Fibrinogen and a Triad of Thrombosis, Inflammation, and the Renin-Angiotensin System in Premature Coronary Artery Disease in Women: A New Insight into Sex-Related Differences in the Pathogenesis of the Disease.

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in women worldwide. Its social impact in the case of premature CAD is particularly devastating. Many differences in the presentation of the disease in women as compared to men, including atypical symptoms, microvascular involvement, and differences in pathology of plaque formation or progression, make CAD diagnosis in women a challenge. The contribution of different risk factors, such as smoking, diabetes, hyperlipidemia, or obesity, may vary between women and men. Certain pathological pathways may have different sex-related magnitudes on CAD formation and progression. In spite of the already known differences, we lack sufficiently powered studies, both clinical and experimental, that assess the multipathogenic differences in CAD formation and progression related to sex in different age periods. A growing quantity of data that are presented in this article suggest that thrombosis with fibrinogen is of more concern in the case of premature CAD in women than are other coagulation factors, such as factors VII and VIII, tissue-type plasminogen activator, and plasminogen inhibitor-1. The rise in fibrinogen levels in inflammation is mainly affected by interleukin-6 (IL-6). The renin-angiotensin (RA) system affects the inflammatory process by increasing the IL-6 level. Unlike in men, in young women, the hypertensive arm of the RA system is naturally downregulated by estrogens. At the same time, estrogens promote the fibrinolytic path of the RA system. In young women, the promoted fibrinolytic process upregulates IL-6 release from leukocytes via fibrin degradation products. Moreover, fibrinogen, whose higher levels are observed in women, increases IL-6 synthesis and exacerbates inflammation, contributing to CAD. Therefore, the synergistic interplay between thrombosis, inflammation, and the RA system appears to have a more significant influence on the underlying CAD atherosclerotic plaque formation in young women than in men. This issue is further discussed in this review. Fibrinogen is the biomolecule that is central to these three pathways. In this review, fibrinogen is shown as the biomolecule that possesses a different impact on CAD formation, progression, and destabilization in women to that observed in men, being more pathogenic in women at the early stages of the disease than in men. Fibrinogen is a three-chain glycoprotein involved in thrombosis. Although the role of thrombosis is of great magnitude in acute coronary events, fibrinogen also induces atherosclerosis formation by accumulating in the arterial wall and enabling low-density lipoprotein cholesterol aggregation. Its level rises during inflammation and is associated with most cardiovascular risk factors, particularly smoking and diabetes. It was noted that fibrinogen levels were higher in women than in men as well as in the case of premature CAD in women. The causes of this phenomenon are not well understood. The higher fibrinogen levels were found to be associated with a greater extent of coronary atherosclerosis in women with CAD but not in men. Moreover, the lysability of a fibrin clot, which is dependent on fibrinogen properties, was reduced in women with subclinical CAD compared to men at the same stage of the disease, as well as in comparison to women without coronary artery atherosclerosis. These findings suggest that the magnitude of the pathological pathways contributing to premature CAD differs in women and men, and they are discussed in this review. While many gaps in both experimental and clinical studies on sex-related differences in premature CAD exist, further studies on pathological pathways are needed.

The association between the insertion/deletion polymorphism of the angiotensin-converting enzyme gene and the plasma fibrinogen level in women and men with premature coronary artery atherosclerosis.

INTRODUCTION: The insertion/deletion (I/D) polymorphism of the angiotensin­converting enzyme (ACE) gene is associated with younger age at coronary artery disease (CAD) onset. Some data indicate the relationship between the DD genotype and the fibrinogen level. At the same time, the regulation of the renin-angiotensin system differs in women and men. OBJECTIVES: The objective of the study was to evaluate the sex­dependentassociation of the ACE I/D polymorphism with the plasma fibrinogen level in patients with premature CAD. PATIENTS AND METHODS: The study included 407 participants with premature CAD: 257 women not older than 55 years and 150 men not older than 45 years. Study participants had at least 1 stenosis ≥50% in a major epicardial coronary artery. The ACE I/D polymorphism (rs4343) was genotyped using polymerase chain reaction. Fibrinogen levels were measured with a modified Clauss method. We found a significant interaction indicating that sex modifies the influence of the I/D polymorphism of the ACE gene on fibrinogen levels (P = 0.02). The highest mean fibrinogen level, adjusted for age and smoking status, was observed in women with the DD genotype (575.7 mg/dl) and it was significantly higher than in men with the DD genotype (367.1 mg/dl; P <0.001) or in women with the ID genotype (491.7 mg/dl; P = 0.04). In men, there was no significant difference in mean adjusted fibrinogen levels across genotypes. CONCLUSIONS: The DD genotype of the ACE gene was associated with higher plasma fibrinogen levels in women with premature CAD yet not in men.

Giant Intrapericardial Myxoma Adjacent to the Left Main Coronary Artery.

A 62-years-old woman was admitted to the hospital because of chronic cough, expectoration of thick mucus, hoarseness and tightness in the precordial area. Computed Tomography (CT) examination revealed the presence of a giant intrapericardial tumor with the dimensions of 80 × 38 × 32 mm. It was located anteriorly and laterally to the left atrium, posteriorly to the pulmonary trunk and the ascending aorta. This hypodense change modeled the left atrium without evidence of invasion. CT coronary angiography and 3-dimensional reconstruction were applied to enable precise planning of cardiac surgery. CT evaluation confirmed that it is possible to remove the tumor without damage to the adjacent left main coronary artery. The patient underwent cardiac surgery with sternotomy and cardiopulmonary bypass. A cohesive, smooth, vascularized tumor pedunculated to the left atrial epicardium was visualized. The location and dimensions corresponded to those determined by CT scan examination. The entire tumor was successfully dissected together with adjacent adipose and fibrous tissue. Histological evaluation revealed the presence of myxoid cells, blood vessels, degenerative changes, and microcalcifications embedded in profuse hyalinized stroma. Those histological features enabled identification of the intrapericardial tumor as a myxoma. Follow-up CT examination did not demonstrate any signs of recurrence of the myxoma. According to our knowledge, a myxoma located inside the pericardial sac has never been described before.

Menopause improves the predictive value of common cardiovascular risk scores in women with premature coronary artery disease.

OBJECTIVE: Menopause, particularly its early stage (≤3 years from onset), may be an important risk factor for premature coronary artery disease. The objective of the study was to assess whether the addition of the presence of menopause in women with premature coronary artery disease could improve the predictive value of the Atherosclerotic Cardiovascular Disease risk estimator and the Systematic COronary Risk Evaluation model. METHODS: The case-control study included 307 women with coronary artery disease aged 55 or less, and 347 age-matched controls without coronary artery disease. Diagnostic accuracy parameters were evaluated for traditional risk models versus those enriched with menopausal status. Early and late postmenopausal periods were defined as ≤3 and >3 years from the onset of menopause, respectively. RESULTS: Only the addition of the presence of the early postmenopausal stage to the 10-year Atherosclerotic Cardiovascular Disease risk classes resulted in significantly increased c-statistics from 0.66 (95% confidence interval [CI] 0.62-0.7) to 0.705 (95%CI 0.66-0.75) (P = 0.0003) and an increase of accuracy from 61.3% to 63.8% (P = 0.0025).Adding the presence of early postmenopause to the Systematic COronary Risk Evaluation risk classes also resulted in significantly increased c-statistics from 0.59 (95% CI 0.55-0.63) to 0.641 (95%CI 0.6-0.68) (P = 0.0024) and an increase of accuracy from 64.1% versus 57.5% (P = 0.001). CONCLUSION: Adding the early menopausal period may significantly improve the predictive value of the 10-year Atherosclerotic Cardiovascular Disease risk score and the Systematic COronary Risk Evaluation model in women with premature coronary artery disease.

Pulmonary artery rupture as a complication of Swan-Ganz catheter application. Diagnosis and endovascular treatment: a single centre's experience.

INTRODUCTION: The placement of a Swan-Ganz catheter into the pulmonary artery may lead to a number of complications (2-17%). In less than 0.2% of cases Swan-Ganz catheterization results in serious vascular damage - pulmonary artery rupture (PAR). This paper presents two distinct forms of iatrogenic PAR treated endovascularly using different vascular devices. AIM: To evaluate the effectiveness of endovascular treatment and the application of different types of vascular devices in the management of pulmonary artery rupture caused by Swan-Ganz catheterization. MATERIAL AND METHODS: In this retrospective study we evaluated 2 patients in whom Swan-Ganz catheter application was used for perioperative monitoring and resulted in pulmonary artery rupture. This complication was treated endovascularly by means of interventional cardiology. RESULTS: We report the cases of 2 patients with a pulmonary artery pseudoaneurysm formed in the perioperative period. In case 1, a single, 4-loop, 3 mm diameter coil was implanted. In case 2, a 5 mm Amplatzer Vascular Plug IV was applied. In both cases, the endovascular approach resulted in total occlusion of the feeding artery and reduced further extravasation of the blood. CONCLUSIONS: Despite its extremely low incidence, iatrogenic PAR is a serious, life-threatening complication of Swan-Ganz catheterization that requires urgent attention. Among available methods of treatment, percutaneous embolization is a relatively quick, safe, accurate and highly effective alternative to traumatizing surgery.

Exercise capacity and mortality in patients with ischemic left ventricular dysfunction randomized to coronary artery bypass graft surgery or medical therapy: an analysis from the STICH trial (Surgical Treatment for Ischemic Heart Failure).

OBJECTIVES: The objective of this study was to assess the prognostic significance of exercise capacity in patients with ischemic left ventricular (LV) dysfunction eligible for coronary artery bypass graft surgery (CABG). BACKGROUND: Poor exercise capacity is associated with mortality, but it is not known how this influences the benefits and risks of CABG compared with medical therapy. METHODS: In an exploratory analysis, physical activity was assessed by questionnaire and 6-min walk test in 1,212 patients before randomization to CABG (n = 610) or medical management (n = 602) in the STICH (Surgical Treatment for Ischemic Heart Failure) trial. Mortality (n = 462) was compared by treatment allocation during 56 months (interquartile range: 48 to 68 months) of follow-up for subjects able (n = 682) and unable (n = 530) to walk 300 m in 6 min and with less (Physical Ability Score [PAS] >55, n = 749) and more (PAS ≤55, n = 433) limitation by dyspnea or fatigue. RESULTS: Compared with medical therapy, mortality was lower for patients randomized to CABG who walked ≥300 m (hazard ratio [HR]: 0.77; 95% confidence interval [CI]: 0.59 to 0.99; p = 0.038) and those with a PAS >55 (HR: 0.79; 95% CI: 0.62 to 1.01; p = 0.061). Patients unable to walk 300 m or with a PAS ≤55 had higher mortality during the first 60 days with CABG (HR: 3.24; 95% CI: 1.64 to 6.83; p = 0.002) and no significant benefit from CABG during total follow-up (HR: 0.95; 95% CI: 0.75 to 1.19; p = 0.626; interaction p = 0.167). CONCLUSIONS: These observations suggest that patients with ischemic left ventricular dysfunction and poor exercise capacity have increased early risk and similar 5-year mortality with CABG compared with medical therapy, whereas those with better exercise capacity have improved survival with CABG. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease [STICH]; NCT00023595).

Lumen and calcium characteristics within calcified coronary lesions. Comparison of computed tomography coronary angiography versus intravascular ultrasound.

INTRODUCTION: Computed tomography coronary angiography (CTCA) is a diagnostic method used for exclusion of coronary artery disease. However, lower accuracy of CTCA in assessment of calcified lesions is a significant factor impeding applicability of CTCA for assessment of coronary atherosclerosis. AIM: To provide insight into lumen and calcium characteristics assessed with CTCA, we compared these parameters to the reference of intravascular ultrasound (IVUS). MATERIAL AND METHODS: Two hundred and fifty-two calcified lesions within 97 arteries of 60 patients (19 women, age 63 ±10 years) underwent assessment with both 2 × 64 slice CT (Somatom Definition, Siemens) and IVUS (s5, Volcano Corp.). Coronary lumen and calcium dimensions within calcified lesions were assessed with CTCA and compared to the reference measurements made with IVUS. RESULTS: On average CTCA underestimated mean lumen diameter (2.8 ±0.7 mm vs. 2.9 ±0.8 mm for IVUS), lumen area (6.4 ±3.4 mm(2) vs. 7.0 ±3.7 mm(2) for IVUS, p < 0.001) and total calcium arc (52 ±35° vs. 83 ±54°). However, analysis of tertiles of the examined parameters revealed that the mean lumen diameter, lumen area and calcium arc did not significantly differ between CTCA and IVUS within the smallest lumens (1(st) tertile of mean lumen diameter at 2.1 mm, and 1(st) tertile of lumen area at 3.7 mm(2)) and lowest calcium arc (mean of 40°). CONCLUSIONS: Although, on average, CTCA underestimates lumen diameter and area as well as calcium arc within calcified lesions, the differences are not significant within the smallest vessels and calcium arcs. The low diagnostic accuracy of CTCA within calcified lesions may be attributed to high variance and not to systematic error of measurements.

The impact of early menopause on risk of coronary artery disease (PREmature Coronary Artery Disease In Women--PRECADIW case-control study).

BACKGROUND: Despite improved understanding of atherothrombosis pathophysiology, risk factors associated with premature coronary artery disease (CAD) in women are poorly recognized. DESIGN AND METHODS: A single-centre, case-control study comprised 323 women (less than 55 years) with established CAD, enrolled between April 2005 and January 2008, and 347 age-matched healthy women selected from the Multi-Center All-Polish Health Survey. We aimed to assess the relationship of menopause and premature CAD. RESULTS: In multivariate analysis smoking, parental history of premature CVD, diabetes, menopause and hypertension were the strongest risk markers for premature CAD with ORs (95% CI): 3.83 (2.52-5.82); 3.08 (1.85-5.14); 2.89 (1.59-5.23); 2.82 (1.91-4.19); 2.39 (1.16-3.54). The most significant association was found for early postmenopause in a model including the early and late stage of postmenopause (≤ and >3 years of its onset), with OR 4.55 (95% CI 2.82-7.35), higher than other risk factors. The receiver operating characteristic (ROC) curves area revealed a significant increase from 0.81 in that model that included traditional risk factors and parental premature CVD to 0.85 after addition of the early and late stage of postmenopause. CONCLUSIONS: We have shown that smoking and early postmenopausal stage (≤3 years) are the most important determinants of premature CAD followed by parental CVD, diabetes and hypertension.

Gender differences in angiotensin II and aldosterone secretion in patients with pressure overloaded systemic right ventricles are similar to those observed in systemic arterial hypertension.

BACKGROUND: There are very few and inconclusive data concerning the renin-angiotensin-aldosterone system activity in adults with systemic right ventricles, compared to classic heart failure patients. Therefore, we prospectively evaluated angiotensin II and aldosterone levels in a series of patients following Mustard or Senning procedures for complete transposition of the great arteries. METHODS: Forty-two patients (31 male and 11 female, mean age 20.8 ± 3.7 years), 18.2 ± 2.8 years following atrial switch procedures, were included in the analysis. All the patients underwent comprehensive echocardiographic examinations. Angiotensin II and aldosterone levels were measured with immunoradiometric assays. RESULTS: The mean angiotensin II level was 11.9 ± 9.4 pg/mL; 15 patients (35.7%) had angiotensin II levels exceeding the upper limit of normal values. There was a negative correlation between angiotensin II levels and treatment with angiotensin enzyme inhibitors (r = -0.33, P = 0.03). The mean aldosterone level was 217.7 ± 160.2 pg/mL; 26 patients (61.9%) had aldosterone levels exceeding the upper limit of normal values. Female patients had significantly higher aldosterone levels than male patients (321 ± 248 vs 180 ± 95 pg/mL, P = 0.01). A negative correlation between angiotensin II levels and fractional area change (r = -0.65, P=0.03), and a positive correlation between aldosterone levels and right ventricular end-diastolic area (r = 0.66, P = 0.03) were observed in female but not in male patients. CONCLUSIONS: Renin-angiotensin-aldosterone axis activation in patients with systemic right ventricles was similar to reported values in other studies of stable heart failure. The gender differences in aldosterone levels in patients with systemic right ventricles were similar to that associated with left ventricular remodeling in systemic arterial hypertension.

Prevalence of classical risk factors in Polish women with premature coronary artery disease.

BACKGROUND: It is generally believed that in 50% of perimenopausal women several factors other than classical risk factors play a significant role in the development of premature coronary artery disease (CAD). AIM: To determine the prevalence of five classical risk factors (cigarette smoking, hypertension, diabetes, hyperlipidaemia and obesity) in women aged〈 55 years with premature CAD. METHODS: We performed a single-centre, case-control study in women〈 55 years with angiographically confirmed CAD or troponin-positive acute coronary syndrome. A total of 330 female patients were enrolled between April 2005 and January 2008. The control group consisted of 347 age-matched healthy women from a similar region selected from the National Health Survey WOBASZ study (Polish Multi-centre Population Health Survey) designed to assess the cardiovascular risk in the Polish adult population. RESULTS: Compared to age-matched healthy controls, women with premature CAD had a very high prevalence of traditional risk factors - hypercholesterolaemia (82% vs 68%), smoking (current and former) (81% vs 48%), and hypertension (68% vs 42%). Women with premature CAD had 4.3 times more often diabetes, 1.68 times smoking and 1.63 times hypertension compared to controls. At least one of five classical risk factors was present in 98.8% of patients, compared to 89% in controls, while 10% of patients vs 1.4% of controls had all five of them. CONCLUSIONS: Classical risk factors are present in the vast majority of females with premature CAD - in 99% of them at least one CAD risk factor is present. Premature CAD is most frequently associated with smoking, hypertension and hyperlipidaemia.

Clinical characteristics of patients undergoing surgical ventricular reconstruction by choice and by randomization.

OBJECTIVES: The aim of this study was to confirm the generalizability of the conclusions of the STICH (Surgical Treatment for Ischemic Heart Failure) trial. BACKGROUND: Surgical ventricular reconstruction (SVR) added to coronary artery bypass grafting (CABG) did not decrease death or cardiac hospitalization in STICH patients randomized to CABG with (n = 501) or without (n = 499) SVR. METHODS: Baseline clinical characteristics of 1,000 STICH SVR hypothesis patients and 1,036 STICH-eligible Society of Thoracic Surgeons (STS) National Cardiac Database patients undergoing CABG plus SVR were entered into a multivariate model equation to predict a mortality that placed these 2,036 patients in 1 of 32 risk at randomization (RAR) groups. The number of patients in each RAR group profiled the risk of STICH treatment arms and of STICH and STS STICH-eligible patients. RESULTS: That 85% of the 1,000 STICH patients known to have no significant differences in baseline characteristics between the 2 treatment arms shared the same RAR group suggests that the RAR methodology has sufficient accuracy to compare RAR profiles of STICH and STS patients. RAR group was shared by 1,522 of 2,036 STICH and STS STICH-eligible patients (75%) who underwent CABG plus SVR. Differences in baseline characteristics responsible for more low-risk STICH patients and more high-risk STS patients were modest. Cox proportional hazard ratios of 1,000 STICH patients in 3 RAR groups suggested by STICH and STS RAR differences showed no differential treatment effect on survival across the low-, intermediate-, and high-risk groups. CONCLUSIONS: The STICH conclusion of no benefit from adding SVR to CABG applies to a broad spectrum of CABG-eligible patients with ischemic cardiomyopathy. (Comparison of Surgical and Medical Treatment for Congestive Heart Failure and Coronary Artery Disease; NCT00023595).

Functional anatomy of tricuspid regurgitation in patients with systemic right ventricles.

OBJECTIVE: Although the functional anatomy of mitral regurgitation has been thoroughly studied and is strongly predictive of postoperative outcome, the functional anatomy of tricuspid regurgitation (TR) in patients with systemic right ventricles has not been described. METHODS: We measured the indices of tricuspid valve deformation, right ventricular remodeling and function, and brain natriuretic peptide (BNP) concentrations in a series of 42 patients (mean age 20.8 +/- 3.7 years) with systemic right ventricles after atrial switch for complete transposition of the great arteries. RESULTS: TR was present in 34 patients. It was associated with predominant annular dilatation in 5 patients (14.7%), valvular prolapse in 14 patients (41.1%), and systolic leaflet tethering in 15 patients (44.1%). Compared with patients with valve prolapse, patients with leaflet tethering had greater end-systolic right ventricular cavity area (21.1 +/- 3.6 cm(2) vs 27.3 +/- 7.9 cm(2); P < .05), lower right ventricular fractional area change (0.40 +/- 0.09 vs 0.34 +/- 0.09, P < .05), and higher BNP levels (14.6 +/- 13.5 pg/mL vs 25 +/- 24.3 pg/mL, P < .05). Intermediate values were observed in patients with annular dilatation (23.9 +/- 5.6 cm(2); 0.37 +/- 0.05 pg/mL and 19.0 +/- 0.07 pg/mL, respectively). CONCLUSION: Three distinct types of TR, caused by predominant annular dilatation, valve prolapse, and valve tethering, were apparent in patients with systemic right ventricles. They were associated with diverse severity of right ventricular dysfunction and BNP activation. Further studies are needed to assess the impact of variable functional anatomy of the systemic tricuspid valve on the outcome of medical and surgical therapies.

Factors associated with the presence of tricuspid valve regurgitation in patients with systemic right ventricles following atrial switch.

BACKGROUND: The development of significant tricuspid regurgitation (TR) is associated with an unfavorable clinical outcome in patients with systemic right ventricles. Increased knowledge about the factors contributing to its presence would help prevent its progression. METHODS: This was a retrospective analysis of the factors predictive of significant TR in 60 patients with systemic right ventricles following an atrial switch procedure for complete transposition of the great arteries. Data from echocardiographic examinations, exercise radionuclide angiography, and myocardial perfusion imaging were analyzed. RESULTS: Significant TR was present in 20% of patients. Compared to patients without significant TR, patients with significant TR were older at the time of surgery (p < or = 0.001), with a higher body mass index (p < or = 0.005), lower right ventricular ejection fraction (RVEF; p < or = 0.01), higher exercise perfusion abnormalities score on radionuclide angiography (p < or = 0.03), and higher systolic blood pressure (p < or = 0.02). At univariate logistic regression analysis systolic blood pressure (p = 0.03), increasing age at surgery (p = 0.01), and RVEF (p = 0.02), were predictors of significant tricuspid regurgitation. The latter two remained significant at multivariate analysis. CONCLUSIONS: Patients operated upon later in life, with decreased RVEF and higher blood pressure, are at risk of significant tricuspid regurgitation and therefore warrant special attention. Prospective studies are needed to ascertain whether appropriate pharmacological intervention would prevent the development and/or progression of TR in these patients.