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Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References
  8. Supporting Information

The aim of the study was to assess the impact of current smoking on 24-hour blood pressure (BP) and inflammatory and hemostatic activity and thereby the incidence of cardiovascular disease (CVD) in Japanese hypertensive patients. A total of 810 hypertensive patients (mean age 72 years; 38% men) were prospectively followed-up (2799 person-years). During the follow-up, 66 cases of CVD occurred (stroke, 55; myocardial infarction, 7; both, 4). At baseline, the current smokers (n=166) had higher levels of high-sensitivity C-reactive protein (hs-CRP) (0.21 mg/dL vs 0.14 mg/dL) and plasminogen activator inhibitor-1 (PAI-1) (46.1 ng/mL vs 37.8 ng/mL; both P=.001), but not of 24-hour BP, compared with nonsmokers. Using a Cox regression analysis, current smoking was independently associated with an increased risk of CVD (hazard ratio [HR], 2.6; P<.01), and the risk was substantially higher in women (HR, 6.1; P<.001) than in men (HR, 1.4; P=.41). The CVD risk of current smokers was magnified when it was accompanied with high hs-CRP (highest quartile range, ≥0.40 mg/L) or PAI-1 levels (≥58.9 ng/mL) compared with that in smokers with low hs-CRP or PAI-1 levels (both P<.05). Among hypertensive patients, current smokers had increased risk of CVD events, and the increase was more prominent when accompanied by circulatory inflammatory and hemostatic abnormalities. J Clin Hypertens (Greenwich). 2012;00:00–00. ©2012 Wiley Periodicals, Inc.

There is compelling evidence of the impact of cigarette smoking on the development of coronary artery disease (CAD), stroke, and sudden cardiac death.1–5 In Japan, smoking could explain a large portion of cardiovascular disease (CVD) mortality and all-cause mortality.5 In particular, the combined effect of smoking and hypertension on CVD and all-cause mortality is large,3 which highlights the importance of elucidating the pathophysiological mechanisms of smoking in hypertensive patients and identification of CVD-prone high-risk patients.

Some studies have shown that current normotensive or hypertensive smokers tend to have higher ambulatory blood pressure (BP), rather than higher office BP, compared with nonsmokers.6,7 Moreover, it is increasingly recognized that low-grade inflammation as well as alterations of coagulation and/or fibrinolysis homeostasis in the circulation or at the vascular interface can occur in current smokers.8–12 These abnormalities may in part explain the increased cardiovascular risk of current smoking. However, we are not aware of any existing data directly assessing the impact of current smoking on the incidence of CVD events in relation to its adverse effects on 24-hour BP and inflammatory and hemostatic activity in hypertensive patients.

Accordingly, in the present study we examined whether current smoking is associated with abnormalities of 24-hour BP and inflammatory and hemostatic factors, and, as a consequence, CVD events in Japanese hypertensive patients.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References
  8. Supporting Information

Patients

The methods of the study have been detailed elsewhere.13,14 Briefly, we initially enrolled 821 hypertensive outpatients (clinic BP ≥140/90 mm Hg and age older than 50 years) in the present study between January 1, 1992, and January 1, 1998. Patients who had a history of stroke, coronary artery disease, chronic heart failure, peripheral vascular disease, atrial fibrillation, and obvious present illness (eg, malignancy or infection) at baseline were excluded from this study. Follow-up examination was successfully conducted in 811 (99%) patients.

Clinic BP was measured after at least 5 minutes of seated rest. Diabetes mellitus was defined as a fasting glucose level ≥126 mg/dL, a random nonfasting glucose level ≥200 mg/dL, hemoglobin A1c≥6.2%, or the use of an oral hypoglycemic agent or insulin. Hyperlipidemia was defined as a total cholesterol level ≥240 mg/dL or the use of an oral lipid-lowering agent. To estimate renal function, the glomerular filtration rate was estimated (eGFR) by the Modification of Diet in Renal Disease study equation modified for Japanese: 194 Cr−1.094×age−0.287×0.739 (for women).15 The patients were asked whether they were currently smoking or not.

This study was approved by the independent research ethics committee, Jichi Medical University School of Medicine, Japan, in 1998. All of the patients studied were ambulatory, and all gave informed consent to participate in the study.

24-Hour ABPM

Twenty-four–hour ambulatory BP monitoring (ABPM) was performed with an automatic oscillometric device at 30-minute intervals.13,14 The ambulatory data used were obtained by the oscillometric method. All patients recorded their waking time and their bedtime. We defined daytime and nighttime BP as the average of values from each of these two periods.

Assay for Inflammatory and Hemostatic Factors

The methods are detailed in the Supporting Information. Briefly, in the morning (8–10 am) after an overnight fast, venous blood was obtained after 10 minutes in the supine position. Serum high-sensitivity C-reactive protein (hs-CRP) level was measured by nephelometry (NA Latex CRP kit; Dade Behring, Fort Lauderdale, FL). The plasma fibrinogen level was determined using a one-stage clotting assay kit (Dade Behring), and the plasma levels of prothrombin fragment 1+2 (F1+2) and plasminogen activator inhibitor-1 (PAI-1) antigen were determined using enzyme-immunosorbent assay kits for F1+2 (Behringwerke AG, Marburg, Germany) and PAI-1 (Biopool, Umea, Sweden). The plasma level of the von Willebrand factor (vWF) was measured using a specific enzyme-linked immunosorbant assay (ELISA) kit (Shield Diagnostics, Ltd, Dundee, UK). This assay uses a monoclonal antibody against the functional epitope of vWF,16 rather than the polyclonal antibody used by previous commercially available ELISA kits, and the value for the commercially available pooled plasma (CTS Standard Plasma; Behringwerke AG) was taken as 100%. All measurements were conducted at a single commercial laboratory (SRL Inc, Tokyo, Japan), and the intra-assay and inter-assay coefficients of all tests were <7%.

Follow-Up and Events

The patients’ medical records were intermittently reviewed after ABPM to check on their antihypertensive drug therapy and to assess the occurrence of clinical CVD events, such as cardiac events or stroke. The follow-up was performed during a 20-month period from 1996 to 1998; the mean follow-up period was 41±14 months, with a range of 1 to 68 months. Among the 811 patients who were successfully followed-up, 426 patients (53%) were taking antihypertensive medication at the time of the final follow-up. When patients failed to come to the clinic, we interviewed them by telephone: none of the cases interviewed by telephone were diagnosed as having had a CVD event. All CVD events were diagnosed by the physician who was caring for the patient at the time of the event, and independent physicians reviewed the cases and confirmed the diagnosis of CVD events. Cardiac events included fatal and nonfatal acute myocardial infarction or events requiring treatment by percutaneous coronary intervention. Stroke was diagnosed on the basis of a sudden onset of a neurological deficit persisting for ≥24 hours in the absence of any other disease that could explain the symptom. Stroke events were categorized as ischemic stroke (cerebral infarction and cerebral embolism) or hemorrhagic stroke; the patients whose diagnoses were defined by clinical symptoms but not with brain computed tomography or magnetic resonance imaging were considered to have had an undefined type of stroke. We excluded transient ischemic attacks, ie, those in which the neurological deficit was cleared completely within 24 hours from the onset of symptoms.

Statistical Analysis

All statistical analyses were performed with SPSS version 18.0 J software (SPSS, Chicago, IL). Variables with normal distribution are expressed as mean±standard deviation (SD), whereas variables with skewed distribution were logarithmically transformed before analysis and expressed as geometric means (SD range). Clinical parameters in patients with or without current smoking were compared using the unpaired t test, and categorical parameters were compared with the chi-square test. Analysis of covariance with adjustment for age, sex, body mass index (BMI), and a history of diabetes or hyperlipidemia was performed to examine the differences in 24-hour BP and inflammatory and hemostatic risk factors in patients with or without current smoking. The hazard ratio (HR) and 95% confidence interval (CI) of clinical CVD events in the current smokers were calculated using Cox regression analyses with adjustments for significant covariates that were determined by the differences in the baseline clinical characteristics between the current smokers and nonsmokers (ie, sex, BMI, history of diabetes, history of hyperlipidemia, and 24-hour pulse rate [PR]). In that model, we also included and calculated the HR and 95% CI of clinical CVD events for each patient with quartiles (highest quartile vs lower quartiles) of inflammatory and hemostatic factors.

Finally, we divided the patients according to the presence of current smoking and the circulatory levels of hs-CRP, another set according to the presence of current smoking and the circulatory levels with or without the highest quartile of F1+2, and a third set according to the presence of current smoking and the circulatory levels with or without the highest quartile of PAI-1. Kaplan-Meier curves were used to compare the unadjusted CVD events-free survival rate among these sets of 4 groups, and the differences were assessed by the log-rank test. The HR (95% CI) of clinical CVD events in the groups of each set were also calculated using Cox regression analyses with adjustments for significant covariates. Statistical significance was defined as P<.05.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References
  8. Supporting Information

Clinical Characteristics

One patient with unsatisfactory blood collection was excluded, thus 810 patients were included in the final analysis. The mean age±SD of the 810 patients was 72.3±9.8 years, and 311 of the patients (38%) were men. The baseline clinical characteristics according to the presence of current smoking are shown Table I. Compared with nonsmokers, current smokers were more likely men, had lower BMI, higher prevalence of type 2 diabetes, and lower prevalence of hyperlipidemia.

Table I. Baseline Clinical Characteristics of the Study Population According to the Presence of Current Smoking Status
 Nonsmoker (n=644)Current Smoker (n=166) P Value
  1. Abbreviations: DBP, diastolic blood pressure; eGFR, glomerular filtration rate; PR, pulse rate; SBP, systolic blood pressure. Data are expressed as means±standard deviation. P values were obtained by an unpaired t test or chi-square test. aVariables expressed as the geometric mean (95% confidence interval) with adjustment for age, sex, body mass index, and a history of diabetes or hyperlipidemia by analysis of covariance. Statistical significance was defined as P<.05.

Patient characteristics
 Age, y72.1 ± 9.873.0 ± 10.1.29
 Men, %2878<.001
 Body mass index, kg/m224.1 ± 3.523.1 ± 3.6.001
 Type 2 diabetes, %924<.001
 Hyperlipidemia, %2110.002
 eGFR, mL/min/1.73m256.2 ± 13.356.3 ± 14.3.93
 Antiplatelet drugs, %2728.70
BP measurements
 Office SBP, mm Hga164 (163 to 166)164 (161 to 167).42
 Office DBP, mm Hga91 (89 to 92)90 (88 to 93).95
 Office PR, beats per mina76 (75 to 77)79 (77 to 81).04
 24-Hour SBP, mm Hga138 (136 to 139)139 (137 to 142).30
 24-Hour DBP, mm Hga78 (77 to 79)79 (77 to 80).40
 24-Hour PR, beats per mina70 (70 to 71)72 (71 to 73).03
 Daytime SBP, mm Hg145 (143 to 146)146 (143 to 149).49
 Daytime DBP, mm Hg82 (81 to 82)82 (80 to 84).83
 Daytime PR, beats per mina76 (76 to 77)77 (76 to 79).22
 Nighttime SBP, mm Hga126 (125 to 128)128 (125 to 131).24
 Nighttime DBP, mm Hga72 (71 to 73)73 (71 to 75).40
 Nighttime PR, beats per mina61 (60 to 61)62 (61 to 64).02
 Nocturnal SBP dipping, %a−12 (−13 to −12)−12 (−13 to −10).48
Inflammatory factors
 White blood cells, ×103/μLa5.7 (5.6 to 5.8)5.7 (5.5 to 6.0).88
 High-sensitivity C-reactive protein, mg/La0.14 (0.12 to 0.15)0.21 (0.17 to 0.27).001
Hemostatic factors
 Fibrinogen, mg/dLa267.7 (263.0 to 272.5)277.8 (267.6 to 288.4).09
 Prothrombin fragment 1+2, nmol/La1.5 (1.4 to 1.5)1.6 (1.5 to 1.7).02
 von Willebrand factor, %a157.4 (153.7 to 161.2)166.0 (157.9 to 174.5).07
 Plasminogen activator inhibitor-1, ng/mLa37.8 (36.0 to 39.7)46.1 (41.6 to 51.1).001

Associations of Smoking With 24-Hour BP, Inflammation, and Hemostasis

Office and nighttime PRs were higher in patients with current smoking than those without it, but no significant differences were found in office, daytime, or nighttime BP levels between the two groups (Table I). In contrast, patients with current smoking had significantly higher levels of hs-CRP, F1+2, and PAI-1 than those without current smoking, and this difference remained unchanged even after adjustment for age, sex, BMI, and a history of diabetes or hyperlipidemia (data not shown).

Smoking and CVD Risk

During an average duration of 41 months (range: 1–68 months, 2799 person-years), 66 CVD events occurred (23.6 events/1000 person-years), including 59 events of clinical stroke (ischemic, 38; hemorrhagic, 9; undefined, 12) and 11 cardiac events. Among the patients with cardiac events, 4 patients had clinical stroke events during the follow-up period. When we analyzed the patients according to the presence of current smoking, the crude incidence of CVD events in current smokers was higher (50.0 events/1000 person-years) than that in noncurrent smokers (17.0 events/1000 person-years).

The baseline clinical characteristics according to the occurrence of clinical CVD events are shown in Table II. At the time of final follow-up, there was no difference in the prevalence of antihypertensive medications between patients with current smoking and those without current smoking (calcium channel blockers: 36% vs 34%, P=.72; diuretics: 3.0% vs 3.6%, P=1.00), except for the use of angiotensin-converting enzyme (ACE) inhibitors (34% vs 18%, P<.01).

Table II. Baseline Clinical Characteristics of the Study Population According to the Occurrence of CVD Event
 CVD Event (−) (n=744)CVD Event (+) (n=66) P Value
  1. Abbreviations: ACE, angiotensin-converting enzyme; BP, blood pressure; CVD, cardiovascular disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; PR, pulse rate; SBP, systolic blood pressure. Data are expressed as the means±standard deviation (SD) or percentage. P values were obtained by an unpaired t test or chi-square test. Variables with skewed distributions (a) were logarithmically transformed before analysis and expressed as geometric means (SD range). Statistical significance was defined as P<.05.

Patient characteristics
 Age, y71.7 ± 9.978.5 ± 7.1<.001
 Men, %3750.05
 Body mass index, kg/m224.0 ± 3.522.7 ± 3.8.003
 Current smoker, %1942<.001
 Type 2 diabetes, %1218.17
 Hyperlipidemia, %19181.00
 eGFR, mL/min/1.73 m256.5 ± 13.552.3 ± 13.5.02
 Antiplatelet drugs, %2644.002
BP measurements
 24-Hour SBP, mm Hg137 ± 16148 ± 16<.001
 24-Hour DBP, mm Hg78 ± 1082 ± 10.003
 24-Hour PR, beats per min71 ± 772 ± 9.29
 Daytime SBP, mm Hg144 ± 18153 ± 16<.001
 Daytime DBP, mm Hg81 ± 1184 ± 10.03
 Daytime PR, bpm77 ± 878 ± 10.32
 Nighttime SBP, mm Hg126 ± 18138 ± 20<.001
 Nighttime DBP, mm Hg72 ± 1076 ± 12.002
 Nighttime PR, beats per min61 ± 863 ± 9.10
 Nocturnal SBP dipping, %−13 ± 9−10 ± 11.01
 Antihypertensive drug use during follow-up5349.52
 Calcium channel blockers, No. (%)34.433.3.89
 ACE inhibitors, No. (%)21.719.7.76
 Diuretics, No. (%)3.53.01.00
 α-Blockers, No. (%)1.31.51.00
 β-Blockers, No. (%)1.50.61
Inflammatory factors
 White blood cells, ×103/μLa5.7 (4.5–7.3)5.8 (4.6–7.4).72
 High-sensitivity C-reactive protein, mg/La0.14 (0.04–0.57)0.25 (0.07–0.88).001
Hemostatic factors
 Fibrinogen, mg/dLa267.8 (213.9–335.3)293.1 (231.1–371.9).002
 Prothrombin fragment 1+2, nmol/La1.5 (1.0–2.2)1.8 (1.1–2.9)<.001
 von Willebrand factor, %a158.1 (117.1–213.5)170.9 (126.1–231.6).04
 Plasminogen activator inhibitor-1, ng/mLa38.1 (20.8–70.0)56.2 (27.9–113.1)<.001

In Cox regression analysis (Table III), patients with current smoking had a significantly higher incidence of clinical CVD events than those without current smoking even after adjusting for sex, BMI, history of diabetes, history of hyperlipidemia, and 24-hour PR (Table III, model 1). Additional adjustment for the use of ACE inhibitors or calcium channel blockers at the time of final follow-up did not change the CVD risk of current smoking (data not shown). When the CVD risk of current smoking was analyzed by sex, it was substantially high in women (HR, 6.1; 95% CI, 2.8–13.4; P<.001) rather than in men (HR, 1.4; 95% CI, 0.7–2.8; P=.41).

Table III. Cox Regression Analysis for Cardiovascular Disease Events
VariableModel 1 HR (95% CI)Model 2 HR (95% CI)
  1. Hazard ratios (HRs) and 95% confidence intervals (CIs) for cardiovascular disease (CVD) events are shown after adjustment for sex, body mass index, history of diabetes, history of hyperlipidemia, and 24-hour pulse rate (model 1). Model 2 was adjusted by model 1 plus high levels of high-sensitivity C-reactive protein, prothrombin fragment 1+2, and plasminogen activator inhibitor-1. The analysis of each hemostatic parameter was based on the following code: 0=the lower 3 quartiles, 1=the highest quartile. Statistical significance was defined as P<.05. aP<.01. bP<.05. cP<.001.

Current smoking (0=no, 1=yes)2.6 (1.5–4.7)a2.1 (1.1–3.8)b
High-sensitivity C-reactive protein (0:<0.40 mg/L, 1: ≥0.40 mg/L)2.4 (1.4–3.9)a
Prothrombin fragment 1+2 (0: <1.8 nmol/L, 1: ≥1.8 nmol/L)2.2 (1.4–3.6)a
Plasminogen activator inhibitor-1 (0: <58.9 ng/mL, 1: ≥58.9 ng/mL)2.5 (1.5–4.1)c

Next, we entered the highest quartile of circulatory hs-CRP (≥0.40 mg/L, n=201), F1+2 (≥1.8 nmol/L, n=202), and PAI-1 (≥58.9 ng/mL, n=202) in model 1 in Table III. As a result, current smoking as well as each of these inflammatory and hemostatic parameters were significantly and independently associated with an increased risk of CVD events (Table III, model 2). When we entered hs-CRP, F1+2, and PAI-1 as continuous variables instead of categorical variables in model 2, the conclusion remained unchanged (data not shown).

We divided the patients into 4 groups according to the presence of current smoking and the highest quartile of circulatory levels of hs-CRP, F1+2, or PAI-1 levels. Kaplan-Meier curves to compare the unadjusted CVD events-free survival rate among each set of 4 groups are shown in Figure S1–S3. We also analyzed the HR and 95% CI of the patients for each of the 4 groups calculated by Cox regression analysis with adjustment for confounding factors (Figure, A–C). The CVD risk of current smoking was significantly higher when it was accompanied with the highest quartile of hs-CRP level or PAI-1 compared with when it was accompanied with the lower quartiles of hs-CRP or PAI-1 level, respectively (Figure, A and C).

image

Figure FIGURE.  Cox regression analysis of cardiovascular disease (CVD) events. The hazard ratio (HR) (95% confidence interval [CI]) of CVD events in patients with or without current smoking and high or low levels of high-sensitivity C-reactive protein (hs-CRP) (a), prothrombin fragment 1+2 (F1+2) (b), and plasminogen activator inhibitor-1 (PAI-1) (c) are shown. The analysis was adjusted for age, sex, body mass index, a history of diabetes, estimated glomerular filtration rate, a use of antiplatelet drugs, antihypertensive medication at the time of final follow-up, and 24-hour systolic blood pressure level. *P<.05 vs group (i), **P<.01 vs group (i), †P<.001 vs group (i), ||P<.05 vs group (ii), ¶P<.05 vs group (iii).

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Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References
  8. Supporting Information

This prospective study is the first report directly demonstrating the impact of current smoking on the incidence of CVD events in relation to its influences on 24-hour BP and inflammatory and hemostatic activity in older hypertensive patients. The main findings of the present study were as follows: (1) current smokers had significantly higher levels of circulatory inflammatory and hypercoagulable and hypofibrinolytic activity than those without current smoking; (2) current smokers had a 2.6-fold increased risk of CVD events than those without current smoking; and (3) the CVD risk of current smokers was magnified when accompanied with high hs-CRP (≥0.40 mg/L) or PAI-1 levels (≥58.9 ng/mL).

Smoking and 24-Hour BP

In contrast with previous reports,6,7 our data indicated that there were no significant differences in office BP, daytime BP, and nighttime BP levels between current smokers and nonsmokers. Despite the acute adverse effects of smoking on BP, epidemiological studies have shown inconsistent associations between smoking and high BP.1,2,17,18 Weight gain, a risk factor for high BP, may be an important confounder in such an association, since any benefit on BP from quitting smoking could be offset by the weight gain that occurs after smoking cessation.19 In the present study, ex-smokers were included as nonsmokers, which might have led to a tendency to underestimate the association between current smoking and BP levels. Moreover, we did not assess the smoking dose (cigarettes/day) or the nicotine content in current smokers, despite the fact that these parameters could have influenced the association between smoking and high BP.20,21 In contrast, an increase in office PR or nighttime PR was observed in current smokers. This may have been caused by an increase in sympathetic nerve activity or impaired parasympathetic nerve activity promoted by smoking;7 however, the CVD risk of current smoking was not affected by the high office PR or nighttime PR levels.

Smoking, Inflammation, Hemostasis, and CVD Risk

Smoking influences the immune system (ie, neutrophils, macrophages, lymphocytes, and dendritic cells) in many ways, including through continual exposure to oxidative stressors.12 As a consequence, a low-grade systemic inflammatory response is evident in smokers as confirmed by numerous population-based studies. Elevated levels of CRP, interleukin 6, and tumor necrosis factor α have been reported.8,11,12 Moreover, several studies have shown that rheological alteration and circulatory procoagulant and hypofibrinolytic activity occurred in current smokers.4,8–12 As a consequence, it has been thought that these abnormalities may in part explain the increased cardiovascular risk of current smoking; however, there has been no report directly assessing whether inflammatory and hemostatic abnormalities accompanied with current smoking are associated with clinical CVD events in hypertensive patients.

Our data indicated that the circulatory levels of hs-CRP, F1+2, and PAI-1 were significantly elevated in current smokers relative to nonsmokers (Table I). Intriguingly, the CVD risk of current smoking can be magnified when it is accompanied with high circulatory hs-CRP or PAI-1 levels (Figure, A and C). Circulatory hs-CRP or PAI-1 levels are determined by not only smoking, but also other pathophysiological conditions, such as metabolic syndrome, some neurohumoral factors (eg, high sympathetic nerve activity and renin-angiotensin-aldosterone system), and sleep apnea,22 but we did not evaluate these factors in the present study; therefore, further investigations are required to examine how conditions or comorbidities can contribute to exaggerate the CVD risk associated with smoking in hypertensive patients.

Sex Difference of Cardiovascular Risk in Current Smoking

As in previous Japanese and Western reports,1,4 the cardiovascular risk of smoking was found to be greater in women than in men. The mechanism is unclear, but possible biological aspects have been suggested. A previous study showed that the CVD risk of smoking was exaggerated by the absence of estrogen status.23 This may be in part due to the fact that estrogen exerts beneficial effects on the hemostatic system, eg, it increases fibrinolytic potential and decreases procoagulant factors.24 Although we could not assess the presence of menopause in the present study, our female patients were sufficiently advanced in age to be postmenopausal, suggesting that they may have lost some of the protection conferred by estrogen. Moreover, unmeasured factors, such as participants’ characteristics, may have been important contributors to this phenomenon. Female smokers may be significantly different from nonsmoking women in terms of their health-related behaviors and social activities, both of which could confound the association between smoking and CVD risk.4,25 In spite of these findings, the result that the Cox regression showed an HR with a wide range of 95% CI values for the CVD risk of female smokers may have been a result of the small sample size, and thus our data should be interpreted with caution.

Study Limitations

There were several limitations in the present study. First, as mentioned above, we did not assess the number of ex-smokers who were categorized as nonsmokers in the present study. Certain adverse reactions, such as high CRP levels, remain elevated for longer periods after smoking cessation,8 and this phenomenon could lead to underestimation of the CVD risk conferred by current smoking. Second, we did not collect any data on the smoking dose or duration (years), or on the lifelong smoking dose (pack-years), which would be of interest to refine the potential dose effect of smoking on inflammatory/hemostatic biomarker levels and CVD risk. Third, the hemostatic factors measured in the present study, in particular PAI-1, showed diurnal variation (ie, they rose in the morning).26 Although all blood sampling was conducted in the morning, there may be intra-individual and inter-individual variation in hemostatic factors, which may lead to an underestimation of the true association between cigarette smoking, hemostatic factors, and CVD events. Lastly, our findings were derived from hypertensive patients, and thus generalization to the general population or other ethnicities is not appropriate.

Conclusions

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References
  8. Supporting Information

This study has clearly shown an increased risk of CVD events conferred by current smoking in Japanese hypertensive patients, and this risk was more prominent when accompanied by circulatory inflammatory and hemostatic abnormalities. These results need to be confirmed in larger studies, and interventional studies will also be needed to establish the precise values of our data.

Acknowledgments:  This study was supported by a research grant for cardiovascular medicine (14-6) from the Ministry of Health, Labor, and Welfare (K.K.) and a research grant (C-2) from the Ministry of Education, Culture, Sports, Science, and Technology (K.K.) of Japan.

Disclosure:  None.

References

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  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References
  8. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. Conclusions
  7. References
  8. Supporting Information

Data S1. Methods.

Figure S1–S3. Kaplan-Meier cumulative incidence of CVD.

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jch12047_sm_Suppdata.doc125KSupporting info item

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