Autoimmune pancreatitis results from loss of TGFbeta signalling in S100A4-positive dendritic cells.

BACKGROUND AND AIMS: Autoimmune pancreatitis (AIP) is a poorly understood human disease affecting the exocrine pancreas. The goal of the present study was to elucidate the pathogenic mechanisms underlying pancreatic autoimmunity in a murine disease model. METHODS: A transgenic mouse with an S100A4/fibroblast-specific protein 1 (FSP1) Cre-mediated conditional knockout of the transforming growth factor beta (TGFbeta) type II receptor, termed Tgfbr2(fspKO), was used to determine the direct role of TGFbeta in S100A4(+) cells. Immunohistochemical studies suggested that Tgfbr2(fspKO) mice develop mouse AIP (mAIP) characterised by interlobular ductal inflammatory infiltrates and pancreatic autoantibody production. Fluorescence-activated cell sorting (FACS)-isolated dendritic cells (DCs) from diseased pancreata were verified to have S100A4-Cre-mediated DNA recombination. RESULTS: The Tgfbr2(fspKO) mice spontaneously developed mAIP by 6 weeks of age. DCs were confirmed to express S100A4, a previously reported protein expressed by fibroblasts. Adoptive transfer of bone marrow-derived DCs from Tgfbr2(fspKO) mice into 2-week-old syngenic wild-type C57BL/6 mice resulted in reproduction of pancreatitis within 6 weeks. Similar adoptive transfer of wild-type DCs had no effect on pancreas pathology of the host mice. The inability to induce pancreatitis by adoptive transfer of Tgfbr2(fspKO) DCs in adult mice suggested a developmental event in mAIP pathogenesis. Tgfbr2(fspKO) DCs undergo elevated maturation in response to antigen and increased activation of naïve CD4-positive T cells. CONCLUSION: The development of mAIP in the Tgfbr2(fspKO) mouse model illustrates the role of TGFbeta in maintaining myeloid DC immune tolerance. The loss of immune tolerance in myeloid S100A4(+) DCs can mediate mAIP and may explain some aspects of AIP disease pathogenesis.

Effect of enhanced external counterpulsation on medically refractory angina patients with erectile dysfunction.

Patients with refractory angina often suffer from erectile dysfunction. Enhanced external counterpulsation (EECP) decreases symptoms of angina, and increases nitric oxide release. This study evaluated the effect of EECP on sexual function in men with severe angina. The International Index of Erectile Function (IIEF) was used to assess erectile function of severe angina patients enroled in the International EECP Patient Registry. Their symptom status, medication use, adverse clinical events and quality of life were also recorded before and after completing a course of EECP. A cohort of 120 men (mean age 65.0+/-9.7) was enroled. The men had severe coronary disease with 69% having a prior myocardial infarction, 90% prior coronary artery bypass graft or percutaneous coronary intervention, 49% with three vessel coronary artery disease, 86% were not candidates for further revascularisation, 71% hypertensive, 83% dyslipidaemia, 42% diabetes mellitus, 75% smoking and 68% using nitrates. Functional status was low with a mean Duke Activity Status Inventory score of 16.6+/-14.8. After 35 h of EECP anginal status improved in 89%, and functional status in 63%. A comparison of the IIEF scores pre- and post-EECP therapy demonstrated a significant improvement in erectile function from 10.0+/-1.0 to 11.8+/-1.0 (p=0.003), intercourse satisfaction (4.2+/-0.5 to 5.0+/-0.5, p=0.009) and overall satisfaction (4.7+/-0.3 to 5.3+/-0.3, p=0.001). However, there were no significant changes in orgasmic function (4.2+/-0.4 to 4.6+/-0.4, p=0.19) or sexual desire (5.3+/-0.2 to 5.5+/-0.2). The findings suggest that EECP therapy is associated with improvement in erectile function in men with refractory angina.

Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF.

BACKGROUND: While idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease, the aetiology of IPF is poorly understood. Familial cases of pulmonary fibrosis suggest a genetic basis for some forms of the disease. Recent reports have linked genetic mutations in surfactant protein C (SFTPC) with familial forms of pulmonary fibrosis, including one large family in which a number of family members were diagnosed with usual interstitial pneumonitis (UIP), the pathological correlate to IPF. Because of this finding in familial cases of pulmonary fibrosis, we searched for SFTPC mutations in a cohort of sporadic cases of UIP and non-specific interstitial pneumonitis (NSIP). METHODS: The gene for SFTPC was sequenced in 89 patients diagnosed with UIP, 46 patients with NSIP, and 104 normal controls. RESULTS: Ten single nucleotide polymorphisms in the SFTPC sequence were found in IPF patients and not in controls. Only one of these created an exonic change resulting in a change in amino acid sequence. In this case, a T to C substitution resulted in a change in amino acid 73 of the precursor protein from isoleucine to threonine. Of the remaining polymorphisms, one was in the 5' UTR, two were exonic without predicted amino acid sequence changes, and six were intronic. One intronic mutation suggested a potential enhancement of a splicing site. CONCLUSIONS: Mutations in SFTPC are identified infrequently in this patient population. These findings indicate that SFTPC mutations do not contribute to the pathogenesis of IPF in the majority of sporadic cases.

Enhanced external counterpulsation as initial revascularization treatment for angina refractory to medical therapy.

Enhanced external counterpulsation (EECP) is effective in patients with angina refractory to medical therapy or revascularization. However, as a noninvasive treatment it should perhaps be considered the first-line treatment with invasive revascularization reserved for EECP failures or high-risk patients. The International EECP Patient Registry was used to analyze a cohort of patients with prior percutaneous coronary intervention (PCI) and/or coronary artery bypass graft (CABG) (n = 4,454) compared with a group of patients (PUMPERS) who were candidates for PCI and/or CABG and chose EECP as their initial revascularization treatment (n = 215). The PUMPERS responded to treatment with EECP with decreased anginal episodes and nitroglycerin use and with improvement in their Canadian Cardiovascular Society functional class, similarly to previously revascularized patients. Treatment with EECP resulted in sustained, and often progressive, reduction in angina over the succeeding 6 months. Given the findings of this study, it is interesting to speculate on the possibility of using EECP as the primary revascularization intervention after medical therapy proves unsatisfactory.

Benefit and safety of enhanced external counterpulsation in treating coronary artery disease patients with a history of congestive heart failure.

Enhanced external counterpulsation (EECP) is used to noninvasively treat refractory angina patients, including those with a history of heart failure. The International EECP Patient Registry was used to examine the benefit and safety of EECP treatment, including a 6-month follow-up, in 1,957 patients, 548 with a history of heart failure. The heart failure cohort was older, with more females, a greater duration of coronary artery disease, more prior infarcts and revascularizations. Significantly fewer heart failure patients completed the course of EECP, and exacerbation of heart failure was more frequent, though overall major adverse cardiac events (MACE, i.e. death, myocardial infarction, revascularization) during treatment were not significantly different. The angina class improved in 68%, with comparable quality of life benefit, in the heart failure cohort. At 6 months, patients with congestive heart failure maintained their reduction in angina but were significantly more likely to have experienced a MACE end point.

Direct coronary stenting without balloon or device pretreatment: acute success and long-term results.

Improvements in coronary stents have made planned direct coronary stenting technically feasible, though safety, acute success, cost-effectiveness, and long-term results remain to be determined. Sequential patients eligible for direct stenting were prospectively characterized and treated with either direct or secondary stenting. Major adverse cardiovascular events (MACE) such as cardiac death, myocardial infarction (MI), target vessel ischemia, or revascularization (TVR) were followed for 6 months post-PCI. Enrollment included 128 direct (1.38 lesions/patient) and 69 secondary (1.39 lesions/patient) stented patients. Direct stenting was successful in 99% (with 5% crossover to secondary stenting) without major procedural complications and with a similar rate of vessel wall dissection or no-reflow phenomenon (2.3% vs. 2.1%; P > 0.05) as the secondary stenting group. There was a trend toward less postprocedural CPK-MB elevation in the nonacute MI patients with direct vs. secondary stenting (3% vs. 11%, respectively). At 6 months, there were no statistically significant differences in overall MACE. Direct stenting has a high success rate, low complication rate, and durable long-term results. Procedural cost and time savings, less contrast use and radiation exposure make direct stenting attractive in properly selected patients.

Acute hemodynamic effects and angina improvement with enhanced external counterpulsation.

Enhanced external counterpulsation (EECP) is an effective noninvasive treatment for coronary artery disease. The mechanism of action is felt to be hemodynamic. The complex hemodynamic effects have been simply quantified by calculating a previously described effectiveness ratio (ER). The EECP Clinical Consortium, a clinical registry of 37 centers, prospectively enrolled 395 chronic stable angina patients (79 women, 316 men, mean age 66 years) to examine the relation of the ER to posttreatment improvement in Canadian Cardiovascular Society angina class (CCS). Women and the elderly underwent planned subgroup analysis. The ER was calculated during the first and last hours of a 35-hour course of EECP treatment. After EECP, CCS improved by at least 1 class in 88% of patients, 87% of men and 92% of women (p = NS), and in 89% of patients < or = 66 years and 88% of patients > 66 years old (p = NS). The initial and final ER were similar in patients with and without improvement in CCS. Significant first-hour ER differences were seen between men and women (0.96 +/- 0.03 vs 0.76 +/- 0.04, p<0.005), and between ages < or = 66 and > 66 years old (1.04 +/- 0.04 vs 0.81 +/- 0.03, p<0.0001). However, all subgroups responded equally well to EECP treatment. EECP is effective in improving CCS in chronic stable angina patients; it has comparable effects in men and women and across a broad range of ages. The hemodynamic effect of EECP (ER) does not predict improvement in CCS and may indicate that other factors, such as neurohormonal changes, may have a significant role in mediating the observed EECP benefits.

Optimizing safe femoral access during cardiac catheterization.

This article describes the natural variability of femoral arterial anatomy as seen by angiography in a standard position. An analysis of 60 consecutive peripheral angiograms revealed data on average vessel diameter, variability in that diameter and the level of bifurcation of the common femoral artery into its two main branches. The statistical likelihood of optimal femoral arterial access through a standard dermotomy placed midway between, and 3 cm below, the imaginary line extending from the superior anterior iliac spine to the pubic symphysis was calculated. Our research disclosed average vessel diameters of 6.6 mm (3.9-8.9 mm), 5.2 mm (2.5-9.6 mm), and 4.9 mm (2.7-7.6 mm) for the common femoral artery, superficial femoral artery and deep femoral artery, respectively. The bifurcation of the common femoral artery into its branches averaged 5.5 mm below the inferior margin of the femoral head in most cases (76% of the time). In our laboratory, the average distance from the inferior border of the femoral head to our actual arteriotomy was 14.0 mm. Using our standard dermotomy, we achieved this favorable access position in 97% of cases.

Treatment benefit in the enhanced external counterpulsation consortium.

The present study utilized a cohort of 2,289 consecutive patients enrolled in the Enhanced External Counterpulsation (EECP) Consortium to evaluate whether results of university studies showing EECP safety and effectiveness in treating angina can be generalized. EECP was found to be safe and well tolerated with a 4.0% rate of adverse experiences. Angina class improved in 74% of patients with limiting angina (Canadian Cardiovascular Society, CCS, functional class II-IV), with patients most impaired at baseline demonstrating the greatest improvement (39.5% of patients in CCS III and IV improved 2 or more classes). Efficacy was independent of provider setting or experience, women responded as well as men, and although younger patients demonstrated a greater likelihood of improvement, EECP was effective in patients ranging from 19 to 97 years. Extending the benefit of EECP treatment to a wider range of patients may be indicated based on these findings.

Demonstration of myocardial ischemia by an internal loop recorder.

An internal loop recorder (ILR) implanted to evaluate syncope was activated during an episode of chest pain. Analysis of the recorded event revealed a marked increase in the amount of ST-segment depression over baseline. In addition to rhythm analysis, the ILR may be able to assess myocardial ischemia. Further refinements of filtering may make analysis more accurate.

Does aspirin attenuate the beneficial effects of angiotensin-converting enzyme inhibition in heart failure?

Ischemic heart disease is the most common underlying cause of congestive heart failure, and thus aspirin (acetylsalicylic acid [ASA]) and angiotensin-converting enzyme (ACE) inhibitors are commonly used together for treatment in this setting. The issue of possible attenuation of the effect of ACE inhibitors by ASA has been an area of intense debate. Currently, it is perceived that a significant part of the beneficial effect of ACE inhibitors is related to augmentation of bradykinin levels, which among other effects stimulate the release of prostacyclin. Aspirin, on the other hand, inhibits the production of prostacyclin by blocking cyclooxygenase. Prostaglandins play an important endogenous vasodilatory role and counteract the enhanced peripheral vasoconstriction state in congestive heart failure. Thus, the counteracting effect of ASA on the augmentation of prostacyclin synthesis by ACE inhibitors could result in a potential reduction of the beneficial effects of the ACE inhibitor's and could be of great importance. This article reviews reports from large clinical trials pertaining to this issue and relates their findings to the currently available theoretical bases for support of the counteracting effect of ASA on augmentation of prostacyclin synthesis by ACE inhibitors. The clinical implications of such an interaction are discussed.

Long-term prognosis of patients with angina treated with enhanced external counterpulsation: five-year follow-up study.

BACKGROUND: Enhanced external counterpulsation (EECP) is a noninvasive treatment for coronary artery disease (CAD) that has been used successfully in patients not responding to medical and/or surgical therapy. HYPOTHESIS: The study was undertaken to evaluate the effect of EECP on long-term prognosis in such patients. METHODS: Major adverse cardiovascular events (MACE) were tracked in 33 patients with CAD treated with EECP. Patients were subgrouped based on whether or not they demonstrated an early improvement in radionuclide stress perfusion imaging (Responders vs. Nonresponders) and followed for MACE over a mean follow-up of 5 years. Patient population characteristics included 73% with multivessel disease; 45% with prior myocardial infarction(s); and 61% who had undergone either coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA), or both. RESULTS: There were 26 of 33 (79%) Responders, and 7 of 33 (21%) Nonresponders. Subsequent MACE over the 5-year follow-up included four deaths and eight patients with cardiovascular events [acute myocardial infarct (4), new CABG or PTCA (6), valve replacement (1), unstable angina (1)]. Nonresponders had significantly (p < 0.01) more MACE (6/7 or 86%) than Responders (6/26 or 23%). Overall, 21 of the 33 (64%) patients remained alive and without MACE and the need for revascularization 5 years post EECP treatment. CONCLUSION: This study suggests that, particularly for the majority of patients demonstrating improvement in radionuclide stress perfusion post treatment, EECP may be an effective long-term therapy.

Coronary vasomotor tone: determinants and effect on coronary angioplasty.

BACKGROUND: Coronary artery reference diameters increase during coronary angioplasty (PTCA). However, in clinical practice, balloon selection is often based on a preceding diagnostic coronary angiogram. It is common to find that the initially selected balloon is undersized due to resting vasomotor tone. This may contribute to a suboptimal angioplasty result. METHODS: Quantitative coronary angiography (QCA) was used to determine the magnitude of coronary artery vasodilatation over baseline angiography and its impact on balloon size choice. Pre-PTCA clinical and treatment variables were analyzed for their potential contribution to resting vasomotor tone. RESULTS: QCA of reference coronary diameters was performed in a group of 103 patients undergoing PTCA. Post PTCA proximal and distal reference diameters significantly increased over baseline. The average increase of the proximal segment was 0.368 mm (13.6%) p < 0. 001 and of the distal segment 0.567 mm (24.8%) p < 0.001. The initial nominal balloon diameter was smaller than the post PTCA proximal segment by an average of 0.34 mm (12.6%) p < 0.001. Of the clinical and treatment variables examined age < 65 years and pre-PTCA beta blocker use, significantly affected baseline vasomotor tone p < 0.05. CONCLUSIONS: Routine diagnostic angiography underestimates the true diameter of the coronary artery. Due to baseline vasomotor tone, coronary reference segments can be expected to increase approximately 13% in diameter during successful PTCA. Patients under 65 years of age and those using beta-blockers may have a significantly increased baseline vasomotor tone. Underestimation of coronary artery diameter based on initial angiography necessitated a second, larger balloon in 16.5% of cases.

Prior revascularization increases the effectiveness of enhanced external counterpulsation.

BACKGROUND AND HYPOTHESIS: Enhanced external counterpulsation (EECP) is an effective noninvasive treatment for chronic angina. However, its usefulness has been felt to be limited in patients with angiographically demonstrated triple-vessel coronary artery disease (CAD), in accord with the hypothesis that a patent vessel is necessary for transmission of the EECP-augmented coronary artery pressure and volume to the distal coronary vasculature. METHODS: The effect of revascularization [coronary artery bypass grafting (CABG)] prior to EECP was examined in 60 patients with CAD and chronic angina (35 without and 25 with prior CABG). Patients were grouped by the extent of CAD (single-, double-, triple-vessel disease in the unrevascularized group) and by the extent of residual disease (number of stenotic native vessels unbypassed or supplied by a stenotic graft in the CABG group). Significant CAD or graft stenoses were defined as stenoses demonstrating > or = 70% luminal diameter narrowing. Benefit was assessed by improvement in post-EECP treatment over pretreatment radionuclide stress testing. RESULTS: Radionuclide stress testing demonstrated a comparable favorable response (80 vs. 71%; p = NS) in patients with prior CABG versus unrevascularized patients. Enhanced external counterpulsation was highly and comparably effective in patients with unrevascularized native single- and double-vessel CAD and in patients with CABG with residual single- and double-vessel CAD (88 vs. 80%; p = NS). Most notably, CABG significantly increased the beneficial response to EECP in those patients with triple-vessel CAD and stenotic grafts compared with unrevascularized patients with triple-vessel CAD (80 vs. 22%; p < 0.05 by chi-square test). CONCLUSION: The results suggest a new role for EECP as an effective treatment for post CABG ischemia, despite extensive CAD and even in the presence of stenotic grafts.

Maximizing the hemodynamic benefit of enhanced external counterpulsation.

BACKGROUND: Enhanced external counterpulsation (EECP) has been demonstrated to be an effective treatment for angina and exertional ischemia in patients with coronary disease. HYPOTHESIS: It is hypothesized that the ability of EECP to enhance the recruitment or development of coronary collaterals in coronary artery disease may be determined by the relative magnitude of diastolic augmentation (DA) and systolic unloading (SU). This study examines the relation between the proposed EECP effectiveness ratio (DA/SU), as assessed by finger plethysmography, and changes in descending aortic flow as assessed by Doppler echocardiography in 15 patients during EECP. METHODS: Varying external cuff pressures (0-275 mmHg) were used to generate a range of DA/SU ratios. The effect on aortic antegrade systolic and retrograde diastolic flow was assessed by Doppler echocardiography to determine whether there was an optimal EECP effectiveness ratio that maximizes the hemodynamic effects of EECP. With increasing DA/SU there was an initial positive linear increase in both systolic and diastolic flow volume. Systolic flow maximized at an effectiveness ratio of 1.5 and diastolic flow at a ratio of 2.0 RESULT: Therefore, effectiveness ratios (DA/SU) in the range of 1.5-2.0 are optimal for maximizing the hemodynamic effects of EECP.

Lipoprotein(a) level does not predict restenosis after percutaneous transluminal coronary angioplasty.

The serum lipoprotein(a) [Lp(a)] level is a known risk factor for arteriosclerotic coronary artery disease. However, its association with restenosis after percutaneous transluminal coronary angioplasty (PTCA) is controversial. We hypothesized that the Lp(a) level is a significant risk factor for restenosis after angioplasty through a pathophysiological mechanism leading to excess thrombin generation or inhibition of fibrinolysis. We designed a prospective study of the relation of Lp(a) to outcome after PTCA, in which we measured selected laboratory variables at entry and collected clinical, procedural, lesion-related, and outcome data pertaining to restenosis. Restenosis was defined as >50% stenosis of the target lesion by angiography or as ischemia in the target vessel distribution by radionuclide-perfusion scan. Before the patients underwent PTCA, blood was obtained by venipuncture for measurement of Lp(a), total cholesterol, thrombin-antithrombin (TAT) complex, alpha2-antiplasmin-plasmin (APP) complex, and plasminogen activator inhibitor-1 (PAI-1). Evaluable outcome data were obtained on 162 subjects, who form the basis of this report. Restenosis occurred in 61 subjects (38%). The Lp(a) level was not correlated significantly with TAT, APP, PAI-1, or the TAT-APP ratio. Levels of TAT, APP, and PAI-1 were not statistically different in the patients with versus those without restenosis. The median ratio of TAT to APP was 2-fold higher in the restenosis group, and this difference approached statistical significance (P=0.07). Univariate analysis was performed for the association of clinical, lesion-related, and procedural risk factors with restenosis. Lp(a) levels did not differ significantly in the restenosis versus no-restenosis group, whether assessed categorically (>25 mg/dL versus <25 mg/dL) or as a continuous variable by Mann-Whitney U test. The number of lesions dilated and the lack of family history of premature heart disease were significantly associated with restenosis (P=0.002 and P=0.008, respectively). A history of diabetes mellitus was of borderline significance (P=0.055). By multiple logistic regression analysis, the number of lesions dilated was the only variable significantly associated with restenosis (P=0.03). We conclude that the number of lesions dilated during PTCA is a significant risk factor for restenosis, whereas the serum Lp(a) level was not a significant risk factor for restenosis in our patient population. The TAT to APP ratio merits further study as a possible risk factor for restenosis.

Enhanced external counterpulsation as an adjunct to revascularization in unstable angina.

Enhanced external counterpulsation (EECP) is an effective noninvasive treatment for chronic stable angina. Despite intensive risk factor modification, a patient required two surgical coronary revascularizations and seven multivessel angioplasties over a 26-month period, demonstrating recurrent unstable angina and persistent thallium perfusion defects despite revascularization. Post EECP, angina was relieved, thallium defects were resolved and the patient has remained asymptomatic for 36 months.

Acute myocardial infarction with dynamic outflow obstruction precipitated by intra-aortic balloon counterpulsation.

Dynamic left ventricular outflow obstruction is associated with structural findings of asymmetric septal hypertrophy (less commonly concentric left ventricular hypertrophy) and systolic anterior motion of the anterior mitral valve leaflet. A patient who did not have this usual substrate for outflow obstruction presented with an acute anterior wall myocardial infarction complicated by congestive heart failure and cardiogenic shock. When an intra-aortic balloon pump was placed, the patient rapidly deteriorated and a dynamic outflow gradient was detected.

Improved exercise tolerance following enhanced external counterpulsation: cardiac or peripheral effect?

The effect of treatment with enhanced external counterpulsation (EECP) on exercise hemodynamics and myocardial stress perfusion in 27 patients with chronic stable angina was studied. A majority (22/27 or 81%) of patients improved their exercise tolerance after EECP treatment, and a similar percentage (21/27 or 78%) of patients improved their radionuclide stress perfusion images. Post-EECP maximal exercise heart rate and blood pressure, while demonstrating a linear relation with exercise duration, did not increase significantly despite the increased exercise duration. This suggests that the increase in exercise duration after treatment with EECP is due to both improved myocardial perfusion and altered exercise hemodynamics. EECP therapy thus appears to exert a "training' effect, decreasing peripheral vascular resistance and the heart rate response to exercise. Coronary disease patients may improve their exercise tolerance after EECP because of both improved myocardial perfusion and a decrease in cardiac work load.

Can angiographic findings predict which coronary patients will benefit from enhanced external counterpulsation?

Enhanced external counterpulsation is an effective treatment for chronic angina. Theoretical considerations predict greatest benefit in patients with at least 1 patent conduit in this group of 50 patients (all of whom improved clinically). Improvement in radionuclide stress perfusion imaging was seen in 80% of treated patients and was inversely related to extent of coronary disease.