2 tailed. A p value <0.05 was considered statistically significant.
Results
We analyzed 512 masked hypertension patients with a median follow-up of 6 years (maximum 8 years). Patients were stratified into tertiles on the basis of D-dimer levels, and baseline characteristics and MACE rates are shown in Table 1. Age, diabetes mellitus, history of MI, and left atrial diameter were significantly higher with increasing D-dimer levels (all p < 0.05). However, although office and AMBPs were higher with increasing D-dimer levels, they did not show statistical significance (all p > 0.05). Among the laboratory parameters, HbA1c and fasting blood glucose increased significantly with increasing D-dimer levels (all p < 0.05).
Table 1.
Baseline characteristics of patients and outcome rates according to D-dimer tertile
| Variables | Baseline D-dimer, mg/dL | |||
|---|---|---|---|---|
| Tertile 1 (n = 173) | Tertile 2 (n = 168) | Tertile 3 (n = 171) | p value | |
| (<155.3 mg/dL) | (155.3–256.7 mg/dL) | (>256.7 mg/dL) | ||
| Age, years | 49.7±11.5 | 49.8±11.6 | 54.3±11.1 | <0.001 |
| Sex (male) | 98 (56.6) | 91 (54.2) | 80 (46.8) | 0.229 |
| Smoking | 20 (11.5) | 21 (12.6) | 23 (13.4) | 0.285 |
| Diabetes mellitus | 18 (10.4) | 15 (8.9) | 56 (32.7) | <0.001 |
| Previous MI | 5 (2.9) | 11 (6.5) | 26 (15.2) | <0.001 |
| Previous stroke | 1 (0.6) | 0 (0) | 1 (0.6) | 0.612 |
| Heart failure | 7 (4.0) | 4 (2.4) | 7 (4.1) | 0.622 |
| LVH | 43 (24.9) | 48 28.6) | 49 (28.7) | 0.665 |
| Left atrium, mm | 34.5±4.0 | 35.1±4.0 | 36.2±4.1 | <0.001 |
| LVEF (%) | 63.7±3.5 | 63.5±5.9 | 63.0±3.6 | 0.364 |
| Systolic BP, mm Hg | ||||
| Office | 128.1±5.2 | 128.8±5.0 | 128.2±5.7 | 0.314 |
| Ambulatory 24-h | 144.4±7.4 | 147.1±7.6 | 148.5±6.9 | 0.017 |
| Ambulatory daytime | 146.5±7.5 | 150.2±18.4 | 155.1±21.0 | 0.052 |
| Ambulatory nighttime | 137.3±11.2 | 136.9±11.5 | 139.2±11.4 | 0.137 |
| Diastolic BP, mm Hg | ||||
| Office | 78.6±5.6 | 79.4±4.9 | 80.2±4.1 | 0.058 |
| Ambulatory 24-h | 91.2±8.7 | 93.0±7.0 | 91.3±6.7 | 0.059 |
| Ambulatory daytime | 94.3±6.8 | 95.2±6.7 | 94.0±7.4 | 0.269 |
| Ambulatory nighttime | 83.7±6.9 | 84.3±8.0 | 83.1±7.9 | 0.406 |
| Laboratory values | ||||
| Total cholesterol, mg/dL | 206.4±41.8 | 204.3±41.0 | 202.4±33.1 | 0.629 |
| HDL-c, mg/dL | 45.2±12.2 | 45.8±12.7 | 46.9±12.3 | 0.491 |
| LDL-c, mg/dL | 136.0±37.1 | 133.3±35.0 | 1,316±34.0 | 0.495 |
| Triglyceride, mg/dL | 173.4±110.1 | 155.4±75.8 | 162.4±103.5 | 0.222 |
| Creatinine, mg/dL | 0.80±0.22 | 0.83±0.58 | 0.82±0.23 | 0.821 |
| HbA1c, % | 5.7±0.69 | 5.7±0.55 | 6.4±1.11 | <0.001 |
| FPG, mg/dL | 100.8±23.3 | 100.3±21.8 | 126.5±55.8 | <0.001 |
| All-cause mortality | 0 (0) | 0 (0) | 5 (2.9) | 0.007 |
| CV mortality | 0 (0) | 0 (0) | 2 (1.2) | 0.135 |
| Nonfatal MI | 8 (4.6) | 20 (11.9) | 50 (29.2) | <0.001 |
| Nonfatal stroke | 1 (0.6) | 3 (1.8) | 6 (3.5) | 0.140 |
| MACE | 10 (5.8) | 26 (15.5) | 67 (39.2) | <0.001 |
Data presented as mean ± SD or number (%).
BP, blood pressure; CV, cardiovascular; FPG, fasting plasma glucose; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; LDL-c, low-density lipoprotein cholesterol; LVEF, left ventricular ejection fraction; MACE, major adverse cardiac event; MI, myocardial infarction.
At a median follow-up of 6 years, 103 patients developed MACE. Higher D-dimer levels were significantly associated with higher MACE rates (5.8% vs. 15.5% vs. 39.2%, respectively, p < 0.001). All-cause mortality and nonfatal MI increased significantly with increasing D-dimer (all p < 0.05). However, the groups were similar in terms of CV mortality and nonfatal stroke.
The univariate and multivariate analyses of the independent predictors of long-term MACE in masked hypertension patients are displayed in Table 2. In multivariable analysis, D-dimer and diabetes mellitus were independent predictors of long-term MACE in masked hypertension patients (OR: 1.006 [1.004–1.007]; p < 0.001, OR: 1.674 [1.005–2.988]; p = 0.048, respectively). Compared to the lowest tertile, MACE was about 3-fold higher in tertile 2 and about 10.5-fold higher in the highest tertile (OR: 2.984 [1.391–6.402]; p = 0.005 vs. OR: 10.519 [5.170–21.321]; p < 0.001). In addition, MACE was approximately 3.5-fold more common in tertile 3 than in tertile 2 (OR: 3.518 [2.094–5.911]; p < 0.001) (Fig. 1).
Table 2.
Multivariate regression analysis for potential predictors of MACE
| Variables | Univariate analysis | Multivariate analysis | ||
|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | |
| Age (per year) | 1.015 (0.991–1.039) | 0.237 | ||
| Diabetes mellitus | 2.325 (1.396–3.873) | 0.001 | 1.674 (1.005–2.988) | 0.048 |
| Previous MI | 1.344 (0.564–3.203) | 0.500 | ||
| Ambulatory 24-h systolic BP | 0.973 (0.933–1.013) | 0.184 | ||
| Ambulatory 24-h diastolic BP | 1.012 (0.970–1.057) | 0.581 | ||
| Left atrium | 0.978 (0.917–1.043) | 0.500 | ||
| D-dimer | 1.005 (1.003–1.007) | <0.001 | 1.006 (1.004–1.007) | <0.001 |
BP, blood pressure; CI, confidence interval; OR, odds ratio; MACE, major adverse cardiac event; MI, myocardial infarction.
Fig. 1.
OR and 95% CI for MACE according to D-dimer tertile.
The ROC curves of D-dimer for the prediction of MACE in patients with masked hypertension are displayed in Figure 2. The AUC of D-dimer for the prediction of MACE in patients with masked hypertension was 0.778 (95% CI: 0.724–0.832; p < 0.001). The cutoff value of D-dimer for the prediction of MACE was 262.1 mg/dL, the sensitivity was 0.709, and the specificity was 0.707.
Fig. 2.
ROC curve analysis to determine the value of D-dimer to predict long-term MACE.
Figure 3 illustrates the Kaplan-Meier survival curve for follow-up without MACE (MACE free) according to the D-dimer cutoff value. In masked hypertensive patients, the long-term frequency of MACE was markedly higher in the high D-dimer group compared to the low D-dimer group (p < 0.001).
Fig. 3.
Follow-up without a MACE (MACE free) survival curve of groups.
Discussion
Our study aimed to identify independent predictors of long-term MACE in masked hypertensive patients with focus on the role of D-dimer. The significant results obtained were as follows: (1) D-dimer was significantly related to an increased risk of long-term MACE in masked hypertensive patients and (2) the ROC curve demonstrated that D-dimer has a predictive value for MACE in masked hypertensive patients.
An important phenotype of hypertension is the masked hypertension. Masked hypertension is characterized by a normal clinical BP level but elevated BP outside the clinic. Numerous studies have also demonstrated that masked hypertension is related to increased CV events [7, 8]. One meta-analysis reported that CV events were approximately 2-fold higher in patients with masked hypertension compared with normotension. It also shows that the prognostic impact of masked hypertension is not affected by the different out-of-office BP measurements used to detect it [18]. Thus, the incidence of CV events in masked hypertension is at least twice as high as in true normotensive patients and is similar or even higher in incidence in patients with sustained hypertension [18, 19]. In a study conducted in Japan, the masked hypertension group had a greater risk of stroke compared with the controlled BP group (hazard ratio, 2.77; 95% CI, 1.20–6.37), independent of traditional CV risk factors, urine albumin-to-creatinine ratio, and circulating B-type natriuretic peptide levels. In contrast, masked hypertension was not associated with the risk of coronary heart disease [6]. In our study, we were unable to make comparisons because of a lack of data on urine albumin-to-creatinine ratio and circulating B-type natriuretic peptide levels. The fact that masked hypertension is largely undetected and untreated may have contributed to this finding. The incidence of CV events and stroke is similar in normotensive patients with masked hypertension and prehypertensive patients with masked hypertension [20]. Therefore, masked hypertension should never be considered an innocent condition.
Masked hypertension covers a broad spectrum of patients and patient groups in a variety of risk categories and CV disease may be more severe in patients with masked hypertension, which may lead to an elevated risk of CV events in these patients. However, this risk may not be the same in every patient. Identifying markers with prognostic value in masked hypertensive patients may therefore help to stratify risk, thereby modifying treatment and helping to reduce the incidence of CV events.
D-dimer is a fibrin degradation product that plays a key role in the coagulation and fibrinolysis systems. Elevated D-dimer levels reflect an increase in blood coagulation, thrombin generation, and conversion of cross-linked intravascular fibrin [21, 22]. D-dimer has been evaluated as a potential diagnostic marker for thromboembolic disorders such as pulmonary embolism, disseminated intravascular coagulation, and deep vein thrombosis. Circulating D-dimer levels are also known to be elevated for a variety of reasons, including stroke, coronary artery disease, pregnancy, cancer, trauma, recent surgery, severe kidney disease, advanced age, and many other conditions. [23–25]. In addition, increased D-dimer levels have been reported to be associated with CV diseases and prognosis [15, 26]. There are many studies investigating the relationship between hypertension and D-dimer levels. One study showed that D-dimer levels were higher in hypertensive patients with left ventricular enlargement, LVH, and left atrial enlargement [27]. In our study, LVH was similar between the groups, although the left atrial diameter was significantly larger with increasing D-dimer levels. In addition, a previous study showed that higher D-dimer levels in patients with hypertension were associated with target organ damage [28]. Another study reported that D-dimer levels were higher in patients with hypertension than in the controls; these levels were found to increase significantly with the severity of hypertension. [16, 29]. Since there are no previous studies examining the impact of D-dimer levels on long-term MACE in masked hypertension patients, we investigated the long-term prognostic effect of D-dimer in masked hypertension patients. We showed that D-dimer was an independent predictor of long-term MACE including all-cause death, CV death, nonfatal MI, and nonfatal stroke in masked hypertension patients.
The findings of this study support the potential application of D-dimer for early risk assessment in patients with masked hypertension and potentially as a predictor of MACE in these patients. Therefore, monitoring D-dimer levels in patients with masked hypertension may help to define high-risk groups that need a more extensive diagnostic approach, including in-depth investigations, follow-up strategies, and timely and appropriate medical interventions. However, whether patients with masked hypertension benefit from treatment to lower D-dimer levels requires further study.
The mechanism through which D-dimer levels are predictive of MACE has not been elucidated. The findings reported in our study can be explained by several mechanisms. First, patients in the higher D-dimer tertile are more likely to have traditional CV risk factors and comorbidities such as diabetes, older age, chronic kidney disease, hypertension, coronary heart disease stroke, and heart failure than those in the lowest tertile. Second, a higher D-dimer level may reflect greater systemic fibrin formation and an increased propensity for thrombosis, given the mechanism of D-dimer formation [9, 23]. Patients with essential hypertension are known to have an imbalance in the fibrinolytic system, which tends toward a hypercoagulable state compared to normotensive individuals [29]. The higher incidence of thrombotic complications in hypertensive patients compared with normotensive patients may be partly explained by this. Therefore, hypercoagulability associated with hypertension-induced endothelial damage is more likely to be present in hypertensive patients with higher D-dimer levels. Third, it is known that elevated D-dimer levels represent increased coagulation and fibrinolytic activity and may be clinically useful in predicting the risk of venous thromboembolism as well as the risk of stroke, future MI, abdominal aortic aneurysm, or acute aortic dissection. Therefore, undiagnosed CV disease is more likely to be present in patients with high D-dimer levels. The mechanism underlying the association between D-dimer levels and MACE in masked hypertensive patients requires further study.
When interpreting the results of this study, several limitations should be taken into account. First, the generalizability of our findings to other populations may be limited because this retrospective observational study was conducted in a single center. Second, we only measured D-dimer levels once, and repeated measurements were not analyzed. The predictive value of monitoring changes in D-dimer levels over time could not be assessed. Third, our results may have been affected by confounding variables that were not measured. Information on anticoagulant treatment, which could be a relevant confounder, was not included in this study. Other unknown confounders may have affected our results, despite our efforts to control for multiple variables. Fourth, not all masked hypertensive patients underwent D-dimer testing, and it is possible that the frequency of testing was higher in high-risk patients than in the low-risk patients, leading to selection bias. Finally, it was not possible to assess variables that are thought to have a direct impact on patient prognosis, such as changes in treatment regimen, adherence to antihypertensive therapy, and BP control at follow-up.
Conclusion
This study shows that elevated D-dimer levels in patients with masked hypertension are significantly associated with increased long-term risk of MACE. This study provides the utility of D-dimer to enhance baseline CV risk assessment. It also suggests that assessment of D-dimer levels during antihypertensive therapy may help monitor CV risk. These findings suggest that masked hypertension patients with elevated D-dimer levels need special attention and a more comprehensive treatment approach through in-depth investigation and close follow-up. Clinicians need to pay more attention to masked hypertension patients with high D-dimer levels as they may be at high risk of MACE.
Acknowledgments
We are very grateful to the biostatistics and cardiology department members of the İstanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Training and Research Hospital for giving this study so much of their attention and time.
Statement of Ethics
The Basaksehir Cam and Sakura City Hospital Ethics Committee approved the study (Approval No.: 2024-250, date: 03.05.2024).
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors declare that this study received no financial support.
Author Contributions
All authors contributed to (1) conception and design, or acquisition of data, or analysis and interpretation of data, (2) drafting the article or revising it critically for important intellectual content, and (3) final approval of the version to be published.
Funding Statement
The authors declare that this study received no financial support.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.