Diffuse LAD and LV Thrombus as Possible Manifestation of Protein-S Deficiency in a Young Patient.

Patients with inherited hypercoagulopathies such as protein-S deficiency commonly present with venous thrombosis. However, there are rare cases of arterial thrombosis. We describe a rare case of a diffuse left anterior descending and left ventricular thrombus in a young patient with protein-S deficiency complicated with mid cerebral artery occlusion. (Level of Difficulty: Intermediate.).

Metastatic malignancies and the effect on arterial stiffness and blood pressure levels: the possible role of chemotherapy.

BACKGROUND: The aim of the prospective study was to evaluate blood pressure (BP) and the arterial stiffness before and after chemotherapy in three subgroups of patients with metastatic colorectal, renal cell, and gastrointestinal carcinoma and exploit, if possible, the effect of chemotherapy and biological agents in the event of cardiotoxicity. METHODS: A total of 171 patients were included in the study: 60 with kidney cancer, 18 with gastrointestinal stromal tumors (GISTs), and 93 with metastatic colorectal cancer. All patients were subjected to full clinical and laboratory evaluation before and after chemotherapy. Arterial-stiffness indices were assessed before the initiation and after the completion of chemotherapy by means of pulse wave velocity (PWV; Complior) and augmentation index (AIx; SphygmoCor). RESULTS: Patients in all three cancer cohorts exhibited significantly (P<0.001) higher levels of carotid-radial PWV, carotid-femoral PWV, and AIx postchemotherapy, which remained significant after adjustment for BP and body-mass index. AIx exhibited greater change in the bowel-cancer cohort compared to the kidney and GIST cohorts (median 3.6, 1.75, and 1.4, respectively; P<0.001), which remained significant after adjustment for BP and body-mass index. Multiple regression analysis showed that patients with higher baseline systolic BP, diastolic BP, ejection fraction, and carotid-femoral PWV exhibited smaller differences postchemotherapy, while AIx75 baseline levels showed no difference postchemotherapy. CONCLUSION: There is a clear burden in arterial stiffness in patients under chemotherapy for kidney, GIST, and metastatic colorectal cancer, irrespective of BP and other confounders.

Aldosterone Levels, Aortic Stiffness, and Wave Reflection in Essential Hypertensive Patients.

BACKGROUND: The aim of the present study was to evaluate the grade of arterial stiffening, in relation to aldosterone (ALDO) and plasma renin activity (PRA) levels, in essential never-treated hypertensive patients. MATERIALS AND METHODS: We studied 1,330 consecutive patients without clinical and/or laboratory findings of primary or secondary aldosteronism. Arterial stiffness indices Aix75 and carotid-femoral pulse wave velocity (PWVc-f) were measured and a 24-hour urine collection for ALDO was carried out to classify patients with low ALDO <12 mcg/24 hours and high ALDO >12 but <24 mcg/24 hours. Patients were divided according to PRA (high PRA > 1ng/ml/hour, low PRA < 1ng/ml/hour) and ALDO levels (high ALDO > 12 but <24 mcg/24 hours, low ALDO < 12 mcg/24 hours) in four groups. Also patients were grouped according to serum ALDO quartiles, 24-hour urine ALDO quartiles, PRA quartiles, and serum ALDO/PRA quartiles. RESULTS: Patients were classified in 4 groups: group I (high ALDO and low PRA), group II (high ALDO and high PRA), group III (low ALDO and low PRA), and finally group IV (low ALDO and high PRA). PWVc-f and AoAIx75 were significantly higher in group I followed by group II, III, and IV (P < 0.001). Comparison of arterial stiffness indices according to PRA quartiles and PWVc-f and AoAIx75 showed significantly higher in the 1st quartile compared to 2nd, 3rd, and 4th, respectively (P < 0.001). PWVc-f and AoAIx75 were also compared among the four quartiles of aldosterone-renin ratio and they were significantly higher (P < 0.001) in the 4th quartile followed by the 3rd, 2nd, and 1st, respectively. CONCLUSIONS: Arterial stiffness indices are higher among essential hypertensive patients with high normal serum and urine ALDO levels, pointing to a causal relationship between renin-angiotensin-aldosterone system activation and large artery properties.

Early adverse effect of abnormal glucose metabolism on arterial stiffness in drug naive hypertensive patients.

Arterial stiffness is independently related to increased cardiovascular risk in the hypertensive population. The aim of the present study was to investigate whether various stages of abnormal glucose metabolism may differently affect arterial stiffness in hypertensive patients and whether there is any difference in arterial stiffness among patients with normal glucose regulation. We studied 1375 never-treated hypertensive subjects. Participants were divided into four metabolic groups: normal glucose regulation (NG), impaired fasting glucose, impaired glucose tolerance and type-2 diabetes mellitus (DM 2). Hypertensive subjects with NG were subdivided into three groups according to glucose levels. Arterial stiffness was estimated by carotid-femoral pulse wave velocity (PWV). PWV showed a significant increase from patients with NG to DM 2 (from 7.74 ± 1.38 to 8.40 ± 1.30 to 8.86 ± 1.30 to 10.09 ± 2.07 m/s respectively, p<0.001). Among hypertensive subjects with NG there was an increase in PWV from low normal to high normal values of glucose (p<0.01). PWV was independently related to all glucose metabolic parameters (p<0.001 for all). In the present study, we demonstrated an association between arterial stiffness and glucose tolerance in hypertensive subjects. Given the prognostic significance of arterial stiffness, aims should be towards closer monitoring and intensive care of hypertensive patients with abnormal glucose metabolism.

Prostate-specific antigen levels are associated with arterial stiffness in essential hypertensive patients.

INTRODUCTION: Prostate-specific antigen (PSA) has been recently related to cardiovascular system in a multifactorial way. Arterial stiffness is a independent predictor of cardiovascular events and is involved in the pathogenesis of hypertension. The aim of the present study was to investigate whether PSA values, are associated with arterial stiffness indices in patients with essential arterial hypertension. METHODS: The study comprised 150 consecutive male patients (mean age 60 years) with uncomplicated never-treated essential hypertension. All patients underwent a complete clinical and laboratory evaluation, including measurement of PSA levels. Aortic stiffness and arterial wave reflection assessment was made by using carotid-femoral (PWVc-f) pulse wave velocity and aortic augmentation index corrected for heart rate (AIx75). Patients with prostate cancer or benign prostate hyperplasia (PSA > 4 ng/mL) were excluded from the study. RESULTS: PSA was positively associated with waist-to-hip ratio (r = 0.235, P = 0.04), PWVc-f (r = 0.426, P < 0.001), AIx75 (r = 0.264, P = 0.001), and high sensitivity C-reactive protein (hsCRP; r = 0.376, P < 0.001). In categorization to PSA quartiles, patients in the higher quartile presented with higher waist-to hip ratio (P = 0.009), PWVc-f (P < 0.00001), AIx75 (P < 0.001) and hsCRP (P < 0.001) values. In multivariate analysis after adjustment for various confounders PSA remained a significant determinant of PWVc-f values (beta [SE] = 0.477 [0.13], R(2) = 0.405, P < 0.001). CONCLUSION: The present study points towards an association between PSA levels and aortic stiffness in untreated essential hypertensive males. Potential causal relationships between PSA and arterial stiffness remain to be further explored.

Relationships of osteoprotegerin with albuminuria and asymmetric dimethylarginine in essential hypertension: integrating vascular dysfunction.

OBJECTIVES: To investigate the inter-relationships of osteoprotegerin (OPG) with albumin to creatinine ratio (ACR) and asymmetric dimethylargine (ADMA) in hypertensive patients. METHODS: In 198 untreated non-diabetic hypertensive patients [130 males, mean age=51.5 years, office blood pressure (BP)=152/98 mmHg] ACR values and OPG and ADMA levels were determined. RESULTS: Based on the median value of OPG distribution (5.03 pmol/l) patients with high (n=101) compared with those with low OPG values (n=97) had greater 24-h systolic BP (152±5 versus 137±7 mmHg, p<0.0001), ACR [25.3 (5-190) versus 17.3 (5-92) mg/g, p=0.003) and ADMA [0.62 (0.58-0.68) versus 0.57 (0.48-0.62) µmol/l, p=0.001), independently of confounding factors. Multiple regression analyses revealed that ADMA (b=0.388, p<0.0001), 24-h systolic BP (b=0.228, p=0.01) and ACR (b=0.470, p<0.0001) were independent predictors of OPG (R2=0.398, p<0.0001). CONCLUSIONS: In hypertensive patients, high OPG levels are accompanied by pronounced albuminuria and endothelial dysfunction, as reflected by raised ADMA levels. Furthermore, the independent associations of OPG with ACR and ADMA, suggests a link between OPG and the progression of diffuse hypertensive vascular damage.

Ambulatory blood pressure profile in hypertensive patients with ß-thalassemia minor.

ß-thalassemia trait (ß-TT) is a common genetic disorder in Mediterranean countries, including Greece. Previous studies have shown the protective effect of ß-TT against myocardial infarction. However, the ambulatory blood pressure (BP) profile of such patients has not yet been investigated. Thus, the purpose of the present study was to investigate the ambulatory BP monitoring (ABPM) profile of hypertensives with ß-TT, in comparison with all-cause anemic and non-anemic essential hypertensive patients. The study ultimately comprised of 8861 essential hypertensive, nondiabetic patients who were divided into three groups: group I (n=191, with ß-TT), group II (n=655, anemic) and group III (n=8015, nonanemic). All patients underwent full clinical, laboratory and echocardiographic evaluations, whereas all were subjected to ABPM. Anemia was defined as Hb <12 g per 100 ml for women and <13 g per 100 ml for men, whereas patients with ß-TT were self-referred. The distribution of dipping patterns among the three groups was 61.3 vs. 41.2 vs. 45.8% (P<0.001), whereas for nondippers it was 20.4 vs. 31.5 vs. 27.7% (P<0.001), for extreme-dippers it was 15.7 vs. 15.0 vs. 17.5% (P<0.001) and for reverse dippers it was 2.6 vs. 12.4 vs. 9.0% (P<0.001). Furthermore, mean daytime systolic BP (SBP) among the three groups was 140.13 ± 7.79 vs. 142.02 ± 11.61 vs. 141.99 ± 9.87 mm Hg (P=0.03), and mean nighttime SBP was 125.87 ± 10.4 vs. 131.13 ± 15.7 vs. 129.62 ± 13.31 mm Hg (P<0.001). In the multiple regression analysis, after adjustments for age, body mass index and lipid levels, the differences among daytime and nighttime SBP remained significant at 140.18 ± 9.84 vs. 142.02 ± 9.85 vs. 141.99 ± 9.85 mm Hg (P=0.04) and 125.99 ± 13.07 vs. 131.19 ± 13.08 vs. 129.61 ± 13.07 mm Hg (P<0.001), respectively. Hypertensive patients with ß-TT present with a better 24-h BP profile in comparison with anemic and nonanemic hypertensives. Thus, ß-TT may function protectively in their total cardiovascular risk profile.

Urine albumin excretion, within normal range, reflects increasing prevalence of metabolic syndrome in patients with essential hypertension.

Microalbuminuria is a prognostic marker of cardiovascular disease and is related to metabolic syndrome (MetS). For this purpose, the authors examined the relationship of low grade albuminuria to MetS, using 4 current definitions and a MetS score. They studied 6650 consecutive, nondiabetic, hypertensive patients with normal microalbumin excretion. MetS was defined by Adult Treatment Panel III, American Heart Association, World Heart Organization, International Diabetes Federation criteria, and MetS Gruppo Italiano per lo Studio della Streptochinasi nell'Infarcto Miocardico (GISSI) score. Urine microalbumin concentration was measured after a 24-hour urine collection by immunonephelometry. By all definitions, hypertensive patients with MetS had higher microalbumin levels. Significantly higher microalbumin levels were observed as the number of metabolic components rose. After adjustment for systolic blood pressure, the strength of this association was reduced to a nonsignificant level. Microalbumin levels, within normal range, are increased in patients with MetS, irrespective of the definition criteria.

Serum phosphate in white-coat hypertensive patients: focus on dipping status and metabolic syndrome.

Recent studies indicate an association between serum phosphate levels and blood pressure in hypertensive patients. A growing body of evidence suggests that white-coat hypertension (WCH) is associated with target organ damage. Furthermore, metabolic syndrome (MS) and a non-dipping pattern are associated with increased cardiovascular risk. The purpose of this study was to explore the nocturnal blood pressure fall in patients with WCH according to their serum phosphate levels and number of MS components fulfilled. The study included 2600 patients with WCH who attended our outpatient clinics. All patients underwent repeated office blood pressure measurements, 24-h ambulatory blood pressure monitoring and full clinical and laboratory evaluation. The diagnosis of MS was made according to the Adult Treatment Panel III criteria. Dipping pattern was defined as follows: 'dippers' had a nocturnal systolic blood pressure (NSBP) fall > or =10% but <20%; 'non-dippers' had an NSBP fall <10%; 'extreme dippers' had an NSBP fall > or =20% and 'reverse dippers' had an NSBP increase. There were 314 extreme dippers, 1337 dippers, 734 non-dippers and 116 reverse dippers. Reverse dippers presented with significantly lower levels of serum phosphate, whereas extreme dippers had significantly higher levels (3.39+/-3.29 vs. 3.58+/-3.52 mg per 100 ml, P<0.0001). The patients were classified according to the number of MS components and the main observation was the inverse relationship of serum phosphate with MS components (3.53+/-0.36, 3.50+/-0.38, 3.49+/-0.38, 3.44+/-0.36 and 3.35+/-0.31 mg per 100 ml, respectively, P=0.003). Patients with WCH and low serum phosphate levels appear to have a higher incidence of a non-dipping NSBP profile and an impaired metabolic profile. This observation may be important for the stratification of the cardiovascular risk in WCH patients.

Environmental determinants of blood pressure, arterial stiffness, and central hemodynamics.

BACKGROUND: Arterial stiffness and wave reflection alterations may be implicated in the association between cardiovascular mortality, meteorological variables and ambient particulate matter air pollution. The present study explored the cross-sectional relations between ambient environmental parameters, arterial stiffness, peripheral and central hemodynamics in a large-scale cohort of hypertensive patients and normotensive controls. METHODS: The study comprised 1222 consecutive individuals who sought medical consultation in the hypertension outpatient clinics of the Hippokration' and 'Onassis' Hospitals (Athens, Greece) during a 3-year period (2004-2006). All individuals underwent a complete clinical and lipid-profile assessment at drug-free baseline. Carotid radial, carotid-femoral pulse wave velocity measurements and aortic pressure waveform analysis were performed noninvasively to all participants. Data from the National Technical University of Athens and the air quality department of the Hellenic Ministry for the Environment were used to estimate daily meteorological conditions and PM10 exposure. RESULTS: In the total population, multiple-linear regression analysis revealed no significant associations between environmental variables and arterial stiffness. However, in men, the mean 5 day PM10 air concentration was independently associated with the augmentation pressure [2.0 mmHg (95% confidence interval (CI) 0.56-3.39) per 43.4 microg/m3] and the aortic-pulse pressure [2.78 mmHg (95% CI 3.91-5.12)] denoting a significant effect of particulate matter on the aortic-wave reflection magnitude and central hemodynamics. In addition, globally, the mean-daily temperature was related to the aortic-pulse pressure [-2.38 mmHg (95% CI -4.51 to -0.26) per 23.6 degrees C change] and the subendocardial viability ratio [5.85% (95% CI 1.1-10.6 per 23.6 degrees C)]. CONCLUSION: The exposure to lower environmental temperatures is related to impaired hemodynamics not only to the periphery but also to the aorta. In men, PM10 air-pollution levels are associated with heightened amplitude of the reflection wave leading to significant alterations in central-pulse pressure.

Differential impact of metabolic syndrome on arterial stiffness and wave reflections: focus on distinct definitions.

BACKGROUND: Arterial stiffness and wave reflections are independent predictors of cardiovascular disease. Metabolic syndrome (MS) is related to increased aortic stiffness in several populations. However, it is unclear whether the association of MS with aortic stiffness differs according to the considered definition. Moreover, data regarding the association of wave reflections with MS are limited. For this purpose, we examined the relationship of arterial stiffness and wave reflections with MS by using four current definitions and a score. METHODS: We studied 732 never treated, non-diabetic hypertensive patients. Metabolic syndrome was defined by Adult Treatment Panel III, American Heart Association, World Health Organization (WHO), International Diabetes Federation criteria and MS (GISSI) score. Arterial stiffness was assessed by measuring carotid-femoral pulse wave velocity (PWVc-f). Heart rate-corrected augmentation index (AIx(75)) was estimated as a measure of wave reflections. RESULTS: By all definitions, hypertensive patients with MS had higher PWVc-f compared to hypertensives without MS. On the contrary, no significant difference was observed in AIx(75) between patients with and those without MS except when MS was defined by WHO criteria. An independent association emerged between PWVc-f and GISSI score and MS components (p=0.038 and 0.033 respectively) in patients with MS, after adjustment for age, gender, LDL cholesterol and smoking. Nevertheless, after further adjustment for systolic blood pressure or body mass index, the strength of this association was reduced to a non-significant level. CONCLUSION: Arterial stiffness is increased in patients with metabolic syndrome irrespective of the definition criteria. On the contrary, metabolic syndrome has no effect on wave reflections, except when this is defined by WHO criteria. Regarding the high prognostic significance of both arterial stiffness and wave reflections, these findings might have important clinical implications.

Nocturnal blood pressure fall and metabolic syndrome score in patients with white coat hypertension.

BACKGROUND: Accumulating data report that white coat hypertension (WCH) is associated with target organ damage. Metabolic syndrome (MS), and nondipping pattern is also associated with increased cardiovascular risk. The purpose of this study was to explore the nocturnal blood pressure fall in WCH patients according to their MS score. METHODS: The study comprised 2300 patients with WCH who attended our outpatient clinics. All underwent repeated office blood pressure measurements, 24-h ambulatory blood pressure monitoring, full clinical and laboratory evaluation. The diagnosis of MS was made according to the Adult Treatment Panel III criteria and patients were classified into five groups: group I (hypertension), group II (hypertension and any one component), group III (hypertension and any two components), group IV (hypertension and any three components), and group V (all five components). Dipping pattern was defined as 'dippers' with nocturnal systolic blood pressure (NSBP) fall greater than or equal to 10% but less than 20%, 'nondippers' with NSBP fall greater than or equal to 0% but less than 10%, 'extreme dippers' with NSBP fall greater than or equal to 20%, and 'reverse dippers' with NSBP increase. RESULTS: Patients were divided into two groups according to the presence (n=522) and absence (n=1778) of MS. The overall prevalence of MS in the study population was 22.7%. Comparing the non-MS group with the MS we observed significant differences for nondippers (24.5% vs. 38.9%, P<0.001), dippers (54.4% vs. 43.5%, P<0.001), extreme dippers (17.8% vs. 11.3%, P<0.001), and reverse dippers (3.3% vs. 6.3%, P=0.007). CONCLUSION: Patients with WCH and increased number of MS components present with elevated nighttime SBP levels. This observation is of a great significance in the assessment of the cardiovascular risk in these patients.

Microalbuminuria and global myocardial function in patients with essential hypertension [correction of hypertensive].

INTRODUCTION: The myocardial performance index, Tei index, is a relatively new echocardiography indice which is related to parameters which express both the systolic and diastolic myocardial function. The purpose of the present study was to investigate the possible correlation of Tei index to microalbuminuria, which is an indice of kidney target-organ damage in hypertensive patients. MATERIALS AND METHODS: We evaluated 9680 consecutive patients (mean age 55.2 years, 5144 male and 4536 female) with chronic uncomplicated essential hypertension and the correlation between Tei index, defined as the sum of the isovolumetric relaxation and contraction time divided by the ejection time, and kidney target damage (microalbuminuria) was evaluated. RESULTS: In univariate analysis we noticed a positive correlation of Tei index with microalbuminuria (r=0.353 p<0.001). Furthermore, a significant difference was found in each Tei quartile for microalbumin levels (p<0.001). In multivariate analysis with Tei index as a dependent variable (high versus low quartile) and independent variables gender, age, body mass index, plasma glucose, heart rate, blood pressure, kidney function indices and lipids, the independent prognostic correlation to microalbuminuria was noticed (OR: 1.002 p<0.001). CONCLUSIONS: In the present study we found that Tei index correlates with microalbuminuria in essential hypertensive patients. Thus we can assume that this index could be used not only for the evaluation of the global myocardial performance of hypertensive patients but also for the assessment of the cardiovascular risk in arterial hypertension since it correlates with kidney damage.

Beneficial effect of angiotensin II type 1 receptor blocker antihypertensive treatment on arterial stiffness: the role of smoking.

The purpose of the present study was to assess angiotensin receptor blocker (ARB) treatment on arterial stiffness in select hypertensive patients and define possible differences between smokers and nonsmokers. The authors evaluated 81 consecutive, nondiabetic patients (mean age, 52 years; 47 men) with uncomplicated essential hypertension with high plasma renin activity who were administered monotherapy with irbesartan, an ARB, at maximal dose. Patients were divided into smokers (n=24) and nonsmokers (n=57). Carotid-radial pulse wave velocity (PWVc-r), carotid-femoral pulse wave velocity (PWVc-f), and augmentation index (AIx) were measured before and 6 months after ARB antihypertensive treatment. All mean values of elastic effect indices were decreased after irbesartan monotherapy (AIx, from 26.3%to 21.2% [P<.01;] PWVc-f, from 7.7 m/s to 7.3 m/s [P<.05], and PWVc-r, from 8.9 m/s to 8.3 m/s [P<.001]). When comparing smokers vs nonsmokers, no difference was noted in AIx and PWVc-f change (P=not significant), while PWVc-r change was greater in smokers compared with nonsmokers (P<.05). Chronic ARB treatment may favorably affect arterial stiffness and wave reflections in hypertensive chronic smokers with elevated plasma renin levels.

Nocturnal blood pressure fall and metabolic syndrome score in hypertensive patients.

BACKGROUND: Data relating dipping status to metabolic syndrome (MS) scores are not available. The purpose of this study is to investigate any possible association of different dipping patterns to MS scores in untreated patients with essential hypertension. METHODS: The study included 6256 consecutive, treatment-naive patients with essential hypertension who attended our outpatient clinics. All underwent repeated office blood pressure measurements, 24-h ambulatory blood pressure monitoring, and full clinical and laboratory evaluation. The diagnosis of MS was made according to the Adult Treatment Panel III criteria and patients were classified into five groups: group I (hypertension), group II (hypertension+any one component), group III (hypertension+any two components), group IV (hypertension+any three components), and group V (all five components). Dipping pattern was defined as 'dippers' with nocturnal systolic blood pressure (NSBP) falling >or=10 but <20%, 'nondippers' with NSBP falling >or=0% but <10%, 'extreme dippers' with NSBP falling >or=20%, and 'reverse dippers' with NSBP increasing. RESULTS: Hypertensive patients with MS (n=2573) had higher clinical and ambulatory blood pressure values (P<0.001), whereas the dominant dipping pattern in the non-MS group was nondippers (47.6%), and in the MS group, extreme dippers (37.8%). Furthermore, a considerable decrease in the prevalence of dippers was noticed with the increasing number of MS components (21.1 vs. 19.2 vs. 14.5 vs. 8.4 vs. 7.2%, P<0.001). In contrast, a significant rise in the prevalence of reverse dippers was observed with the increasing number of MS components (7.4 vs. 10.1 vs. 14.9 vs. 20.4 vs. 31.2%, P<0.001). CONCLUSIONS: It seems that hypertensive patients have an increased prevalence of abnormal dipping patterns as the number of MS components rises.

Beneficial effects of angiotensin II type 1 receptor blocker antihypertensive treatment on inflammation indices: the effect of smoking.

The effect of long-term angiotensin II type 1 receptor blocker (ARB) therapy on inflammation indices has not been fully investigated in a hypertensive population. The authors evaluated 323 consecutive nondiabetic patients (mean age, 57 years; 176 men; 92 smokers) with high renin activity and uncomplicated essential hypertension whose blood pressure levels normalized (from 163.9/100.7 mm Hg to 131.6/82.8 mm Hg) after 4 weeks of ARB or ARB/diuretic treatment. All patients underwent full laboratory evaluation (routine examination of blood and urine, liver, kidney, thyroid function, and lipid and glucose profiles), including measurement of high-sensitivity C-reactive protein and serum amyloid A levels, at drug-free baseline, which was repeated after 6 months of ARB or ARB/diuretic treatment. A significant (P<.001) overall decrease was noted in both high-sensitivity C-reactive protein (-0.41+/-1.56 mg/dL) and serum amyloid A (-0.62+/-2.03 mg/dL), but a smaller decrease in high-sensitivity C-reactive protein and serum amyloid A change was seen in the smoker subgroup compared with nonsmokers (P<.05), indicating that the ARB or ARB/diuretic anti-inflammatory effect may be adversely affected by smoking status.