Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study.

Rapamycin, an mTOR inhibitor affects senescence through suppression of senescence-associated secretory phenotype (SASP). We studied the safety and feasibility of low-dose rapamycin and its effect on SASP and frailty in elderly undergoing cardiac rehabilitation (CR). 13 patients; 6 (0.5mg), 6 (1.0mg), and 1 patient received 2mg oral rapamycin (serum rapamycin <6ng/ml) daily for 12 weeks. Median age was 73.9±7.5 years and 12 were men. Serum interleukin-6 decreased (2.6 vs 4.4 pg/ml) and MMP-3 (26 vs 23.5 ng/ml) increased. Adipose tissue expression of mRNAs (arbitrary units) for MCP-1 (3585 vs 2020, p=0.06), PPAR-γ (1257 vs 1166), PAI-1 (823 vs 338, p=0.08) increased, whereas interleukin-8 (163 vs 312), TNF-α (75 vs 94) and p16 (129 vs 169) decreased. Cellular senescence-associated beta galactosidase activity (2.2% vs 3.6%, p=0.18) tended to decrease. We observed some correlation between some senescence markers and physical performance but no improvement in frailty with rapamycin was noted. (NCT01649960).

Segmental coronary endothelial dysfunction in patients with minimal atherosclerosis is associated with necrotic core plaques.

BACKGROUND/OBJECTIVE: Endothelial dysfunction and atherosclerosis are systemic disorders, but are often characterised by segmental involvement and complications. A potential mechanism for local involvement early in the disease process may be related to plaque composition. This study was designed to test the hypothesis that in patients with minimal coronary atherosclerosis, coronary artery segments with abnormal endothelial function have specific plaque characteristics. METHODS: Intravascular ultrasound (IVUS) images were obtained from 30 patients who underwent coronary endothelial function assessment. Spectral analysis of the IVUS radiofrequency data was used for assessment of plaque composition. IVUS findings of the coronary sections were compared according to the corresponding endothelial response to acetylcholine. RESULTS: Sections with a decrease epicardial coronary arterial diameter in response to acetylcholine had smaller baseline lumen (7.5 (2.4) mm(2) vs 8.8 (3.3) mm(2), p = 0.006) but larger plaque burden (37.1% (9.4%) vs 31% (7%), p = 0.003) than sections with normal endothelial response. Sections with endothelial dysfunction had larger necrotic core plaques: 0.13 (0.03-0.33) mm(2) vs 0.0 (0.0-0.07), p<0.001 and more dense calcium: 0.03 (IQR 0.0-0.13) mm(2) vs 0.0 (0.0-0.10) mm(2), p<0.01), than those with normal endothelial response. Only necrotic core area was associated with endothelial dysfunction (p<0.001) after adjusting for other measures. CONCLUSIONS: This study suggests that local coronary endothelial dysfunction in patients with minimal coronary atherosclerosis is associated with plaque characteristics that are typical of vulnerable plaques.

Stress hormone and circulating biomarker profile of apical ballooning syndrome (Takotsubo cardiomyopathy): insights into the clinical significance of B-type natriuretic peptide and troponin levels.

OBJECTIVE: To evaluate the stress neurohumoral and cardiac biomarker profile of patients with apical ballooning syndrome (ABS). METHODS: Plasma-free metanephrines, B-type natriuretic peptide (BNP), high sensitivity C-reactive protein (hsCRP) and troponin T, as well as 24-hour urine catecholamines, metanephrines and free cortisol were measured in 19 ABS and 10 ST-elevation myocardial infarction (STEMI) patients. RESULTS: An antecedent stressful event was identified in 15 ABS patients. There were no differences in plasma normetanephrine (median 0.64 (IQ range 0.43-0.97) nmol/l vs 0.53 (0.32-0.77) nmol/l, p = 0.44), metanephrine (0.10 (0.10-0.22) nmol/l vs 0.16 (0.10-0.38) nmol/l, p = 0.29), or cortisol levels (16.0 (7.3-44.0) microg/dl vs 13.0 (10.5-23.5) microg/dl, p = 0.95) between ABS and STEMI patients. The 24-hour urine metanephrines, catecholamines and cortisol levels were normal in the majority of ABS patients. Troponin T levels were lower (0.62 (0.18-0.84) ng/ml vs 3.80 (2.04-6.57) ng/ml, p<0.001), but BNP levels were higher in ABS compared with STEMI (944 (650-2022) pg/ml vs 206 (140-669) pg/ml, p = 0.009). HsCRP was similarly elevated in the two groups (11.0 (5.1-110.8) mg/l and 24.3 (8.1-88.6) mg/l, p = 0.78). CONCLUSIONS: Catecholamine and cortisol levels were not elevated in our cohort of ABS, suggesting that routine measurement of these stress hormones is unlikely to be of diagnostic value in practice. In contrast to STEMI, ABS is characterised by a greater elevation in BNP and less myonecrosis.

Immediate improvement in coronary flow reserve after alcohol septal ablation in patients with hypertrophic obstructive cardiomyopathy.

OBJECTIVES: To examine whether percutaneous alcohol septal ablation affects coronary flow reserve (CFR) in patients with hypertrophic cardiomyopathy (HCM). METHODS: CFR was measured immediately before and after septal ablation in patients with symptomatic obstructive HCM. CFR was also obtained in normal subjects (NL) for comparison. RESULTS: Patients with HCM (n = 11), compared with NL (n = 22), had a lower mean (SD) baseline CFR (1.96 (0.5) vs 3.0 (0.7), p<0.001), a lower coronary resistance (1.04 (0.45) vs 3.0 (2.6), p = 0.002), a higher coronary diastolic/systolic velocity ratio (DSVR; 5.1 (3.0) vs 1.8 (0.5), p = 0.04) and a lower hyperaemic coronary flow per left ventricular (LV) mass (0.73 (0.4) vs 1.1 (0.6) ml/min/g, p = 0.007). Septal ablation in the HCM group (n = 7) reduced the outflow tract gradient but not the left atrial or LV diastolic pressures. Ablation resulted in immediate normalisation of CFR (to 3.1 (1), p = 0.01) and DSVR (to 1.9 (0.8), p = 0.09) and an increase in coronary resistance (to 1.91 (0.6), p = 0.02). This was probably related to an improvement in the systolic coronary flow. CONCLUSIONS: This study demonstrates that successful septal ablation in patients with symptomatic HCM results in immediate improvement in CFR, which is reduced in HCM partly because of the increased systolic contraction load.

Predictors of slow flow during primary percutaneous coronary intervention: an intravascular ultrasound-virtual histology study.

OBJECTIVES: Slow flow phenomenon is a serious complication of percutaneous coronary intervention (PCI) and is associated with a poor prognosis. We sought to evaluate the characteristics of lesions predisposing to the slow/no-reflow phenomenon during primary PCI in patients with acute myocardial infarction. METHODS: The study subjects consisted of 57 consecutive patients (mean age 58.5 (SD 14.5) years, 45 males) who underwent primary PCI for acute myocardial infarction and intravascular ultrasound-virtual histology (IVUS-VH) examination. Slow flow was defined as

Comorbid conditions and outcomes after percutaneous coronary intervention.

OBJECTIVE: To evaluate whether adding comorbid conditions to a risk model can help predict in-hospital outcome and long-term mortality after percutaneous coronary intervention (PCI). DESIGN: Retrospective chart review SETTING: Academic medical centre. PATIENTS: 7659 patients who had 9032 PCIs. INTERVENTIONS: PCI performed at Mayo Clinic between 1 January 1999 and 30 June 2004. MAIN OUTCOME MEASURES: The Mayo Clinic Risk Score (MCRS) and the coronary artery disease (CAD)-specific index for determination of comorbid conditions in all patients. RESULTS: The mean (SD) MCRS score was 6.5 (2.9). The CAD-specific index was 0 or 1 in 46%, 2 or 3 in 30% and 4 or higher in 24%. The rate of in-hospital major adverse cardiovascular events (MACE) increased with higher MCRS and CAD-specific index (Cochran-Armitage test, p<0.001 for both models). The c-statistic for the MCRS for in-hospital MACE was 0.78; adding the CAD-specific index did not improve its discriminatory ability for in-hospital MACE (c-statistic = 0.78; likelihood ratio test, p = 0.29). A total of 707 deaths after dismissal occurred after 7253 successful procedures. The c-statistic for all-cause mortality was 0.69 for the MCRS model alone and 0.75 for the MCRS and CAD-specific indices together (likelihood ratio test, p<0.001), indicating significant improvement in the discriminatory ability. CONCLUSIONS: Addition of comorbid conditions to the MCRS adds significant prognostic information for post-dismissal mortality but adds little prognostic information about in-hospital complications after PCI. Such health-status measures should be included in future risk stratification models that predict long-term mortality after PCI.

Endovascular stent implantation in a coronary artery to pulmonary artery fistula in a patient with pulmonary atresia with ventricular septal defect and severe cyanosis.

A 31-year-old male with pulmonary atresia, ventricular septal defect presented with exercise intolerance and severe cyanosis. A restrictive coronary-pulmonary artery fistula was identified as the main source of pulmonary blood flow. We report transcatheter stent implantation in the fistula to augment pulmonary flow as a palliative management option in the adult patient with complex congenital heart disease.

Influence of coronary thrombus on outcome of percutaneous coronary angioplasty in the current era (the Mayo Clinic experience).

Earlier studies documented an increased risk of percutaneous coronary intervention (PCI) in patients with angiographic evidence of thrombus. With newer antiplatelet agents and stents, it is not known whether thrombus is a risk factor after PCI. This study examines whether outcome of PCI in patients with thrombus has improved, and whether thrombus is associated with adverse outcome after PCI in the current era. This single-institution retrospective analysis of PCI in 7,184 patients was divided into 2 periods: group I, 1990 to 1995 (n = 3,640), and group II, 1996 to 1999 (n = 3,544). The groups were subdivided according to the presence or absence of angiographic thrombus before PCI. We compared the outcome of PCI for patients with and without thrombus in group II. A comparison was made in the 2 groups in patients with angiographic thrombus. Procedural success improved in group II compared with group I patients with thrombus (93% vs 88%, p <0.001). There was significant reduction in abrupt closure in the recent era in patients with thrombus (4% vs 7%, p = 0.01). In group II, procedural success remained lower in patients with (93% vs 96%) than without thrombus (p <0.001). After adjusting for the significant univariate characteristics of group II patients, thrombus remained an independent predictor of Q-wave infarction (odds ratio 3.78; 95% confidence interval [CI], 1.8 to 8.0; p <0.0013) and the composite end point of death, Q-wave infarction, and emergency bypass surgery (odds ratio 2.37; 95% CI 1.4 to 4.1; p = 0.002). There was a trend toward increased in-hospital death among patients with thrombus (odds ratio 2.06; 95% CI 0.9 to 4.8; p = 0.09). The 1-year outcome after successful PCI was similar for those with and without thrombus. Despite improvement in the outcome of patients with thrombus undergoing PCI in recent years, thrombus is still an independent predictor of adverse in-hospital outcomes after PCI.

Early coronary angiography improves long-term survival in unstable angina.

BACKGROUND: The role of early coronary angiography in the evaluation of patients with unstable angina has been controversial. This study was designed to determine the effect of early coronary angiography on long-term survival in patients with unstable angina. METHODS: We reviewed the Olmsted County Acute Chest Pain Database, a population-based epidemiologic registry that includes all patients residing within Olmsted County who were seen for emergency department evaluation of acute chest pain from 1985 to 1992. Patients with symptoms consistent with myocardial ischemia qualifying as unstable angina were classified as undergoing early (

Incremental doses of intracoronary adenosine for the assessment of coronary velocity reserve for clinical decision making.

Achievement of maximal vasodilatation of the coronary microcirculation is a prerequisite for the measurement of coronary flow reserve (CFR). The present study was designed to address the hypothesis that intracoronary adenosine yields more complete vasodilation of the coronary microcirculation when incremental doses are used, resulting in higher and more accurate coronary flow reserve measurements. Four hundred and fifty-seven patients were divided in two groups; group I (319 patients) comprised patients without angiographic evidence of significant coronary artery disease, while group II (138 patients) comprised patients with intermediate coronary stenoses (between 40% and 70% diameter stenosis). Coronary velocity reserve (CVR, a surrogate measurement for CFR) was measured during cardiac catheterization using a Doppler-tipped guidewire. Incremental doses of intracoronary adenosine (12 to 54 microg for the left coronary artery and 6 to 42 microg for the right coronary artery) were administered. There was a significant difference between the initial dose of adenosine and the subsequent incremental doses. Of a total of 479 observations, only 192 (40%) had the maximal CVR value at the first dose. Thirty-nine percent of the patients in group I and 27% in group II with an initial CVR value < 2.5 increased CVR to > or = 2.5 with incremental doses of adenosine. This study suggests that incremental doses of adenosine should be used to achieve maximal CVR for the assessment of the functional significance of coronary lesions. Cathet Cardiovasc Intervent 2001;54:34-40.

Calcium embolism of the coronary arteries after percutaneous mitral balloon valvuloplasty.

Two cases of rare, catastrophic calcium emboli to the coronary arteries immediately after percutaneous mitral balloon valvuloplasty are presented. Preoperative echocardiographic findings may identify patients at risk for this complication. These cases should increase the awareness of calcium emboli and lead to consideration of urgent coronary angiography for patients with signs or symptoms of acute coronary occlusion after valvuloplasty.

Alveolar hemorrhage as a complication of treatment with abciximab.

STUDY OBJECTIVE: The use of abciximab, a chimeric monoclonal antibody Fab fragment specific for platelet glycoprotein IIb/IIIa receptors, is associated with improved outcome after angioplasty and stent placement. Major complications include bleeding, but pulmonary hemorrhage has been reported rarely. This study was done to identify patients with pulmonary hemorrhage following abciximab infusion and to define, if possible, any specific risk factors. DESIGN: Retrospective review of institutional coronary angiography and bronchoscopy databases to identify patients who received abciximab and developed pulmonary hemorrhage. SETTING: Tertiary-care teaching hospital. PATIENTS: All patients who underwent coronary angiography and received abciximab between June 1995 and March 2000. INTERVENTION: None. MEASUREMENTS AND RESULTS: Seven of 2,553 patients (0.27%) had documented severe pulmonary hemorrhage associated with chest radiographic abnormalities, impaired oxygenation, and the need for blood product transfusions. The initial symptom was hemoptysis in four of the seven patients. There were two early deaths and one late death. No cases of pulmonary hemorrhage were identified in 5,412 patients who underwent coronary procedures without abciximab infusion. No other risk factors predicting hemorrhage were identified. CONCLUSIONS: Severe pulmonary hemorrhage is a complication of abciximab use. Although hemoptysis is an important alerting symptom, it may not be present initially and the diagnosis may be missed or considered late, with the potential for inappropriate treatment until the diagnosis is established. Lesser degrees of bleeding are potentially easily missed, and this report should alert physicians to this complication so that it can be considered early in the evaluation of patients presenting with pulmonary events after abciximab use.

Infarct artery reocclusion after primary angioplasty, stent placement, and thrombolytic therapy for acute myocardial infarction.

BACKGROUND: The benefits of thrombolytic therapy for acute myocardial infarction (AMI) are limited by reocclusion of the infarct-related artery, which occurs in 25% to 30% of patients after successful reperfusion. The frequency of reocclusion after balloon angioplasty and stenting in this setting is less well documented. The aim of this study was to analyze the frequency and timing of reocclusion after percutaneous transluminal coronary angioplasty (PTCA) and stent placement during AMI from all available studies compared with previously published reocclusion rates after thrombolysis. METHODS AND RESULTS: The previously published thrombolysis data included 4231 patients in 19 studies with > or = 75 patients. Only PTCA studies with > or = 50 patients and stent studies with > or = 30 patients, in which routine angiographic follow-up was obtained in > or = 60% of patients, were included. Ten PTCA studies with a total of 1943 patients were analyzed, with follow-up angiography in 1391 (72%). Reocclusion rates ranged from 5% to 16.7%. The stent studies included 698 patients from 7 studies, with follow-up angiography in 92%. Reocclusion rates ranged from 0% to 6%. With the use of logistic regression analysis with allowance for overdispersion, there was a significantly lower rate of reocclusion after PTCA (odds ratio, 0.38; confidence interval, 0.24 to 0.57; P <.0001) and stent placement (odds ratio, 0.11; confidence interval, 0.05 to 0.22; P <.0001) compared with thrombolysis. Reocclusion after stent placement was lower than after PTCA (odds ratio, 0.28; confidence interval, 0.13 to 0.6; P <.0001). CONCLUSIONS: Reocclusion after PTCA and stent placement during AMI is less frequent than after thrombolysis. This may contribute to the superior outcome of patients treated with PTCA and stent placement in this setting.

Evaluation of long-term survival after successful percutaneous coronary intervention among patients with chronic renal failure.

We studied the long-term outcomes after percutaneous coronary intervention in dialysis patients and in patients with chronic renal failure (CRF) (serum creatinine > or = 3.0 mg/dl). All-cause mortality at 1 year was 2.9% for the control group, 16.2% for the group with CRF, and 14.1% for dialysis patients. Cardiac mortality at 1 year was 1.9% for ther control group, 15.2% for the group with CRF, and 10.0% for dialysis patients.

Immediate and one-year outcome of intracoronary stent implantation in small coronary arteries with 2.5-mm stents.

BACKGROUND: The role of coronary stenting in the treatment of stenoses in small coronary arteries with use of 2.5-mm stents is not well defined. METHODS AND RESULTS: Between January 1995 and August 1999, 651 patients with stenoses in small coronary arteries were treated with 2.5-mm stents (n = 108) or 2.5-mm conventional balloon angioplasty (BA) (n = 543). Patients who received treatment with both 2.5-mm and > or =3.0-mm stent placement or balloons were excluded. Procedural success and complication rates as well as 1-year follow-up outcomes were examined. Baseline clinical characteristics were similar between the two groups, except patients in the stent group were more likely to have hypertension and a family history of coronary artery disease and less likely to have prior myocardial infarction. Angiographic success rates were higher in the stent group (97.2% vs 90.2%, P =.02). In-hospital complication rates were comparable between the two groups. Among successfully treated patients, 1-year follow-up revealed no significant differences in the survival (96.2% vs 95.2%, P =.89) or the frequency of Q-wave myocardial infarction (0% vs 0.4%, P =.60) or coronary artery bypass grafting (8.4% vs 6.8%, P =.89) between the stent and BA groups, respectively. However, patients in the stent group were more likely to have adverse cardiac events (35.4% vs 22.1%, P =.05). Stent use after excluding GR II stent use, however, was not independently associated with reduced cardiac events at follow-up (relative risk 1. 3 [95% confidence interval 0.8-2.3], P =.30). CONCLUSIONS: Intracoronary stent implantation of stenoses in small coronary arteries with 2.5-mm stents can be carried out with high success and acceptable complication rates. However, compared with BA alone, stent use was not associated with improved outcome through 1 year of follow-up.

Improving outcome over time of percutaneous coronary interventions in unstable angina.

OBJECTIVE: This study was performed to evaluate the recent changes in the outcome of coronary interventions in patients with unstable angina (UA). BACKGROUND: An early invasive strategy has not been shown to be superior to conservative treatment in patients with UA. Earlier studies had utilized older technology. Interventional approaches have changed in the recent past, but to our knowledge, no large studies have addressed the impact of these changes on the outcome of coronary interventions. METHODS: We analyzed the in-hospital and intermediate-term outcome in 7,632 patients with UA who underwent coronary interventions in the last two decades. The study population was divided into three groups: group 1, n = 2,209 who had coronary intervention from 1979 to 1989; group 2, n = 2,212 with interventions from 1990 to 1993; and group 3, n = 3,211 treated from 1994 to 1998. RESULTS: Group 2 and 3 patients were older and sicker compared with group 1 patients. The clinical success improved significantly in group 3 (94.1%) compared with group 2 (87%) and group 1 (76.5%) (p < 0.001). There was a significant reduction in in-hospital mortality, Q-wave myocardial infarction and need for emergency bypass surgery in group 3 compared with the earlier groups. One-year event-free survival was also significantly higher in the recent group compared with the earlier groups: 77% in group 3, 70% in group 2 and 74% in group 1 (p < 0.001). With the use of multivariate models to adjust for clinical and angiographic variables, treatment during the most recent era was found to be independently associated with improved in-hospital and intermediate-term outcomes. CONCLUSIONS: There has been significant improvement in the in-hospital and intermediate-term outcome of coronary interventions in patients with UA in recent years; newer trials comparing conservative and invasive strategies are therefore needed.

Application of the New York State PTCA mortality model in patients undergoing stent implantation.

BACKGROUND: This study applied the New York State conventional coronary angioplasty (PTCA) model of clinical outcomes to evaluate whether it has relevance in the current era of stent implantation. The model was developed in 62 670 patients treated with conventional PTCA from 1991 to 1994 to risk adjust mortality and bypass surgery after PTCA. Since then, stents have become the dominant form of intervention. Whether that model remains relevant is uncertain. METHODS AND RESULTS: All patients undergoing stenting at the Mayo Clinic from 1995 to 1998 were analyzed for in-hospital mortality, bypass surgery performed after attempted stenting, and longer-term mortality. No patients were excluded. The New York model was used to risk adjust and predict in-hospital and follow-up mortality. There were 3761 patients with 4063 procedural admissions for stenting; 6,472 target vessel segments were attempted, and 96.1% of procedures were successful. With the New York multivariable risk factor equation, 79 in-hospital deaths were expected (1.95%); 66 deaths (1.62%) were observed. The New York model risk score in a logistic regression model was the most significant factor associated with in-hospital mortality (OR, 1.86; P<0.001). During a mean follow-up of 1.2+/-1.0 years, there were 154 deaths. Multivariable analysis documented 6 factors associated with subsequent mortality; New York risk score was the most significant (chi(2)=16.64, P=0.0001). CONCLUSIONS: Although the New York mortality model was developed in an era of conventional angioplasty, it remains relevant in patients undergoing stenting. The risk score derived from that model is the variable most significantly associated with not only in-hospital but also longer-term outcome.

Prediction of death after percutaneous coronary interventional procedures.

BACKGROUND: The prediction and comparison of procedural death after percutaneous coronary interventional procedures is inherently difficult because of variations in case mix and practice patterns. The impact of modern, expanded patient selection criteria, and newer technologic approaches is unknown. Our objective was to determine whether a risk equation based on patient-related variables and derived from an independent data set can accurately predict procedural death after percutaneous coronary intervention in the current era. METHODS AND RESULTS: An analysis was made of the Mayo Clinic Coronary Interventional Database January 1, 1995, to October 31, 1997. Expected mortality rate was calculated with the use of the New York State multivariate risk score. In 3387 patients, 3830 procedures (55.1% stents) were performed, with an expected mortality rate of 2.32% and observed mortality rate of 2.38% (P = not significant). The risk score derived from the New York multivariate model was highly predictive of death (chi-square = 213.8; P <.0001). The presence of a high-risk lesion characteristic such as calcium, thrombus, or type C lesion was modestly associated with death. CONCLUSIONS: The New York State multivariate model accurately predicted procedural death in our database.