Loss of serum response factor induces microRNA-mediated apoptosis in intestinal smooth muscle cells.

Serum response factor (SRF) is a transcription factor known to mediate phenotypic plasticity in smooth muscle cells (SMCs). Despite the critical role of this protein in mediating intestinal injury response, little is known about the mechanism through which SRF alters SMC behavior. Here, we provide compelling evidence for the involvement of SRF-dependent microRNAs (miRNAs) in the regulation of SMC apoptosis. We generated SMC-restricted Srf inducible knockout (KO) mice and observed both severe degeneration of SMCs and a significant decrease in the expression of apoptosis-associated miRNAs. The absence of these miRNAs was associated with overexpression of apoptotic proteins, and we observed a high level of SMC death and myopathy in the intestinal muscle layers. These data provide a compelling new model that implicates SMC degeneration via anti-apoptotic miRNA deficiency caused by lack of SRF in gastrointestinal motility disorders.

"Aspirin - resistance"? A few critical considerations on definition, terminology, diagnosis, clinical value, natural course of atherosclerotic disease, and therapeutic consequences.

Based upon various platelet function tests and the fact that patients experience vascular events despite taking acetylsalicylic acid (ASA or aspirin), it has been suggested that patients may become resistant to the action of this pharmacological compound. However, the term "aspirin resistance" was created almost two decades ago but is still not defined. Platelet function tests are not standardized, providing conflicting information and cut-off values are arbitrarily set. Interest comparison reveals low agreement. Even point of care tests have been introduced before appropriate validation. Inflammation may activate platelets, co-medication(s) may interfere significantly with aspirin action on platelets. Platelet function and Cox-inhibition are only some of the effects of aspirin on haemostatic regulation. One single test is not reliable to identify an altered response. Therefore, it may be more appropriate to speak about "treatment failure" to aspirin therapy than using the term "aspirin resistance". There is no evidence based justification from either the laboratory or the clinical point of view for platelet function testing in patients taking aspirin as well as from an economic standpoint. Until evidence based data from controlled studies will be available the term "aspirin resistance" should not be further used. A more robust monitoring of factors resulting in cardiovascular events such as inflammation is recommended.

[Complications during exercise testing]. / Komplikationen bei der Ergometrie.

Exercise electrocardiogram forms the basis for diagnosis of ischemia in coronary heart disease. Blood pressure behavior, physical fitness, training heart rate and possible cardiac arrhythmias can additionally be assessed using bicycle ergometry or treadmill testing. When the indications for and contraindications to exercise testing (either bicycle ergometry or treadmill testing) are closely observed, serious complications are rare. However, it is important that the treating physician is aware of and able to recognize possible complications. The present article discusses possible cardiovascular complications and their incidence.

Influence of cardiopulmonary resuscitation on levels of tumour markers.

Tumour markers (TM), including alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3 and prostate-specific antigen (PSA), are serum markers for malignant diseases. Previous studies investigating the effect of acute and chronic inflammation, cardiopulmonary bypass surgery and cardiopulmonary resuscitation (CPR) on levels of TM showed conflicting results. Cardiopulmonary resuscitation (CPR) may result in a profound inflammatory response, and is frequently associated with severe tissue hypoperfusion. The present study investigated whether AFP, CEA, CA 15-3 and PSA are influenced by CPR. Alpha-fetoprotein (AFP), CEA, CA 15-3 and PSA (only in male patients) were assessed immediately after hospital admission, 6 h, 12 h and 2 days after prolonged CPR in eight male and 12 female patients. Serum levels of AFP, CEA, CA 15-3 did not change significantly after CPR. Prostate-specific antigen (PSA) levels increased significantly with a highest level in the study period 48 h after CPR (3.3 +/- 3.1 and 28.3 +/- 30.5 ng/mL for baseline and 48 h levels, respectively; P < 0.001). Alpha-fetoprotein (AFP), CEA, CA 15-3 and PSA (in men) values above the normal range were observed in 0%, 13.8%, 3.8% and 46.9% of all measurements respectively. At least one value above the normal range were observed in 0%, 20%, 5% and 75% of all patients for AFP, CEA, CA 15-3 and PSA (in men) respectively. Baseline values of AFP, CEA, CA 15-3 and PSA (in men) were above the normal range in 0%, 15%, 5% and 10% of all patients respectively. Levels for all markers did not differ significantly between survivors and non-survivors. In conclusion, prolonged CPR does not influence AFP, CEA, CA 15-3 serum levels, but is frequently associated with increases of PSA. Thus, in contrast to PSA, interpretation of AFP, CEA, CA 15-3 serum levels is not influenced by recent CPR.

Chronic total occlusion--a definite state?

Successful recanalisation of a chronic coronary occlusion may result in survival advantage. This report describes a 61-year-old man with an initially chronic occluded right coronary artery. A follow-up angiography 2 years later revealed a spontaneous recanalisation.

Catecholamine therapy inducing dynamic left ventricular outflow tract obstruction.

Hypertrophic obstructive cardiomyopathy with significant hypertrophy of the basal septum is the most frequently reported cause of left ventricular outflow tract (LVOT) obstruction. Additionally, other conditions such as dehydration, sepsis, vasodilatation, or mitral valve repair have been associated with LVOT obstruction. In this report, we present a case of a patient without hypertrophy who developed severe dynamic left ventricular outflow tract obstruction during catecholamine stimulation for shock that complicated severe pancreatitis. The present case serves as a reminder that hypovolemia together with a hyperdynamic state resulting from catecholamine administration may result in the development of dynamic LVOT obstruction even if baseline cardiac evaluation is unremarkable. Early detection and intensive efforts to reverse the underlying conditions, including cessation of catecholamine therapy and correction of hypovolemia are essential.

Obesity, body fat and coronary atherosclerosis.

BACKGROUND: Recent prospective studies have provided compelling evidence that obesity is a risk factor for the occurrence of clinical coronary events. However, the link between angiographically determined coronary atherosclerosis and obesity still remains controversial. We conducted this cross-sectional study in a clinical setting to investigate the relation of the obesity and body fat (BF) with angiographically defined coronary atherosclerosis. PATIENTS AND METHODS: Six hundred and seventy-three men (median age 64 years) and four hundred and twenty-eight women (median age 69 years) who underwent coronary angiography for suspected or known coronary heart disease were analyzed. The body mass index (BMI) and the BF were used as main exposure variables, and either the presence of significant (> or =50%) coronary diameter stenosis or a coronary artery disease severity score were defined as outcome variables, in a sex-specific logistic regression analysis. RESULTS: Among male patients, BF was slightly higher with increasing number of vessels involved (adjusted P for trend <0.05). In contrast, BMI showed no association with presence and severity of coronary artery disease (CAD). The odds ratios (ORs) for the presence of significant stenosis across quartiles of BMI were 1.0 (reference), 0.9, 1.1 and 0.7 (adjusted P for trend 0.61). This result did not differ between younger and older men. Among females, however, both BF and BMI were not significantly associated with an increasing number of vessels involved. CONCLUSION: These results suggested that BF may be predictive of an increasing number of coronary vessels involved among male patients, but not among female patients. This study failed to detect a positive association of presence and severity of CAD with BMI.

Postoperative atrial fibrillation independently predicts prolongation of hospital stay after cardiac surgery.

AIM: Postoperative atrial fibrillation (AF) occurs in up to 50% of cardiac surgery patients and represents the most common postoperative arrhythmic complication. A reduction of the length of hospital stay is a desirable goal in preventive strategies of postoperative AF. The aim of the present investigation was to determine whether prolonged postoperative hospital stay associated with AF after cardiac surgery surgery is attributable to the arrhythmia itself or to baseline characteristics of patients who develop AF. METHODS: Patients undergoing elective cardiac surgery in the absence of heart failure and significant left ventricular dysfunction (n = 253; average age 65+/-11 years) were recruited to the present prospective study. Midline sternotomy procedures with standard surgical techniques for normothermic cardiopulmonary bypass in coronary artery bypass grafting and valvular surgery were used. RESULTS: A total of 99 patients (39.1%) of the study population developed AF during the postoperative period. AF patients were older and more likely to have surgery for valvular heart disease and less likely to have antiarrhythmic drugs including beta-adrenergic blockers than patients without AF, but both patients with and without AF had similar body mass index and duration of surgery. Postoperative hospital stays were longer in patients with AF compared to those without AF (14.9+/-5.7 vs 10.6+/-3.6, respectively; P = 0.001). Multivariate analysis, adjusted for age and postoperative complications, demonstrated that postoperative hospital stay was 14.2+/-5.3 days in patients with AF and 10.8+/-3.8 days in patients without AF (P < 0.01). Treatment with oral antiarrhythmic drugs that reduce AF is associated with a reduction of postoperative hospital stay. CONCLUSIONS: Despite baseline characteristics differed between patients with and without postoperative AF, most of the prolongation of hospital stay can be attributed to the rhythm disturbance itself.

Antiarrhythmic therapy on prevention of postoperative atrial fibrillation in patients after heart surgery.

The incidence of supraventricular arrhythmias is high following open-heart surgery, occurring in 25% to about 50% of patients. The most common of these arrhythmias is atrial fibrillation (AF). Postoperative AF has been associated with increased incidence of other complications and increased hospital length of stay. Atrial arrhythmias are most frequent in the first two to three days after cardiothoracic surgery, but they can occur at any point in the recovery period. Age and concomitant valular heart disease are consistently the independent factors most strongly associated with postoperative atrial fibrillation. Prevention of AF seems to be a reasonable clinical goal, and, consequently, many randomized trials have evaluated the effectiveness of pharmacological and nonpharmacological interventions for prevention of AF. The main indication for AF prophylaxis remains the shorteningof length of hospital stay and possibly reduction in stroke. The optimal treatment strategies for reducing postoperative AF are not well established. Commonly used therapeutic approaches include the use of rate-controlling drugs such as beta-blockers, calcium antagonists, and digoxin. Some pharmacological strategies including beta-blockers, sotalol, and amiodarone have shown to reduce risk of postoperative AF and may reduce length of hospital stay. There is no convincing evidence that reducing postoperative AF reduces stroke. This review summarizes current evidence from randomized controlled trials to estimate the effect of pharmacological and non pharmacologic interventions on the occurrence of AF after open-heart surgery and its effects on postoperative outcome.

Spontaneous coronary artery dissection involving the left main stem: assessment by intravascular ultrasound.

This case report describes the devastating consequences of spontaneous coronary dissection in a 36 year old female patient who otherwise had a normal coronary arteriogram. Intravascular ultrasound showed coronary artery dissection and intramural haematoma at the left main stem coronary artery. Acute coronary syndrome developed and subsequently surgical revascularisation was performed successfully.

[Cardiovascular risk factor profiles and angiography results in young patients]. / Kardiovaskuläres Risikoprofil und koronarangiografischer Befund bei jungen Patienten.

There is a clear correlation between the incidence of coronary artery disease and existing cardiovascular risk factors. Therefore, it is a matter of interest if there is an accumulation of risk factors in younger patients with premature coronary artery disease compared to those without. We evaluated 1708 consecutive patients who underwent coronary angiography at our institution between August 2001 to February 2002; 85 symptomatic patients under the age of 46 were included in our analysis. In 46 patients (54.1%)--mean age 41.5 +/- 3.6 years--a coronary artery disease was documented, in 39 patients (45.9%)--mean age 39.9 +/- 5.6 years (n.s.)--normal coronary arteries were shown at angiography. Regarding the cardiovascular risk factors in young patients with coronary artery disease compared to young patients without we found a family history of premature coronary artery disease in 54.5% versus 43.6% (n.s.), hypercholesterolemia in 56.5% versus 53.8% (n.s.), LDL cholesterol of 138 +/- 40 mg/dl versus 123.3 +/- 27 mg/dl (s.), HDL cholesterol of 39 +/- 9 mg/dl versus 45.6 +/- 12.6 mg/dl (s.), serum triglycerides of 194.6 +/- 114.9 mg/dl versus 162.1 +/- 98.4 mg/dl (n.s.), diabetes mellitus in 15.2% versus 10.3% (n.s.), hypertension in 45.7% versus 46.4% (n.s.), body mass index > 24.9 kg/m2 in 67.4% versus 69.2% (n.s.), cigarette smoking in 54.6% versus 56.4% (n.s.). And finally, a minimum of two of those risk factors was found in 93.5% versus 87.2% (n.s.). Due to the high prevalence of cardiovascular risk factors in both groups it is impossible to reliably predict the incidence of coronary artery disease from those risk factors. This has to be considered while deciding about the indication for coronary angiography.

Thyroid function is associated with presence and severity of coronary atherosclerosis.

BACKGROUND: Overt hypothyroidism has been found to be associated with cardiovascular disease. Moreover, subclinical hypothyroidism is a strong indicator of risk for aortic atherosclerosis and myocardial infarction. HYPOTHESIS: We hypothesized that variation of thyroid function within the normal range may influence the presence and severity of coronary atherosclerosis. METHODS: We studied a total of 100 consecutive men and women (59 men, 41 women, age 63.7 +/- 11.0 years) who underwent coronary angiography. Blood was tested for serum thyrotropin concentrations and for free tri-iodothyronine and free thyroxine concentrations. In addition to the assessment of thyroid function, conventional risk factors for coronary artery disease (CAD), clinical characteristics, serum lipid levels, fasting total homocysteine, and angiographic results of coronary artery assessment were obtained. Two experienced cardiologists blinded to clinical and laboratory data reviewed the cinefilms. The severity of CAD was scored as 0 for those with smooth normal epicardial coronary arteries, 0.5 for plaquing (< 50% diameter stenosis), and 1, 2, or 3 for those with single-, double-, or triple-vessel epicardial coronary artery stenosis of > 50%, respectively. RESULTS: The severity of CAD was scored as 0, 0.5, 1, 2, and 3 in 14, 26, 25, 22, and 13 patients, respectively. Higher levels of serum-free thyroid hormone concentrations were associated with decreased severity of coronary atherosclerosis. Serum-free tri-iodothyronine was 2.99 +/- 0.33 pg/ml in patients with a CAD severity score of 0 to 1 and 2.74 +/- 0.49 pg/ml in patients with CAD severity scores of 2 and 3 (p < 0.01). Moreover, serum-free thyroxine concentrations showed a trend toward higher levels in patients with CAD severity score 0 to 1 compared with patients with CAD severity scores 2 and 3 (11.65 +/- 1.87 pg/ml vs. 10.9 +/- 2.3 pg/ml; p = 0.09). Higher levels of serum thyrotropin concentrations were associated with increased severity of coronary atherosclerosis (1.37 +/- 1.02 mU/l vs. 1.98 +/- 2.13 mU/l in patients with CAD severity score 0 to 1 versus CAD severity scores 2 and 3; p = 0.049). When grouped into three subsets according to their serum free tri-iodothyronine levels (< 2.79, 2.8 to 3.09, and +/- 3.1 pg/ml), the prevalence of CAD scores 2 and 3 was significantly higher in the subset of patients with low serum free tri-iodothyronine levels (48.5%) than in the subsets of patients with medium or high tri-iodothyronine concentrations (32.25 and 25%, respectively, p for trend < 0.05). CONCLUSION: These data in patients referred for coronary angiography suggest that variation of thyroid function within the statistical normal range may influence the presence and severity of coronary atherosclerosis.

Hepatitis A IgG seropositivity and coronary atherosclerosis assessed by angiography.

BACKGROUND: Infectious agents, in particular intracellular pathogens that can establish long-term, persistent infection, may play an important role in atherogenesis. We tested the hypothesis that hepatitis A virus (HAV) could be associated with significant coronary artery disease. METHODS: The possible association between HAV infection and angiographically proven coronary artery disease (CAD) was studied. Blood from 218 patients undergoing coronary angiography was tested for serum IgG antibodies to HAV. RESULTS: Of the 218 patients, 178 (81.7%) had anti-HAV IgG antibodies. CAD prevalence was 66.3% in HAV seropositive and 57.5% in HAV seronegative patients (P=0.385). In contrast, the number of infectious pathogens to which an individual has been exposed correlates with CAD. Four or more of the six seromarkers tested for particular infections (HAV, Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, influenza type A and type B) were positive in 48.8% of patients with CAD and in 31.2% of patients in patients without CAD (P=0.02). CONCLUSIONS: This analysis demonstrated that HAV seropositivity is not a predictor of risk for CAD. HAV infection, therefore, seems not to be associated with CAD. The number of infectious agents to which an individual has been exposed ('infectious burden') correlates with CAD.

[Recanalization of chronic coronary occlusions]. / Rekanalisation von chronisch verschlossenen Koronararterien.

Recanalization of occluded coronary arteries is the aim of percutaneous interventions with acute myocardial infarction. Moreover, chronic coronary occlusion is a common finding during diagnostic coronary angiography and is often a contributing factor in the choice of revascularisation by surgery rather than by percutaneous coronary interventions (PCI). An occluded coronary artery with some degree of collateral supply is functionally comparable to a severe coronary stenosis. Therefore, recanalization of chronic occluded coronary arteries results in less angina and often in improvement of left ventricular function. Success is limited in particular in longer lasting occlusions. Characterization of lesions, where recanalization can performed successfully is warranted. We correlated primary success rates of attempted coronary recanalizations with localisation of lesions and procedural characteristics. We analyzed records of 124 consecutive patients, who underwent attempted coronary recanalization of chronically occluded coronary arteries at our institution in 1998. Revascularisation was successful in 84 (64 male, 20 female) of 124 (92 male, 32 female) patients. Therefore, success rate was 67.7% (69.9% in men, 62.5% in women, p = 0.42). Target vessel was the left anterior descending artery (LAD) in 49 cases. Success rate in the LAD did not differ significantly from that in "non-LAD"-vessels (65.3% versus 69.3%; p = 0.35). Successful recanalizations were performed using only one guide-wire in 77.3%. More than one guide-wires were used during procedures without success in 44.5% and exceeded use in successful interventions (p < 0.05). Procedures, failing to be successful after an attempt with a first guide-wire, could be performed successfully using at least a second wire in 50%. Coronary stenting after recanalization has been performed in 84.4% in the LAD and in 59.7% in non-LAD vessels (p < 0.01). Success rate of attempted recanalizations of chronic occluded coronary arteries in unselected patients is high. Most procedures can be performed successfully using only one guidewire. Additional use of other wires can increase success rates in procedures with primary failure to pass the occlusion. Stenting has been performed in three out of four patients with successful recanalization of chronically occluded coronary arteries.

Clinical significance of pleiotropic effects of statins: lipid reduction and beyond.

Statins significantly reduce cardiovascular-related morbidity and mortality in patients with and without coronary artery disease. The potential of this drug class has yet to be fully explored. Accumulating evidence from basic research and clinical trials indicates that statins have pleiotropic effects that may largely account for the clinical benefits observed. Potential beneficial effects of these agents include enhancement of nitric oxide production in vasculature and the kidney. Statins have been shown to stabilize unstable plaques, improve vascular relaxation, and promote new vessel formation. Clinical trials and animal studies have shown that these agents reduce cardiovascular disease (CVD) risks and events, progression of nephropathy, development of diabetes, and fracture rates; these are benefits that go beyond lipid lowering alone. Potential beneficial effects are due to the positive impact on vascular and glomerular nitric oxide (NO) production and attenuation of vascular inflammation. Effects on bone, including fracture reduction, are thought to be mediated by direct action on bone formation. Moreover, potential reduction in the development of diabetes as observed in the West of Scotland Coronary Prevention Study (WOSCOPS) may relate to the improvement in insulin sensitivity. These actions are mediated, in part, by the effects on small G-proteins, modulation of signaling cascades, transcription, and gene expression. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall. The clinical relevance of these effects is beginning to be recognized, and ongoing studies will be able to answer these many questions in the near future. Actions of statins on vascular, glomerular, bone, and insulin-sensitive tissue as well as effects of statins on cognitive function and oncoprotection will be discussed in this review.

Relation of C-reactive protein levels to presence, extent, and severity of angiographic coronary artery disease.

BACKGROUND: C-reactive protein is a valid marker of cardiovascular risk. It is not known whether C-reactive protein is a marker of atherosclerotic burden or whether it reflects a process (e.g. inflammatory fibrous cap degradation) leading to acute coronary events. This study was performed to determine whetherthe concentration of C-reactive protein is associated with coronary atherosclerosis assessed by coronary angiography. METHODS AND RESULTS: We studied a total of 100 men and women (41 women, 59 men, mean age 63.7 +/- 11.0 years) who were referred for coronary angiography. Baseline data collection comprised clinical characteristics and conventional risk factors for coronary artery disease, levels of serum lipids and fasting total homocysteine levels. The relation between serum C-reactive protein levels and the severity and extension of coronary lesions was studied. The coronary angiograms were evaluated in a blinded manner according to three scores: vessel score (0-3 points for 0-3 vessels with coronary artery disease), stenosis score (0-3 points: number and severity of coronary stenoses or lesions; 0 for no, 1 for coronary lesion with diameter stenosis less than 50%, 2 for 50%-75%, and 3 for more than 75% diameter stenosis), and extent score (0-3 points; segment-extension of all coronary lesions within the total coronary vessel length). According to the total score values obtained, groups for coronary artery disease risk were defined and analyzed forcorrelations with age and levels of total cholesterol. high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, fasting total homocysteine. and C-reactive protein in serum. From the 100 patients, 40 were found to have no or minimal coronary artery disease (group A; score 0-3), 33 had moderate (group B; score 4-8) and 27 had severe (group C: score more than 8) coronary artery disease assessed by coronary angiography. Estimates of the relative risk of coronary heart disease for the third quintile of serum C-reactive protein as compared with the first quintile were 1.79 (95 percent confidence interval 1.23-2.39). Serum C-reactive protein levels were 3.54 (+/- 7.07) mg/L, 11.41 (+/- 13.5) mg/L and 5.66 (+/- 8.32) mg/L in groups A, B and C and represented an independent risk factor for the presence of coronary artery disease assessed by coronary angiography (p<0.01). With step-wise logistic regression analyses, use of C-reactive protein values maintained the ability to predict the probability of coronary artery disease. Moreover, the presence of angiographic coronary artery disease was associated with patient age (p=0.048), male sex (p<0.01), high LDL-cholesterol levels (p=0.02), low HDL-cholesterol levels (p=0.02), high plasma fibrinogen levels (p<0.01) and high fasting total homocysteine levels (p=0.04). CONCLUSIONS: These results suggest that the serum concentration of C-reactive protein is associated with presence, but not severity, of coronary artery disease in patients referred for coronary angiography.

[Intracoronary brachytherapy--an update]. / Intrakoronare Brachytherapie--Ein Update.

Restenosis following angioplasty represents a major clinical problem in the field of percutaneous coronary interventions. Intravascular brachytherapy reduces risk of restenosis following percutaneous interventions of native lesions and in-stent restenosis up to 50%-60%. This effect can be shown for at least one to two years. This novel therapeutic strategy is limited by a higher rate of target vessel reinterventions, and late coronary thrombosis, when platelet inhibiting drugs has been withdrawn or after implantation of multiple stents. Currently, intracoronary brachytherapy is mainly considered for treatment of in-stent-restenosis.