Wayne Tymchak

Long-Term Treatment With Oral Sildenafil Is Safe and Improves Functional Capacity and Hemodynamics in Patients With Pulmonary Arterial Hypertension

Background—The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown. Methods and Results—We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger’s syndrome; New York Heart Association class II to III). Functional class improved by ≥1 class in all patients. Pretreatment versus posttreatment values (mean±SEM) were as follows: 6-minute walk, 376±30 versus 504±27 m, P <0.0001; mean PA pressure, 70±3 versus 52±3 mm Hg, P <0.007; pulmonary vascular resistance index 1702±151 versus 996±92 dyne · s · cm−5 · m−2, P <0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels. Conclusion—This small pilot study suggests that long-term sildenafil therapy might be a safe and effective treatment for PAH. At a monthly cost of

Long-Term Effects of Cholesterol Lowering and Angiotensin-Converting Enzyme Inhibition on Coronary Atherosclerosis: The Simvastatin/Enalapril Coronary Atherosclerosis Trial (SCAT)

492 Canadian, sildenafil is more affordable than most approved PAH therapies. A large multicenter trial is indicated to directly compare sildenafil with existing PAH treatments.

2-Year Follow-Up of Patients Undergoing Transcatheter Aortic Valve Implantation Using a Self-Expanding Valve Prosthesis

BackgroundThis long-term, multicenter, randomized, double-blind, placebo-controlled, 2×2 factorial, angiographic trial evaluated the effects of cholesterol lowering and angiotensin-converting enzyme inhibition on coronary atherosclerosis in normocholesterolemic patients. Methods and ResultsThere were a total of 460 patients: 230 received simvastatin and 230, a simvastatin placebo, and 229 received enalapril and 231, an enalapril placebo (some subjects received both drugs and some received a double placebo). Mean baseline measurements were as follows: cholesterol level, 5.20 mmol/L; triglyceride level, 1.82 mmol/L; HDL, 0.99 mmol/L; and LDL, 3.36 mmol/L. Average follow-up was 47.8 months. Changes in quantitative coronary angiographic measures between simvastatin and placebo, respectively, were as follows: mean diameters, −0.07 versus −0.14 mm (P =0.004); minimum diameters, −0.09 versus −0.16 mm (P =0.0001); and percent diameter stenosis, 1.67% versus 3.83% (P =0.0003). These benefits were not observed in patients on enalapril when compared with placebo. No additional benefits were seen in the group receiving both drugs. Simvastatin patients had less need for percutaneous transluminal coronary angioplasty (8 versus 21 events;P =0.020), and fewer enalapril patients experienced the combined end point of death/myocardial infarction/stroke (16 versus 30;P =0.043) than their respective placebo patients. ConclusionsThis trial extends the observation of the beneficial angiographic effects of lipid-lowering therapy to normocholesterolemic patients. The implications of the neutral angiographic effects of angiotensin-converting enzyme inhibition are uncertain, but they deserve further investigation in light of the positive clinical benefits suggested here and seen elsewhere.

Forced Euvolemic Diuresis With Mannitol and Furosemide for Prevention of Contrast-Induced Nephropathy in Patients With CKD Undergoing Coronary Angiography: A Randomized Controlled Trial

OBJECTIVES The purpose of this study was to evaluate the safety, device performance, and clinical outcome up to 2 years for patients undergoing transcatheter aortic valve implantation (TAVI). BACKGROUND The role of TAVI in the treatment of calcific aortic stenosis evolves rapidly, but mid- and long-term results are scarce. METHODS We conducted a prospective, multicenter, single-arm study with symptomatic patients undergoing TAVI for treatment of severe aortic valve stenosis using the 18-F Medtronic CoreValve (Medtronic, Minneapolis, Minnesota) prosthesis. RESULTS In all, 126 patients (mean age 82 years, 42.9% male, mean logistic European System for Cardiac Operative Risk Evaluation score 23.4%) with severe aortic valve stenosis (mean gradient 46.8 mm Hg) underwent the TAVI procedure. Access was transfemoral in all but 2 cases with subclavian access. Retrospective risk stratification classified 54 patients as moderate surgical risk, 51 patients as high-risk operable, and 21 patients as high-risk inoperable. The overall technical success rate was 83.1%. Thirty-day all-cause mortality was 15.2%, without significant differences in the subgroups. At 2 years, all-cause mortality was 38.1%, with a significant difference between the moderate-risk group and the combined high-risk groups (27.8% vs. 45.8%, p = 0.04). This difference was mainly attributable to an increased risk of noncardiac mortality among patients constituting the high-risk groups. Hemodynamic results remained unchanged during follow-up (mean gradient: 8.5 ± 2.5 mm Hg at 30 days and 9.0 ± 3.4 mm Hg at 2 years). Functional class improved in 80% of patients and remained stable over time. There was no incidence of structural valve deterioration. CONCLUSIONS The TAVI procedure provides sustained clinical and hemodynamic benefits for as long as 2 years for patients with symptomatic severe aortic stenosis at increased risk for surgery.

Exercise Training Improves Aerobic Capacity and Skeletal Muscle Function in Heart Transplant Recipients

BACKGROUND Contrast-induced nephropathy is common in patients with coronary angiography. Mechanistically, forced euvolemic diuresis with mannitol and furosemide ought to prevent contrast-induced nephropathy. Our objectives are to: (1) undertake a randomized trial testing this hypothesis, and (2) conduct a meta-analysis of our findings with 2 earlier studies. STUDY DESIGN (1) Randomized allocation-concealed controlled trial with blinded ascertainment of outcomes, and (2) random-effects meta-analysis of 3 trials. SETTING & PARTICIPANTS Single-center study of consenting adults with serum creatinine level greater than 1.7 mg/dL undergoing coronary angiography; patients unable to tolerate fluid challenge or receiving dialysis were excluded. Two previous trials had randomly assigned 159 patients. INTERVENTION Forced euvolemic diuresis with saline, mannitol, and furosemide compared with saline hydration controls. All patients were pretreated with at least 500 mL of half-normal saline before angiography; during and 8 hours after, urine output was replaced milliliter per milliliter with half-normal saline. OUTCOMES & MEASUREMENTS The primary outcome was contrast-induced nephropathy within 48 hours of the procedure, defined as a 0.5-mg/dL absolute or 25% relative increase in creatinine level. RESULTS Overall, 92 patients were allocated to intervention (n = 46) or control (n = 46). Mean age was 64 +/- 14 (SD) years, 23% were women, 37% had diabetes, 47% used oral furosemide, mean creatinine level was 2.8 +/- 1.6 mg/dL, and most patients (72%) underwent diagnostic catheterization. Patients had a net positive fluid balance (389 +/- 958 mL for intervention versus 655 +/- 982 mL for controls; P = 0.2). Contrast-induced nephropathy occurred in 23 (50%) intervention patients versus 13 (28%) controls (relative risk, 1.77; 95% confidence interval, 1.03 to 3.05; P = 0.03; adjusted odds ratio, 3.73; P = 0.03). Within 48 hours, creatinine level had increased by 0.8 +/- 1.1 mg/dL with intervention versus 0.2 +/- 0.6 mg/dL for controls (P = 0.002). Overall, 11 (12%) patients died or required dialysis, with no difference according to allocation status (P = 0.5). Random-effects meta-analysis of published data (3 trials; 251 patients) suggests furosemide-based interventions lead to significant harm compared with hydration: pooled relative risk, 2.15; 95% confidence interval, 1.37 to 3.37; I(2) = 0%. LIMITATIONS Small single-center study that cannot determine whether harms were related to furosemide, mannitol, or a combination. CONCLUSIONS Forced euvolemic diuresis led to a significantly increased risk of contrast-induced nephropathy. This strategy should be abandoned, and our results suggest that oral furosemide therapy perhaps should be held before angiography.

Oral Sildenafil Is an Effective and Specific Pulmonary Vasodilator in Patients With Pulmonary Arterial Hypertension

The aim of this study was to examine the effects of 12 weeks of supervised aerobic and strength training (SET) versus no‐training (NT) on peak aerobic power (VO2peak), submaximal exercise left ventricular (LV) systolic function, peripheral vascular function, lean tissue mass and maximal strength in clinically stable heart transplant recipients (HTR). Forty‐three HTR were randomly assigned to 12 weeks of SET (n = 22; age: 57 ± 10 years; time posttransplant: 5.4 ± 4.9 years) or NT (n = 21; age: 59 ± 11 years; time posttransplant: 4.4 ± 3.3 years). The change in VO2peak (3.11 mL/kg/min, 95% CI: 1.2–5.0 mL/kg/min), leg and total lean tissue mass (0.78 kg, 95% CI: 0.31–1.3 kg and 1.34 kg, 95% CI: 0.34–2.3 kg, respectively), chest‐press (10.4 kg, 95% CI: 5.2–15.5 kg) and leg‐press strength (34.7 kg, 95% CI: 3.7–65.6 kg) were significantly higher after SET versus NT. No significant change was found for submaximal exercise LV systolic function or brachial artery endothelial‐dependent or ‐independent vasodilation. Supervised exercise training is an effective intervention to improve VO2peak, lean tissue mass and muscle strength in HTR. This training regimen did not improve exercise LV systolic function or brachial artery endothelial function.

Effects of aerobic or aerobic and resistance training on cardiorespiratory and skeletal muscle function in heart failure: a randomized controlled pilot trial

Background—The prognosis of patients with severe pulmonary hypertension (PHT) is poor. To determine prognosis and guide therapy, an acute hemodynamic trial of selective pulmonary vasodilators, usually inhaled nitric oxide (iNO), was performed. We hypothesized that oral sildenafil, a phosphodiesterase-5 inhibitor, is a safe and effective alternative to iNO. Methods and Results—We studied 13 consecutive patients (mean±SEM, 44±2 years of age; 9 women) referred for consideration of heart-lung transplantation or as a guide to medical therapy. All but one were functional class III or IV. Patients had primary PHT (n=9), pulmonary arterial hypertension (n=2), or secondary PHT (n=2). Hemodynamics and serum cyclic guanosine-monophosphate levels (cGMP) were measured at baseline and at peak effects of iNO (80 ppm), sildenafil (75 mg), and their combination. The decrease in pulmonary vascular resistance was similar with iNO (−19±5%) and sildenafil (−27±3%), whereas sildenafil+iNO was more effective than iNO alone (−32±5%, P <0.003). Sildenafil and sildenafil+iNO increased cardiac index (17±5% and 17±4%, respectively), whereas iNO did not (−0.2±2.0%, P <0.003). iNO increased, whereas sildenafil tended to decrease, pulmonary capillary wedge pressure (+15±6 versus −9±7%, P <0.0007). Systemic arterial pressure was similar among groups and did not decrease with treatment. cGMP levels increased similarly with iNO and sildenafil, and their combination synergistically elevated cGMP (P <0.0001). Conclusions—A single oral dose of sildenafil is as effective and selective a pulmonary vasodilator as iNO. Sildenafil may be superior to iNO in that it increases cardiac output and does not increase wedge pressure. Future studies are indicated to establish whether sildenafil could be effective over a longer duration.

Increased circulating monocyte activation in patients with unstable coronary syndromes

Objective: To examined the effects of different training modalities on exercise capacity (Vo 2peak), systolic function, muscular strength and endurance and quality of life in heart failure patients. Design: Randomized controlled trial. Setting: Cardiac rehabilitation centre in Canada. Subjects: Forty-two individuals with heart failure (62 ± 12 years; New York Heart Association (NYHA) classes I—III). Interventions: Aerobic training (n = 14), combined aerobic and resistance training (n = 15) or usual care (n = 13) three times per week for 12 weeks. Main measures: (1) Vo 2peak measured by symptom-limited graded exercise test on cycle ergometer; (2) systolic function assessed by two-dimensional echocardiography; (3) muscular strength and muscular endurance measured by one-repetition maximum procedure; and (4) quality of life assessed by questionnaires. Results: In the intention-to-treat analysis, neither aerobic nor combined aerobic and resistance training significantly improved Vo2peak, systolic function or quality of life compared with usual care. However, combined aerobic and resistance training significantly improved upper extremity strength (40.7 (14.0)—48.5 (16.0) kg, P<0.05) and muscular endurance (5.7 (2.7)—11.6 (7.6) reps, P<0.05) compared with aerobic training or usual care. In compliant participants (exercise adherence 80%), Vo2peak increased in the aerobic group (16.9 (6.0)—19.0 (6.8), P= 0.026) and tended to increase in the combined training group (15.9 (5.0)—17.6 (5.6), P= 0.058) compared with usual care. Quality of life was improved in the aerobic group only. Conclusions: Both aerobic and combined aerobic and resistance training are effective interventions to improve Vo2peak in compliant heart failure patients. Combined training may be more effective in improving muscle strength and endurance.

Supratherapeutic Response to Ezetimibe Administered with Cyclosporine

OBJECTIVES The primary objective of this research was to assess the activation level of circulating monocytes in patients with unstable angina. BACKGROUND Markers of systemic inflammatory responses are increased in patients with unstable coronary syndromes, but the activation state and invasive capacity of circulating monocytes have not been directly assessed. METHODS Peripheral blood mononuclear cell (MC) activation in blood samples isolated from patients with stable and unstable coronary artery disease was measured in two studies. In study 1, a modified Boyden chamber assay was used to assess spontaneous cellular migration rates. In study 2, optical analysis of MC membrane fluidity was correlated with soluble CD14 (sCD14), a cellular activation marker. RESULTS Increased rates of spontaneous monocyte migration (p < 0.01) were detected in patients with unstable angina (UA) (Canadian Cardiovascular Society [CCS] angina class IV) on comparison to patients with acute myocardial infarction (MI), stable angina (CCS angina classes I to III) or normal donors. No significant increase in lymphocyte migration was detected in any patient category. Baseline MC membrane fluidity measurements and sCD14 levels in patients with CCS class IV angina were significantly increased on comparison with MCs from normal volunteers (p < 0.001). A concomitant reduction in the MC response to activation was detected (p < 0.05). CONCLUSIONS Using two complementary assays, activated monocytes with increased invasive capacity were detected in the circulation of patients with unstable angina. This is the first demonstration of increased monocyte invasive potential in unstable patients, raising the issue that systemic inflammation may both reflect and potentially drive plaque instability.

Pharmacokinetics in stable heart transplant recipients after conversion from twice-daily to once-daily tacrolimus formulations

OBJECTIVE: To report the case of a patient who underwent orthotopic heart transplant (OHT) and demonstrated a supratherapeutic response to ezetimibe when administered with cyclosporine. CASE SUMMARY: Ezetimibe 10 mg/day was added to the lipid-lowering regimen (atorvastatin 40 mg/day) of a 64-year-old male patient after OHT to achieve a target low-density lipoprotein cholesterol (LDL-C) level ≤97 mg/dL, as recommended by national guidelines. After 2 months of ezetimibe, the patients LDL-C level had decreased by 60% to 51 mg/dL. Subsequently, the dose of ezetimibe was reduced to 5 mg/day and, after another 2 months, a repeat lipid panel revealed LDL-C 57 mg/dL. DISCUSSION: Hyperlipidemia is a common problem among heart transplant recipients. Combination therapy using a statin plus ezetimibe appears to be an attractive option to achieve target lipid levels in this population. However, the manufacturer warns that ezetimibe should be administered cautiously in patients concomitantly receiving cyclosporine. Unpublished data suggest a pharmacokinetic interaction between ezetimibe and cyclosporine that results in a significant 2.3- to 12-fold increase in exposure to total ezetimibe. An objective causality assessment in this case revealed that this supratherapeutic LDL-C reduction was probably related to coadministration of ezetimibe and cyclosporine. A potential mechanism to explain this interaction might be an alteration in glucuronidation induced by cyclosporine. CONCLUSIONS: When ezetimibe is prescribed for patients concomitantly receiving cyclosporine, it should be initiated at a lower than recommended dose (≤5 mg/day) and titrated upward. Careful and consistent monitoring of patients on this combination is also advised.