Canadian Cardiovascular Society Functional Class Research Articles

Epicardial delivery of XC001 gene therapy for refractory angina coronary treatment (The EXACT Trial): Rationale, design, and clinical considerations

Patients with refractory angina (RA) have poor quality of life and new therapies are needed. XC001 is a novel adenoviral vector expressing multiple isoforms of vascular endothelial growth factor (VEGF) promoting an enhanced local angiogenic effect. The Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment (EXACT) trial is a 6-month (with 6-month extension) phase 1/2, first-in-human, multicenter, open-label, single-arm, dose-escalation study to evaluate the safety, tolerability, and preliminary efficacy of XC001 in patients with RA. The trial will enroll 33 patients in an initial (n = 12) ascending dose-escalation phase (1×109, 1×1010, 4×1010, and 1×1011 viral particles), followed by phase 2 (n = 21) assessing the highest tolerated dose. Patients must have stable Canadian Cardiovascular Society (CCS) class II-IV angina on maximally tolerated medical therapy without options for conventional revascularization, demonstrable ischemia on stress testing, and angina limiting exercise tolerance. XC001 will be delivered directly to ischemic myocardium via surgical transthoracic epicardial access. The primary outcome is safety via adverse event monitoring through 6 months. Efficacy assessments include difference from baseline to month 6 in time to 1 mm of ST segment depression, time to angina, and total exercise duration; myocardial blood flow at rest, and stress and coronary flow reserve by positron emission tomography; quality of life; CCS functional class; and angina frequency. The EXACT trial will determine whether direct intramyocardial administration of XC001 in patients with RA is safe and evaluate its effect on exercise tolerance, myocardial perfusion, angina and physical activity, informing future clinical investigation. NCT04125732.

Cardiopulmonary Exercise Test Parameters at Three Months After Alcohol Septal Ablation in Hypertrophic Obstructive Cardiomyopathy Are Associated With Late Clinical Outcome

Alcohol septal ablation (ASA) is an established interventional treatment for hypertrophic obstructive cardiomyopathy (HOCM) patients with drug refractory symptoms. This study investigated the prognostic value of cardiopulmonary exercise test (CPET) in relation to the late clinical outcome. Twenty-one (21) HOCM patients underwent CPET before and 3 months after ASA and were followed yearly thereafter. Clinical success was considered to be a decrease of ≥1 (New York Heart Association or Canadian Cardiovascular Society) functional class. Cardiopulmonary exercise test parameters [maximal oxygen uptake (PeakVO2), % predicted VO2 (PeakVO2%), oxygen uptake at anaerobic threshold (AT), maximal workload (W), % predicted W (W%), ventilation (VE), % predicted VE (VE%), ventilation to maximal carbon dioxide production slope (VE/VCO2), % predicted maximal heart rate (HR%), and maximal systolic blood pressure (SBP)] were compared before and 3 months after ASA. After follow-up of 29 ± 13 months, 16 patients had a good clinical results (clinical responders), while five did not improve (clinical non-responders). The CPET parameters did not change in non-responders, while clinical responders showed significant improvement in VO2, VO2%, W, VE/VCO2, VE, VE%, as well as an increase in HR% and SBP at 3 months. The data confirmed a good association between the improvement in CPET parameters and the clinical results 3 months after ASA. This may therefore serve as an early marker of HOCM-ASA treatment success.

A multicenter trial of extracorporeal cardiac shock wave therapy for refractory angina pectoris: report of the highly advanced medical treatment in Japan.

We have previously demonstrated that cardiac shock wave therapy (CSWT) effectively improves myocardial ischemia through coronary neovascularization both in a porcine model of chronic myocardial ischemia and in patients with refractory angina pectoris (AP). In this study, we further addressed the efficacy and safety of CSWT in a single-arm multicenter study approved as a highly advanced medical treatment by the Japanese Ministry of Health, Labour and Welfare. Fifty patients with refractory AP [mean age 70.9 ± 12.6 (SD) years, M/F 38/12] without the indications of percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) were enrolled in 4 institutes in Japan. Ischemic myocardial regions in the left ventricle (LV) were identified by drug-induced stress myocardial perfusion imaging (MPI). Shock waves (200 shots/spot at 0.09mJ/mm2) were applied to 40-60 spots in the ischemic myocardium 3 times in the first week. The patients were followed up for 3months thereafter. Forty-one patients underwent CSWT and completed the follow-up at 3months. CSWT markedly improved weekly nitroglycerin use [from 3.5 (IQR 2 to 6) to 0 (IQR 0 to 1)] and the symptoms [Canadian Cardiovascular Society functional class score, from 2 (IQR 2 to 3) to 1 (IQR 1 to 2)] (both P < 0.001). CSWT also significantly improved 6-min walking distance (from 384 ± 91 to 435 ± 122m, P < 0.05). There were no significant changes in LV ejection fraction evaluated by echocardiography and LV stroke volume evaluated by cardiac magnetic resonance imaging (from 56.3 ± 14.7 to 58.8 ± 12.8%, P = 0.10, and from 52.3 ± 17.4 to 55.6 ± 15.7mL, P = 0.15, respectively). Percent myocardium ischemia assessed by drug-induced stress MPI tended to be improved only in the treated segments (from 16.0 ± 11.1 to 12.1 ± 16.2%, P = 0.06), although no change was noted in the whole LV. No procedural complications or adverse effects related to the CSWT were noted. These results of the multicenter trial further indicate that CSWT is a useful and safe non-invasive strategy for patients with refractory AP with no options of PCI or CABG.

Abstract 32: Intravenous Mobilized Autologous Peripheral Blood CD34+ Stem Cell Transplantation for Angina

Background: Intramyocardial CD34+ stem cell therapy for patients with refractory angina shows that this is safe and feasible. We aimed to determine whether intravenous transplantation of mobilized autologous peripheral blood CD34+ stem cells provides beneficial effects for patients with angina pectoris. Methods: We administered granulocyte colony stimulating factor (G-CSF, 5.0 μg/kg/day) subcutaneously once a day for 4 days to 15 patients (4 women and 11 men aged 50-78 years) with intractable angina pectoris (Canadian Cardiovascular Society functional class III-IV) for mobilization of CD34+ cells into the peripheral blood. Ischemia was assessed by exercise stress testing. Leukapheresis procedure was started on the day 4 of G-CSF using the Spectra Optia cell separator. Circulating and intravenous transplantation of autologous CD34+ cells after leukapheresis were measured by flow cytometry. The effects of G-CSF on blood were measured by hematology analyzer and semi-auto chemistry analyzer. Results: Intravenous peripheral blood CD34+ cells increased after leukapheresis (from 1.12±0.48 cells/μL to 107.42±23.83 cells/μL, p&lt;0.001) and total white blood cells count (from 7.82 ± 2.63x10 3 /μl to 37.47±15.07 x10 3 /μl, p&lt;0.001). Indices of hsCRP, platelets, hemoglobin, alanine aminotransferase, lactic dehydrogenase, and uric acid were not changed by treatment. At week 4, angina frequency was significantly lower after intravenous CD34+ cells (from 15.07±4.03 to 3.27±1.49, p&lt;0.001). Similarly, improvement in exercise tolerance was significantly higher by stem cell transplantation (from 5.90±2.53 minutes to 8.41±2.49 minutes, p&lt;0.001). Most patients reported mild myalgia which were easily managed with acetaminophen. Conclusions: Intravenous autologous CD34+ stem cell transplantation improved angina frequency and exercise tolerance. The cell mobilization and leukapheresis procedures were found safe and tolerable in patients with angina pectoris.

Enhanced External Counterpulsation Is Cost-Effective in Reducing Hospital Costs in Refractory Angina Patients.

Enhanced external counterpulsation (EECP) is effective in the treatment of refractory angina, a condition suffered by 1.7 million Americans. Declining cardiovascular mortality and appropriate use criteria may further increase this number. EECP is hypothesized to be cost-effective in reducing hospitalizations in refractory angina patients. The data used in this analysis were collected in phase II of the International EECP Patient Registry (IEPR-II). Data were collected on changes in Canadian Cardiovascular Society functional class, Duke Activity Status Index, and number of hospitalizations in the 6 months prior to EECP and in the 6- and 12-month intervals following EECP. Estimates of the changes in annual cost of all-cause hospitalization before and after EECP therapy were calculated by the product of the differences in hospitalization rates in the 6-month interval before and after EECP treatment and estimated hospitalization and physician charges after subtracting the average cost of EECP. Data for 1015 patients were analyzed. Hospitalization occurred in 55.2% of patients, an average of 1.7 ± 1.4 hospitalizations/patient, in the 6-month period before 35 hours of EECP; and in 24.4%, an average of 1.4 ± 1.0 hospitalizations/patient, during the 6- to 12-month period after EECP. The average hospitalization and physician charge in the US was $17,995, and the average EECP cost was $4880, yielding an annual cost savings/patient of $17,074. Treatment of refractory angina patients with EECP resulted in improvement in angina and functional class accompanied by a sustained reduction in health care costs over 1 year of follow-up.

Pentraxin-3 concentrations in stable coronary artery disease depend on the clinical presentation.

Pentraxin-3 (PTX3) is an acute-phase reactant that shares structural and functional homology with C-reactive protein (CRP). However, unlike CRP, which is synthesized mainly in the liver, PTX3 is produced at the site of inflammation. It has been suggested that PTX3 plays the same role in the periphery that CRP does in circulation. PTX3 may represent a rapid marker of local inflammation. Fifty-one patients with stable coronary artery disease (CAD) were enrolled. Blood samples were collected on admission. Plasma concentration of PTX3 and high-sensitivity CRP (hsCRP) were determined. Median PTX3 concentration was 0.92 μmol/L (0.58-1.40). Median hsCRP concentration was 0.90 mg/L (0.75-1.10). There was a positive correlation between PTX3 and total cholesterol (R=0.34; P=0.01), PTX3 and LDL cholesterol (R=0.35; P=0.01), and PTX3 and hsCRP (R=0.46; P = 0.0005). We found no correlation between hsCRP and all laboratory parameters. We found higher PTX3 concentrations in patients with Canadian Cardiovascular Society (CCS) functional class 3 (compared to CCS functional class 2) and in patients taking nitrates. Lower PTX3 concentrations were reported in patients taking calcium channel blockers (amlodipine). hsCRP concentrations remained similar among these subgroups of patients. PTX3 is a marker of clinically more advanced CAD (CCS2 vs CCS3; nitrates vs no nitrates). PTX3 is also associated with other cardiovascular risk factors (total cholesterol, LDL cholesterol, and hsCRP). PTX3 may be a potential early marker of cardiovascular risk before the increase of systemic markers like hsCRP.

Abstract P86: Cost-Effectiveness of Enhanced External Counterpulsation in Reducing Hospital Costs in Refractory Angina Patients

Background: Repeat hospitalizations represent significant direct costs of care in patients (pts) with refractory angina. Enhanced external counterpulsation (EECP) is effective in treating coronary pts with disabling angina, who are not candidates for revascularization, and have limited treatment options. This study evaluated the cost savings in hospitalizations using EECP therapy. Methods: Annual EECP hospitalization cost savings/pt was calculated by the product of estimated hospitalization and physician charge based on a sample-size weighted average of Healthcare Cost and Utilization Project Nationwide Inpt Sample database and the reduction of hospitalizations/year after subtracting the cost of EECP. Pre- and post- EECP hospitalization rates were derived using data from the International EECP Pt Registry. The prevalence of refractory angina in the US in 2008 was estimated from the AHA Heart Disease and Stroke Statistics, heartstats.org, and the Incidence and Prevalence Database. Results: The annual pre-EECP treatment hospitalization rate for 1,015 refractory angina pts with 95% in Canadian Cardiovascular Society (CCS) functional class III and IV was 1.85 /pt/year. 92% of these pts had prior PCI or CABG with multivessel coronary disease and were no longer candidates for revascularization. EECP therapy was effective in reducing the proportion of CCS class III and IV pts to 21% at 1-year follow-up. Post-EECP 23% of the pts were hospitalized with a mean of 1.4 ± 1.0 hospitalizations in the 1 year after EECP. The post-EECP hospitalization rate was 0.63/pt/year, giving a hospitalization rate reduction of 1.22/pt/year. The average hospitalization and physician charge in the US was $17,995, and the average EECP treatment cost was $4,880, yielding an annual cost savings/pt of $17,025. Estimates of total savings were calculated by the product of cost savings/pt and the low and high estimates of the incidence of refractory angina (low: 422,000 pts; high: 1,273,000 pts). This calculation translated the total annual hospitalization cost savings as a potential 7.185 billion to 21.673 billion dollars. Conclusions: Appropriate use of EECP in refractory angina pts could result in a substantial decrease in hospital costs at an attractive cost-effectiveness.

Intramyocardial plasmid-encoding human vascular endothelial growth factor A165/basic fibroblast growth factor therapy using percutaneous transcatheter approach in patients with refractory coronary artery disease (VIF-CAD)

VIF-CAD randomized, placebo-controlled, double-blind trial was an attempt to induce therapeutic angiogenesis by percutaneous intramyocardial transfer of bicistronic (vascular endothelial growth factor/fibroblast growth factor [VEGF/FGF]) plasmid (pVIF) in patients with refractory heart ischemia. Myocardial perfusion, clinical symptoms, exercise tolerance, left ventricular function, and safety were assessed. Fifty-two patients with refractory coronary artery disease were randomized to receive VEGF/FGF plasmid (n = 33) or placebo plasmid (n = 19) into myocardial region showing stress-induced perfusion defects. Repeat stress and rest technetium Tc 99m sestamibi single-photon emission computed tomography at 5 months was the primary efficacy measure. Secondary assessment included Canadian Cardiovascular Society class and exercise tolerance at 5 and 12 months. Rest- and stress-induced perfusion defects did not differ between groups. Canadian Cardiovascular Society functional class improved after 5 (P = .0210) and 12 months (P = .0607) in the treatment group. The exercise tolerance of treated patients improved: total exercise time increased marginally (P = .0541); maximum workload (P = .0419) and total test distance (P = .0473) increased significantly, compared to placebo. Bicistronic VEGF/FGF plasmid therapy did not improve myocardial perfusion measured by single-photon emission computed tomography. However, treated patients experienced improvement with respect to exercise tolerance and clinical symptoms. Intramyocardial VEGF/FGF bicistronic plasmid transfer seemed safe throughout the follow-up period of 1 year.

Unexpected Cause for Chest Pain

A 71-year-old man was admitted to our hospital with new onset of typical symptoms of angina on exertion corresponding to a Canadian Cardiovascular Society functional class III. The patient had undergone mitral valve replacement with a mechanical bileaflet valve (ATS medical prosthesis, ATS Medical Inc., Minneapolis, Minn.) in December 1997 and transvenous pacemaker implantation for intermittent high-degree atrioventricular node block (Biotronik Philos II DR, ventricular demand inhibited pacemaker mode VVIR0, Biotronik SE & Co. KG, Berlin, Germany) in 2006. Medical history revealed chronic kidney disease and diabetes mellitus. He had chronic atrial fibrillation and was taking oral anticoagulants. The ECG showed discrete ST depression in leads I, II, III, and aVF (Figure 1). Cardiac troponin T on admission was slightly elevated (0.046 ng/mL; reference value at our institution is <0.0014 ng/mL), and his creatine kinase-MB was negative. Anterior-posterior and lateral chest x-ray showed a fracture of the sixth sternal wire with the lateral view showing a protrusion of the cerclage loop into the anterior mediastinum (Figure 2). Transthoracic echocardiography revealed moderately …

The impact of left ventricular hypertrophy on early and long-term survival after coronary artery bypass grafting

Background Left ventricular hypertrophy (LVH) can itself contribute to increased rates of cardiovascular events. We sought to determine the impact of LVH on in-hospital and long-term mortality after coronary artery bypass grafting (CABG). Methods Between 1992 and 2003, 4140 consecutive patients underwent CABG. Long-term survival data (mean follow-up 7.0 years) were obtained from the National Death Index. The impact of LVH on in-hospital mortality was determined by multivariate logistic regression analysis. Patients with and without LVH were compared by Cox proportional hazard models and risk-adjusted Kaplan–Meier curves. Results There were 977 patients (23.6%) with LVH. Their mean EuroSCORE was 7.4 ± 3.4 and there were 40 in-hospital deaths (4.1%) in this group. Multivariate logistic regression showed that patients with LVH had less elective operations, higher Canadian Cardiovascular Society Functional Class, more previous myocardial infarctions and higher percentages of 3-vessel disease, hypertension, current congestive heart failure, malignant ventricular arrhythmias, chronic obstructive pulmonary disease, calcified aorta, low ejection fraction, intravenous nitroglycerine, previous percutaneous coronary interventions and smoking. After adjustment for all available pre, intra and postoperative variables LVH was not an independent predictor for in-hospital mortality (OR 1.04, 95% CIs 0.60–1.81, P = 0.891). Risk-adjusted Kaplan–Meier survival curves showed decreased long-term survival in patients with LVH after the first 3 years (HR 1.24, 95% CIs 1.06–1.44, P = 0.006). Conclusions Patients with LVH showed similar in-hospital mortality when compared with patients without LVH. However, LVH was a detrimental risk factor for late mortality, especially after the third postoperative year. These data suggest the need for a more frequent long-term follow-up among patients with LVH undergoing CABG.

Discharge to Home Rates Are Significantly Lower for Octogenarians Undergoing Coronary Artery Bypass Graft Surgery

The incidence of coronary artery bypass graft surgery (CABG) performed in elderly patients has been increasing over recent years. We sought to evaluate clinical outcomes of octogenarians undergoing CABG using an audited state-wide mandatory database. New York State Department of Health's Cardiac Reporting System was analyzed from 1998 to 2002. In all, 88,154 patients undergoing isolated CABG were identified. Patients were divided into four age groups: less than 50 years (group 1, n = 6,527), 50 to 64 years (group 2, n = 30,088), 65 to 79 years (group 3, n = 43,369), and 80 years and above (group 4, n = 8,170). Of all patients, 9.3% were octogenarians. In addition to marginally worse coronary artery disease, octogenarians generally manifested a higher incidence of preoperative risk factors such as cerebrovascular disease, peripheral vascular disease, and congestive heart failure compared with younger patients at baseline. Both length of hospital stay and in-hospital mortality rate were significantly higher among octogenarians. The incidence of postoperative complications was higher among octogenarians. Multivariate analysis demonstrated renal failure requiring dialysis (odds ratio [OR] = 4.4), myocardial infarction within 6 hours before surgery (OR = 3.6), chronic obstructive pulmonary disease (OR = 1.7), congestive heart failure at admission (OR = 1.7), emergent operation (OR = 1.6), Canadian Cardiovascular Society functional class IV (OR = 1.5), hypertension (OR = 1.4), and low ejection fraction (OR = 0.98) to be significant independent predictors of in-hospital mortality of octogenarians. Discharge to home rates were significantly lower for octogenarians. Although early outcomes in octogenarians are acceptable, these factors alone are not sufficient to reflect overall success of CABG in these patients, given the strikingly lower discharge to home rates. Attention to full functional recovery in octogenarians is essential.

A novel, simple scale for assessing the symptom severity of atrial fibrillation at the bedside: The CCS-SAF Scale

The severity of symptoms caused by atrial fibrillation (AF) is extremely variable. Quantifying the effect of AF on patient well-being is important but there is no simple, commonly accepted measure of the effect of AF on quality of life (QoL). Current QoL measures are cumbersome and impractical for clinical use. To create a simple, concise and readily usable AF severity score to facilitate treatment decisions and physician communication. The Canadian Cardiovascular Society (CCS) Severity of Atrial Fibrillation (SAF) Scale is analogous to the CCS Angina Functional Class. The CCS-SAF score is determined using three steps: documentation of possible AF-related symptoms (palpitations, dyspnea, dizziness/syncope, chest pain, weakness/fatigue); determination of symptom-rhythm correlation; and assessment of the effect of these symptoms on patient daily function and QoL. CCS-SAF scores range from 0 (asymptomatic) to 4 (severe impact of symptoms on QoL and activities of daily living). Patients are also categorized by type of AF (paroxysmal versus persistent/permanent). The CCS-SAF Scale will be validated using accepted measures of patient-perceived severity of symptoms and impairment of QoL and will require 'field testing' to ensure its applicability and reproducibility in the clinical setting. This type of symptom severity scale, like the New York Heart Association Functional Class for heart failure symptoms and the CCS Functional Class for angina symptoms, trades precision and comprehensiveness for simplicity and ease of use at the bedside. A common language to quantify AF severity may help to improve patient care.

Extracorporeal cardiac shock wave therapy ameliorates myocardial ischemia in patients with severe coronary artery disease

Prognosis of severe coronary artery disease with no indication of percutaneous coronary intervention or coronary artery bypass grafting remains poor. We have recently demonstrated that shock wave therapy effectively induces neovascularization and improves myocardial ischemia in a porcine model in vivo. With permission from the Ethical Committee of our Institute, we treated nine patients with end-stage coronary artery disease with no indication of percutaneous coronary intervention or coronary artery bypass grafting (55-82 years old, five men and four women) with our cardiac shock wave therapy (200 shots/spot at 0.09 mJ/mm for 20-40 spots, 3 times a week/series). We followed-up the patients at 1, 3, 6, and 12 months after the therapy to examine the amelioration of myocardial ischemia. When needed, shock wave therapy was performed up to three series at 0, and 1, 3 or 6 months. The cardiac shock wave therapy improved symptoms (Canadian Cardiovascular Society functional class score, from 2.7+/-0.2 to 1.8+/-0.2, P<0.01) and reduced nitroglycerin use (from 5.4+/-2.5 to 0.3+/-0.3/week, P<0.05). The treatment also improved myocardial perfusion as assessed by dipyridamole stress thallium scintigraphy (severity score, 25.2+/-7.2% improvement, P<0.05; extent score, 23.3+/-9.0% improvement, P=0.10; washout rate, 20+/-3 to 34+/-3, P<0.05). Myocardial perfusion was improved only in the ischemic area treated with the therapy. These beneficial effects persisted for 12 months. No procedural complications or adverse effects were noted. These results indicate that our extracorporeal cardiac shock wave therapy is an effective and non-invasive treatment for end-stage coronary artery disease, although further careful evaluation is needed.

Poster 41: Functional Status is Measurably Improved in Patients With Angina Treated With Enhanced External Counterpulsation

Objective: To assess the effect enhanced external counterpulsation (EECP) has on overall functional status of individuals treated for angina. Design: Prospective cohort study with 6-month follow-up. Setting: Outpatient EECP clinic. Participants: 30 subjects (average age, 69.4y) with Canadian Cardiovascular Society (CCS) functional class III (n=21) and class IV (n=9) angina. Intervention: EECP utilizes electrocardiographic sequencing to trigger pneumatic cuffs wrapped around the lower extremities. The cuffs inflate and deflate during diastole, resulting in diastolic augmentation, increased venous return, presystolic unloading, and improved cardiac output. Main Outcome Measures: LIFEware System, a comprehensive, valid, and reliable tracking and reporting system for functional outcomes, and CCS functional angina classification. Results: 30 patients were assessed at baseline, after EECP, and at 6-month follow-up. At the conclusion of EECP patients rated their level of satisfaction with function and comfort achieved. Values ranged from 0 to 100 with the higher number referencing a better state, ie, more ability or less distress. Ratings at or above 70 were considered to define a prespecified threshold of clinical significance in functional status. Using that standard, 25 of 30 (83%) patients responded favorably to EECP. These responders reported considerable improvement in 4 variables: fatigue (mean, 41.0–59.8); satisfaction with life (mean, 45.5–68.2); social interactions (mean, 60.4–77.9); and role participation (mean, 63.2–78.8). At 6 months there was further improvement in the same four variables (mean, 76.6, 80.0, 83.2, and 86.8, respectively). CCS angina classification improved from a mean value of 3.36 to 1.24. Conclusions: EECP affords patients with angina significant improvement in quality of daily living, particularly in fatigue level, satisfaction with life, social interactions, and role participation. The overall functional status continues to improve 6 months after EECP is completed.

New Graduated Pressure Regimen for External Counterpulsation Reduces Mortality and Improves Outcomes in Congestive Heart Failure: A Report From the Cardiomedics External Counterpulsation Patient Registry

External counterpulsation (ECP) has been shown to increase exercise tolerance and reduce angina episodes, Canadian Cardiovascular Society Functional (CCSF) class, anginal medication usage, and hospitalizations in refractive CCSF class III and IV stable angina. However, the high pressures and resulting 1.5:1-2:1 peak diastolic to peak systolic pressure (D/S) ratios shown to be optimal in the treatment of angina can cause excessive preload and adverse effects in congestive heart failure (CHF) patients, particularly those with left ventricular ejection fractions <40%. Data were retrospectively analyzed from the Cardiomedics ECP Registry on 127 New York Heart Association (NYHA) class II-IV CHF patients (79.6% men; average age +/- SD, 68.2+/-15.6 years), with a comorbidity of CCSF class III-IV refractive angina, who were serially treated with 35 hours of ECP (1 h/d, 5 d/wk for 7 weeks) at unconventionally low pressures and D/S ratios under a new graduated pressure regimen. The pressures and D/S ratios were gradually increased in stages over the 7-week ECP regimen. The patients were divided into three groups based on the pressures applied and the resulting average D/S ratios (Low, Mid, and High). In the Low D/S ratio group (average D/S ratio 0.7:1), all-cause mortality in the year following ECP treatment was only 1.85% (one of 54 patients), whereas over the same time period in the Mid D/S ratio group (average D/S ratio 1.08:1), all-cause mortality was 7.69% (three of 39 patients) and in the High D/S ratio group (average D/S ratio 1.32:1), all-cause mortality was 8.82% (three of 34 patients). For the Low, Mid, and High D/S ratio groups, respectively: 1) average left ventricular ejection fractions increased 23.0%, 20.1%, and 17.5%; 2) NYHA class declined 36.6%, 29.6%, and 29.6%; and 3) all-cause hospitalizations, including terminal admissions, were reduced 85.7%, 82.6%, and 57.1% in the year following ECP therapy from the prior year. There were no adverse effects or withdrawals from the ECP therapy and no significant difference in sex-based outcomes. Consequently, ECP applied at low pressures and average D/S ratios of 0.7:1 under the new graduated pressure regimen is safe and effective in the treatment of CHF and produces a significant reduction in mortality, compared with the 8.5% annualized mortality of the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) (N=1232) of NYHA class II-III CHF and the 12.2% annual mortality of the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) study (N=595) of NYHA class III-IV CHF. Lower pressures improve patient comfort and may encourage more CHF patients to seek treatment. The reduction in hospitalizations should significantly reduce the cost of treating CHF.

Direct intramyocardial plasmid vascular endothelial growth factor-A165gene therapy in patients with stable severe angina pectoris: A randomized double-blind placebo-controlled study: The Euroinject One trial

In the Euroinject One phase II randomized double-blind trial, therapeutic angiogenesis of percutaneous intramyocardial plasmid gene transfer of vascular endothelial growth factor (phVEGF-A(165)) on myocardial perfusion, left ventricular function, and clinical symptoms was assessed.Evidence for safety and treatment efficacy have been presented in phase I therapeutic angiogenesis trials.Eighty "no-option" patients with severe stable ischemic heart disease, Canadian Cardiovascular Society functional class 3 to 4, were assigned randomly to receive, via the NOGA-MyoStar system (Cordis Corp., Miami Lakes, Florida), either 0.5 mg of phVEGF-A(165) (n = 40) or placebo plasmid (n = 40) in the myocardial region showing stress-induced myocardial perfusion defects on (99m)Tc sestamibi/tetrofosmin single-photon emission computed tomography.No differences among the groups were recorded at baseline with respect to clinical, perfusion, and wall motion characteristics. After three months, myocardial stress perfusion defects did not differ significantly between the VEGF gene transfer and placebo groups (38 +/- 3% and 44 +/- 2%, respectively). Similarly, semiquantitative analysis of the change in perfusion in the treated region of interest did not differ significantly between the two groups. Compared with placebo, VEGF gene transfer improved the local wall motion disturbances, assessed both by NOGA (p = 0.04) and contrast ventriculography (p = 0.03). Canadian Cardiovascular Society functional class classification of angina pectoris improved significantly in both groups but without difference between the groups. No phVEGF-A(165)-related adverse events were observed; however, NOGA procedure-related adverse events occurred in five patients.The VEGF gene transfer did not significantly improve stress-induced myocardial perfusion abnormalities compared with placebo; however, improved regional wall motion, as assessed both by NOGA and by ventriculography, may indicate a favorable anti-ischemic effect. This result should encourage more studies within the field. Transient VEGF overexpression seems to be safe.

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.

Poster 23: Enhanced external counterpulsation and functional improvement in octogenarians with symptomatic ischemic heart disease

Objective: To assess the functional outcomes of octogenarians with angina who receive enhanced external counterpulsation (EECP). Design: Retrospective review. Setting: Outpatient cardiac treatment facility. Participants: 24 octogenarians (avg age, 84.75y) with Canadian Cardiovascular Society (CCS) functional class III angina. Interventions: EECP is a safe, noninvasive outpatient therapy that uses computerized electrocardiographic sequencing to trigger pneumatic cuffs wrapped around the lower extremities. These cuffs sequentially inflate during diastole and rapidly deflate just prior to systole, resulting in diastolic augmentation, presystolic unloading, increased venous return, and improved cardiac output. The clinical outcomes of EECP therapy include marked symptom reduction and improved exercise tolerance in nearly 80% of patients. Main Outcome Measures: CCS angina classification and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Results: Our patients received an average of 38.75 hours of EECP therapy and reported no adverse events. 23 of the 24 patients improved their CCS angina classification by at least 1 class (8 by 2 classes) and 3 patients were entirely asymptomatic by the end of the program. All patients demonstrated improvement in exercise tolerance and functional status. The SF-36 was used to assess functional outcomes. The improvement in physical functioning ( P<.015) and emotional role ( P<.003) were statistically significant. The improvements in perception of health status was also significant ( P<.0001). Conclusions: EECP is a safe, efficacious treatment alternative for octogenarians with angina. This therapeutic physical modality leads to significant functional improvement, particularly in mobility and emotional outlook, in octogenarians with symptomatic ischemic heart disease and should be considered readily as a treatment option for this high-risk population.

Systemic T-cell activation in stable angina pectoris

However, there have beenfew studies on the systemic cell-mediated immuneresponse in stable angina pectoris (SAP), and the dataobtained so far have not provided any strong supportfor continuous T-cell activation. This study examinesthe T-cell profi le, including subsets and activationstatus of circulating T cells, as well as serum levels ofthe soluble interleukin-2 receptor (sIL-2R) in SAP.•••We studied 38 men ( 60 years of age) who all hadangiographically verifi ed coronary artery disease with 2 coronary stenoses ( 50% reduction of lumendiameter). The diagnosis of SAP was defi ned as ef-fort-related angina of Canadian Cardiovascular Soci-ety functional class II and III. Patients with myocar-dial infarction or UAP within the 2 last months beforethe study were excluded. Other exclusion criteria werediabetes, immunologic disorders, neoplastic disease,evidence of acute or recent ( 2 months) infection,recent major trauma, surgery or coronary revascular-ization, and treatment with antibiotic, immunosup-pressive, or anti-infl ammatory agents. Forty-two pre-sumably healthy men of equivalent age served ascontrols. Informed consent was obtained from all sub-jects. The research protocol was approved by thelocally appointed ethics committee.Blood was obtained by vein puncture in the morn-ing after a 12-hour fast. T-lymphocyte subpopulationswere measured by 3 color fl ow cytometry usingFACScan (Becton Dickinson Immunocytometry Sys-tems, Jo¨nko¨ping, Sweden). The cells were stained bydifferent triples of monoclonal antibodies against thefollowing antigens: CD3 (all T cells), CD4 (T-helpercells), CD8 (T cytotoxic/suppressor cells), CD25 (IL-2R; an early marker of T-cell activation), andHLA-DR (a marker of late T-cell activation). Theantibodies were marked with 1 of 3 fl uorochromes:fl uorescein isothiocyanate, phycoerythrin, and peri-dinin chlorofyll protein. A sample of 20 l of eachmonoclonal reagent triple was added to 100 lofwhole blood in 12 75 test tubes, centrifuged gently,and incubated at 4°C for 30 minutes. Red blood cellswere lysed using 3 ml of FACS lysing solution during2 minutes incubation at room temperature in the dark.The cells were washed twice with phosphate-bufferedsaline with 0.1% sodium azide, resuspended in washbuffer, fi xed with 1% paraformaldehyde, and analyzedafter 2 to 3 hours. Data were analyzed using CELLQuest software (Becton-Dickinson, Stockholm, Swe-den). Instrument setups, adjustments, and viabilitycontrols were performed as previously described.

Intra-aortic balloon counterpulsation: Outcome in cardiac surgical patients

Objective: To identify the major determinants of survival and nonsurvival for patients in need of intra-aortic balloon pump (IABP) support after cardiac surgery and to define the role of ventilator-associated pneumonia. Design: Retrospective study. Setting: University and general hospital. Participants: A total of 105 consecutive patients undergoing cardiac surgery requiring IABP support and prolonged mechanical ventilation for >24 hours. Intervention: All patients were assigned into 1 of 2 groups: survival (n = 69) and nonsurvival (n = 36). Measurements and Main Results: Differences between the survival and nonsurvival groups were tested with the Student's t-test, chi-square test, and frequency analysis. The overall survival rate was 65.7%. Nonsurvivors (34.3%) had higher rates of acute myocardial infarction (27.7% v 4.3%; p < 0.002), Canadian Cardiovascular Society functional class III and IV (44.4% and 13.8%; p < 0.001), and depressed left ventricular ejection fraction (31.3 ± 6.4% v 42.4 ± 7.2%; p < 0.001). The nonsurvival group had longer duration of cardiopulmonary bypass (165 ± 74.3 minutes v 135 ± 36 minutes; p < 0.006) and aortic occlusion (81.8 ± 9 minutes v 68.6 ± 25.7 minutes; p < 0.004). In the nonsurvival group, 21 patients were not weaned from the IABP, and 15 patients were weaned from the IABP but died from renal failure (26.6%), multiorgan failure (13.3%), infection, and respiratory failure (66.6%). In the nonsurvival group, mechanical ventilation time was longer in patients weaned from the IABP. Conclusion: These data suggest that for patients not weaned from the IABP, the major determinants of death are low cardiac output (33.3%) and multiorgan failure (47.6%). Patients with a left ventricular ejection fraction of <30% have a poorer outcome. In patients weaned from the IABP, ventilator-associated pneumonia (66.6%) was the major cause of death. Copyright © 2001 by W.B. Saunders Company