Human platelets release TGFBIp in acute myocardial infarction.

Transforming growth factor-ß-induced protein (TGFBIp) is released from activated platelets and promotes pro-thrombotic complications like pulmonary embolism. The role of TGFBIp in acute coronary syndrome, especially with a focus on platelets, has not been investigated so far. Using ELISA and immunoblotting, we demonstrate platelet TGFBIp release in patients with myocardial infarction (MI). We investigated TGFBIp-induced platelet adhesion and rolling by flow chamber and chemotactic effects of TGFBIp in transwell experiments. Immunochemistry staining of arterial vessels detected TGFBIp and the platelet-specific protein GPVI in the vessel wall.We demonstrate for the first time that platelet TGFBIp release is significantly increased in MI and correlates with the severity of acute coronary syndromes (STEMI, NSTEMI). After activation with TRAP, platelets release TGFBIp and TGFBIp itself activates platelets. Under flow, TGFBIp-mediated platelet rolling and adherence similarly to collagen. TGFBIp significantly increased platelet transmigration and we demonstrate TGFBIp deposits in the wall of human arteries. In this study, we add novel aspects to the role of TGFBIp in acute coronary syndrome by demonstrating that TGFBIp is partially released from platelets during MI and has activating, pro-adhesive and pro-migratory effects on platelets that could contribute to the disease development of coronary vascular inflammation and MI.

Clustering Inflammatory Markers with Sociodemographic and Clinical Characteristics of Patients with Diabetes Type 2 Can Support Family Physicians' Clinical Reasoning by Reducing Patients' Complexity.

Diabetes mellitus type 2 (DM2) is a complex disease associated with chronic inflammation, end-organ damage, and multiple comorbidities. Initiatives are emerging for a more personalized approach in managing DM2 patients. We hypothesized that by clustering inflammatory markers with variables indicating the sociodemographic and clinical contexts of patients with DM2, we could gain insights into the hidden phenotypes and the underlying pathophysiological backgrounds thereof. We applied the k-means algorithm and a total of 30 variables in a group of 174 primary care (PC) patients with DM2 aged 50 years and above and of both genders. We included some emerging markers of inflammation, specifically, neutrophil-to-lymphocyte ratio (NLR) and the cytokines IL-17A and IL-37. Multiple regression models were used to assess associations of inflammatory markers with other variables. Overall, we observed that the cytokines were more variable than the marker NLR. The set of inflammatory markers was needed to indicate the capacity of patients in the clusters for inflammatory cell recruitment from the circulation to the tissues, and subsequently for the progression of end-organ damage and vascular complications. The hypothalamus-pituitary-thyroid hormonal axis, in addition to the cytokine IL-37, may have a suppressive, inflammation-regulatory role. These results can help PC physicians with their clinical reasoning by reducing the complexity of diabetic patients.

Low Psychological Resilience in Older Individuals: An Association with Increased Inflammation, Oxidative Stress and the Presence of Chronic Medical Conditions.

The term resilience, which has been present in science for almost half a century, stands for the capacity of some system needed to overcome an amount of disturbance from the environment in order to avoid a change to another stable state. In medicine, the concept of resilience means the ability to deal with daily stress and disturbance to our homeostasis with the intention of protecting it from disturbance. With aging, the organism becomes more sensitive to environmental impacts and more susceptible to changes. Mental disturbances and a decline in psychological resilience in older people are potentiated with many social and environmental factors along with a subjective perception of decreasing health. Distinct from findings in younger age groups, mental and physical medical conditions in older people are closely associated with each other, sharing common mechanisms and potentiating each other's development. Increased inflammation and oxidative stress have been recognized as the main driving mechanisms in the development of aging diseases. This paper aims to reveal, through a translational approach, physiological and molecular mechanisms of emotional distress and low psychological resilience in older individuals as driving mechanisms for the accelerated development of chronic aging diseases, and to systematize the available information sources on strategies for mitigation of low resilience in order to prevent chronic diseases.

The Effect of Hypertension Duration and the Age of Onset on CV Risk Factors Expression in Perimenopausal Women.

BACKGROUND: The impact of hypertension duration and the time of onset on the expression of metabolic syndrome (MS) and other CV risk factors, in perimenopausal women, have not been studied so far. Methods. A total of 202 women, old 47-59 years, and diagnosed with hypertension, were recruited from primary care practices in eastern Croatia. The categories of hypertension duration were defined as <5, 5-10, and >10 years. Data were analyzed by standard statistical procedures. RESULTS: The proportion of women with MS increases in parallel with hypertension duration (p = 0.025). Among the examined CV risk factors, significant increase in parallel with hypertension duration was found for body mass index (p = 0.007) and triglycerides (p = 0.07). The highest proportion of women with diabetes duration of less than 5 years, indicating recent diabetes onset, was found in the category of hypertension duration of less than 5 years, corresponding with the onset of hypertension in the time around menopause (p = 0.003). The strongest linear correlations with BMI and waist circumference were found for total serum cholesterol (r = 0.355 and 0.499, respectively). CONCLUSION: Hypertension onset at the time around menopause appears together with abdominal obesity and may be a driving force for CV risk factor accumulation in postmenopausal women.

Surgical reconstruction of the left main coronary artery with patch-angioplasty.

BACKGROUND: Conventional coronary artery bypass grafting (CABG) has been established as the treatment of choice for left main coronary artery (LMCA) stenosis However, the conventional grafting provides a retrograde perfusion to extensive myocardial area and leads prospectively to competitive flow of the non-occluded coronaries thus consuming the grafts. Surgical reconstruction of the LMCA with patch-angioplasty is an alternative method that eliminates these drawbacks. METHODS: Between February 1997 and July 2007, 37 patients with isolated LMCA stenosis were referred for surgical ostial reconstruction. In 27 patients (73%) surgical angioplasties have been performed. All patients were followed up clinically and with transesophageal echocardiography (TEE) and coronary angiography when required. RESULTS: In 10 patients (27%) a LMCA stenosis could not be confirmed. There were no early mortality or perioperative myocardial infarctions. The postoperative course was uneventful in all patients. In 25 patients, TEE demonstrated a wide open main stem flow pattern one to six months after reconstruction of the left main coronary artery with one patch mild aneurysmal dilated. CONCLUSIONS: The surgical reconstruction with patch-angioplasty is a safe and effective method for the treatment of proximal and middle LMCA stenosis. Almost one third of the study group had no really LMCA stenosis: antegrade flow pattern remained sustained and the arterial grafts have been spared. In the cases of unclear or suspected LMCA stenosis, cardio-CT can be performed to unmask catheter-induced coronary spasm as the underlying reason for isolated LMCA stenosis.

PI3 kinase-dependent stimulation of platelet migration by stromal cell-derived factor 1 (SDF-1).

Platelets have been regarded as static cells that do not move once they adhere to a matrix. The present study explored, whether platelets are able to migrate. In contrast to the current opinion, we found that platelets were mobile, able to migrate over a surface, and transmigrate through a transwell membrane and endothelium toward a source of stromal cell-derived factor 1 (SDF-1). Platelet migration was stimulated by SDF-1, which led to the downstream activation and phosphorylation of Wiskott-Aldrich syndrome protein. SDF-1 signaling and subsequent platelet migration could be inhibited by CXCR4-receptor blocker AMD3100, pertussis toxin, inhibition of phosphoinositol 3-kinase (PI3 kinase) with LY294002 or wortmannin, and disruption of actin polymerization with cytochalasin B. The potential of platelets to migrate in an SDF-1-mediated fashion may redefine the role of platelets in the pathophysiology of vascular inflammation, subsequent atherosclerotic degeneration, and vascular regeneration.

Evaluation of the spatial resolution with 1.5-4 tesla in a stenosis model.

Since it was first described in the early 1990s, magnetic resonance coronary angiography has evolved into a promising noninvasive modality for imaging the coronary arteries. The aim of this study was to evaluate the detection accuracy and spatial resolution of vascular stenosis in contrast-enhanced 3-dimensional magnetic resonance angiography on a flow phantom. The examinations were performed with 1.5, 3, and 4 T whole-body imaging systems. For imaging at 4 T, we used a gradient-echo-multi-slice sequence. The system was flushed with gadopentetate dimeglumine contrast medium at flow rates of 40 and 60 mL.min(-1). The accurate detection of in vitro stenoses was possible in segments of 0.4 mm in diameter at 4 T. The best results were obtained at a flow velocity of 40 mL.min(-1) and a contrast medium concentration of 0.2 mmol.L(-1). Contrast-enhanced high-field 3-dimensional magnetic resonance imaging provided a highly accurate evaluation of the degree of stenosis in this model. Exact evaluation of vessel diameters < 0.4 mm was not possible, even with 4 T. In vivo studies are necessary to overcome the current limitations in the visualization of small distal vessel segments.

Assessment of coronary artery bypass grafts patency with different magnetic resonance technologies.

OBJECTIVE: The aim of the study was to evaluate the diagnostic accuracy of different magnetic resonance (MR) sequences in the assessment of coronary artery bypass graft patency and the evaluation of distal anastomoses with a spin echo sequence (Haste). PATIENTS AND METHODS: Twenty-five patients were examined with all the three techniques and 185 patients with 481 distal anastomoses were examined with the Haste sequence at a 1.5 TMR scanner and coronary angiography. A two-dimensional T(2)-weigthed breath-hold half-Fourier acquisition single-shot turbo spin echo sequence (Haste), a Navigator sequence and a gadolinium-enhanced Fisp-3-D sequence were performed. All images were evaluated independently by a radiologist and cardiologist and compared to the conventional coronary angiography. The observers were blinded to the coronary angiography findings, but informed in regard to the surgical graft anastomosis. RESULTS: With the Haste sequence 80% of the distal anastomoses were recognized. The sensitivity and specificity for the evaluation of the distal anastomosis with the Haste sequence was 94% and 75%. The Navigator and the Fisp-3-D sequences showed a sensitivity of 74% and 94% and a specificity of 78% and 88%. CONCLUSION: The best results were achieved with the Haste sequence, a reliable assessment of graft patency of the distal anastomosis is possible. The best imaging of proximal IMA segments was possible with the Fisp-3-D sequence. Due to the low sensitivity and specificity, the use of the Navigator sequence was stopped in our center. Further improvements of the spatial resolution and the image quality are necessary to recommend this MR techniques for routine clinical use.

Imaging of calcified coronary arteries with multislice computed tomography.

Reliable noninvasive detection of coronary artery disease is a prime goal in clinical cardiology. The aim of this study was to investigate the accuracy of multislice computed tomography in detecting coronary artery disease in correlation to the calcium score. Fifty patients with 61 stenoses > 50% and 41 occlusions underwent multislice computed tomography and conventional coronary angiography. Calcium scoring was calculated for the total coronary artery territory and patients were divided into 3 groups based on this score. Multislice computed tomography visualized 89% (365/500) of all coronary segments. The sensitivity and specificity for detection of stenoses > 50% or occlusion was 47%-92%, and 97%-100% for the calcium score. Forty of 500 segments were underestimated by multislice computed tomography, of which 39 were in the group with a calcium score > 400. Multislice computed tomography allows noninvasive angiographic evaluation of coronary artery disease with high diagnostic accuracy. However, the method strongly depends on the degree of vascular calcification and underestimates the degree of stenosis according to the calcium score. This new technology holds promise for noninvasive risk assessment in patients with known or suspected coronary artery disease.

Elevated monocyte chemoattractant protein-1 serum levels in patients at risk for coronary artery disease.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is involved in the recruitment of monocytes into the arterial vessel wall as one of the major events leading to atherosclerotic vascular diseases, such as coronary artery disease (CAD). METHODS AND RESULTS: The study group comprised 263 volunteers aged between 18 and 85 years who were admitted to hospital or clinic for scheduled invasive and non-invasive diagnostic procedures. MCP-1 serum levels were determined using a sandwich-enzyme-linked immunosorbent assay. In each patient, the coronary risk factors (CRF), such as hypertension, high cholesterol, diabetes mellitus, obesity, positive family history, and smoking were evaluated. Low-density lipoprotein-cholesterol, lipoprotein(a), and hemoglobinA1C levels were determined. Patients with CAD proven by angiography had significantly increased MCP-1 levels. In patients without CAD, the increase in MCP-1 depended on the number of CRF. As a marker for endothelial activation the soluble adhesion molecules, soluble intercellular adhesion molecule and soluble E-selectin were measured and both markers were significantly elevated in patients with CAD or multiple CRF when compared with patients without CRF. Although this is not a direct proof, endothelial activation could contribute to elevated MCP-1 levels in atherosclerosis. CONCLUSION: Elevated MCP-1 serum levels could serve as a direct marker of the inflammatory activity in patients at risk for coronary artery and other atherosclerotic vascular diseases.

Eight-year results after aortic valve replacement with the CryoLife-O'Brien Stentless Aortic Porcine Bioprosthesis.

OBJECTIVE: The long-term durability and hemodynamics of stentless valves are largely unknown. In this study we prospectively analyzed 8-year clinical results with the CryoLife-O'Brien Stentless Aortic Porcine Bioprosthesis (CryoLife Inc, Kennesaw, Ga) and assessed its hemodynamic performance by serial echocardiography. METHODS: A total of 206 patients with a mean age of 72.8 years were followed up prospectively after aortic valve replacement with the CryoLife-O'Brien stentless bioprosthesis. Patients have been followed up from 2 to 96 months for mean 56 months. Echocardiography was performed by a single echocardiographer preoperatively, intraoperatively, postoperatively at discharge, 3 to 6 months later, and annually thereafter. RESULTS: The 30-day operative mortality was 4.8%. Sixty-five percent of patients received a valve 25 mm in diameter or larger, and 37% underwent concomitant coronary bypass grafting. Twelve late deaths, none valve-related, have occurred. Severe aortic insufficiency caused by oversizing led to early reoperation in 3 patients. The peak and mean systolic gradients decreased significantly during the first 12 months after implantation (P < .001), and the effective valve areas increased significantly during this interval (P < .001). At 8 years, 2 patients have mild to moderate aortic insufficiency. The actuarial survival at 8 years was 82% +/- 3%. The freedom from endocarditis was 100%, and the freedom from thromboembolic events was 93%. CONCLUSION: Despite more demanding surgical technique than with conventional bioprostheses, the CryoLife-O'Brien bioprosthesis can be implanted safely in a population predominantly older than 70 years at the time of the operation, with excellent measures of hemodynamics, clinical outcomes, prosthesis durability, and survival through 8 years.

Midterm results after aortic valve replacement with a stentless bioprosthesis aortic valve.

BACKGROUND: It is suggested that a simplified implant model Cryolife-O'Brien (CryoLife International, Kennesaw, GA) offers less satisfactory outcome compared with standard stentless models. This study was conducted to prospectively evaluate the midterm results after aortic valve replacement with the Cryolife-O'Brien stentless bioprosthesis. METHODS: In 1996, a prospective clinical trial using different stentless valves was initiated. From September 1996 through September 2002, 156 consecutive patients with a mean age of 74.5 years underwent aortic valve replacement with the Cryolife-O'Brien porcine stentless bioprosthesis. The predominant aortic valve lesion was stenosis in 128 and insufficiency in 28 cases. Patients have been followed from 2 to 72 months (mean, 42 months). Echocardiography was performed by one echocardiographer preoperatively, intraoperatively, postoperatively at discharge, 2 to 6 months later, and annually thereafter. RESULTS: Sixty percent of patients received a valve 25 mm in diameter or larger; 39% had concomittant coronary bypass grafting. The 30-day operative mortality rate was 6.4%. Ten late nonvalve-related deaths have occurred. Severe aortic insufficiency caused by oversizing leads to early reoperation in 3 patients. The peak and mean systolic gradients decreased significantly during the first 12 months after implantation, p < 0.001, and the effective valve areas increased significantly during this time interval p < 0.001. At 5 years, ten patients have moderate aortic insufficiency. The actuarial survival at 5 years was 88 +/- 3%. The rate for freedom from endocarditis was 100% and for freedom from thromboembolic events was 94%. CONCLUSIONS: Midterm results after aortic valve replacement with the Cryolife-O'Brien stentless bioprosthesis are encouraging. Good hemodynamics have been coupled with low rate of valve-related complications, thus representing a very good alternative to conventional stented bioprostheses.

Surgery for right ventricle to pulmonary artery conduit obstruction: risk factors for further reoperation.

OBJECTIVE: To identify the surgical approaches and risk factors which influence longevity of right ventricle to pulmonary artery (RV-PA) conduits following first reoperation for obstruction. METHODS: Between January 1993 and August 2003, 114 patients underwent 141 reoperations for RV-PA conduit obstruction. Diagnoses included 'Truncus Arteriosus' (n=52), 'Pulmonary atresia/Tetralogy of fallot' (n=39), 'Double outlet right ventricle' (n=10), 'Transposition of great arteries, VSD, and pulmonary atresia' (n=9), and the 'Ross operation' (n=4). All patients had undergone a previous biventricular repair. The first reoperation for conduit obstruction was performed in 112 hospital survivors by: total conduit replacement (Group A, n=73) with valved (homograft=10 and xenograft=54) or non-valved (n=9) conduit, and patch enlargement of the obstructed RV outflow tract with preservation of the posterior and sides of the conduit wall after removing of the fibrocalcific peel and degenerated valve (Group B, n=39). Mean age at first reoperation was 8.8+/-6.7 and 7.5+/-5.3 years in patients of groups A and B, respectively. Seven patients in Group A and 18 in Group B required a second reoperation and two patients in Group B a third reoperation. RESULTS: There were two hospital deaths and no late deaths. Mean follow-up was 5.8+/-3.2 years. Risk factors for second reoperation by univariate analysis were: homograft conduit use (P=0.004), Group B surgical approach (P=0.0001), higher RV-PA systolic pressure gradient at discharge (P=0.02), and age <5-years-old (P=0.01). Multivariate analysis showed that inclusion in Group B and younger age (<5-years-old) at repair were independent risk factors for second reoperation. Group B surgical approaches had higher RV-PA systolic pressure gradient at discharge (P=0.02) and required more PA bifurcation repair at the time of second reoperation (P=0.05). Freedom from second reoperation for conduit obstruction was significantly higher in Group A patients at 5 and 8 years (P<0.04) and those with xenografts rather than homograft (P=0.04). CONCLUSIONS: Our results support the optimal surgical approach for RV-PA conduit obstruction is total replacement with a xenograft. RV outflow reconstruction by other techniques without complete dissection of PA bifurcation does not completely relieve the stenosis and could cause early restenosis. Higher systolic gradients at discharge and younger age at first reoperation are predictors of earlier reoperation.

Left-sided lesions after anatomic repair of transposition of the great arteries, ventricular septal defect, and coarctation: surgical factors.

OBJECTIVE: This study was undertaken to identify potential anatomic and surgical factors creating left-sided lesions, namely recoarctation of the aorta and neoaortic regurgitation, after anatomic repair of transposition of the great arteries with ventricular septal defect and aortic coarctation. METHODS: From 1983 to September 2002, 109 survivors out of 120 patients were studied. Two-stage repair was performed in 42 patients (group A), and single-stage repair was performed in 67 (groups B and C). Before repair, the diameters of the ascending aorta and main pulmonary artery were measured. In the patients with single-stage repair, coarctation was repaired by extended end-to-end anastomosis in 35 patients (group B) and by pulmonary homograft patch augmentation in 32 patients (group C). The ventricular septal defect was closed through the pulmonary artery in 70 patients and through the right ventricle or atrium in 39 patients. The neoaorto-aortic discrepancy was treated by V-shaped resection of the posterior sinus of Valsalva in 7 cases, pulmonary homograft patch in 32 cases, and anterior splitting of the ascending aorta in all cases. Before discharge from the hospital, neoaortic root and ascending aorta diameters and aortic regurgitation grade were recorded. Neoaortic regurgitation progression and reintervention were the end points of follow-up (97.2 +/- 61.2 months). RESULTS: Early and late survivals were significantly better in group C (P <.001). Risk factors for neoaortic regurgitation at discharge by univariate analysis were single-stage repair (P <.05) and ventricular septal defect closure through the pulmonary artery (P =.0076). On multivariate analysis, the latter was the only risk factor for neoaortic regurgitation at discharge and at last follow-up. Multivariate analysis showed that higher neoaortic root/ascending aorta ratio and ventricular septal defect closure through the pulmonary artery were risk factors for neoaortic regurgitation evolution at last follow-up. There were 29 reinterventions, 19 for recoarctation of the aorta and 10 for neoaortic regurgitation with or without aortic root dilatation. Group B (P <.05), high neoaortic root/ascending aorta ratio (P <.01), and progressive neoaortic regurgitation (P <.05) were risk factors for recoarctation of the aorta. Group A was a risk factor for aortic valve replacement at 10 years (P <.05). CONCLUSION: Neonatal single-stage repair with pulmonary homograft aortic augmentation remains the optimal approach to transposition of the great arteries with ventricular septal defect and aortic coarctation. It provides better early and late survivals and freedoms from left-sided lesions. Avoidance of late recoarctation of the aorta and progressive neoaortic regurgitation requires meticulous closure of the ventricular septal defect and evenly sized reconstruction of the aorta from root to distal arch.

Angiotensin-converting enzyme polymorphisms and their potential impact on left ventricular myocardial geometry after aortic valve surgery.

BACKGROUND AND AIM OF THE STUDY: Genetic variants of the angiotensin-converting enzyme (ACE) cascade may influence left ventricular myocardial mass (LVMM) regression after aortic valve surgery. Postoperative long-term changes in LV indices were investigated in patients with asymptomatic aortic regurgitation (AR) and symptomatic aortic stenosis (AS) and related to alleles of ACE polymorphisms. METHODS: A total of 96 patients was included in the study, 21 with class IIa AR (22%) and 75 with class I AS (78%) recommendations for surgery. Patients were evaluated for demographic risk factors and underwent a thorough clinical examination including 3-D cardiac imaging by ultrafast-computed tomography. Genomic DNA was isolated for genotyping. RESULTS: AR patients were younger (55.8 +/- 8.9 versus 64 +/- 9.1 years, p = 0.0014), had a larger body surface area (1.92 +/- 0.21 versus 1.82 +/- 0.19 m2, p = 0.039), and were more likely to be asymptomatic (myocardial infarction, p = 0.04; syncope, p = 0.0099; thromboembolism, p = 0.03; NYHA class IV, p = 0.04). Postoperatively, the reduction in absolute LVMM (from 297.1 +/- 52.6 to 190.1 +/- 57.1 g versus 214.4 +/- 55.7 to 143.8 +/- 40.0 g; pT = 0.0000001) and indexed LVMM (from 156.0 +/- 31.7 to 99.3 +/- 28.4 g/m2 versus 118.7 +/- 28.3 to 79.3 +/- 20.6 g/m; pT = 0.0000001) over time was more significant in AR patients, but never reached normal values. Enforced ACE inhibitor medication resulted in significantly higher postoperative indexed LVMM differences in homozygote DD patients compared to AR patients with II/ID alleles of ACE 16 ins/del polymorphism. CONCLUSION: AR patients showed a statistically significant decrease in absolute/indexed LVMM during follow up, but never achieved LV mass recovery compared to standard values or to values in patients undergoing aortic valve replacement for AS. The benefits of ACE inhibitors were observed among AR patients with homozygote DD alleles of ACE 16 ins/del polymorphism.