Mathias Wolfrum

Acetaminophen Increases Blood Pressure in Patients With Coronary Artery Disease

Background— Because traditional nonsteroidal antiinflammatory drugs are associated with increased risk for acute cardiovascular events, current guidelines recommend acetaminophen as the first-line analgesic of choice on the assumption of its greater cardiovascular safety. Data from randomized clinical trials prospectively addressing cardiovascular safety of acetaminophen, however, are still lacking, particularly in patients at increased cardiovascular risk. Hence, the aim of this study was to evaluate the safety of acetaminophen in patients with coronary artery disease. Methods and Results— The 33 patients with coronary artery disease included in this randomized, double-blind, placebo-controlled, crossover study received acetaminophen (1 g TID) on top of standard cardiovascular therapy for 2 weeks. Ambulatory blood pressure, heart rate, endothelium-dependent and -independent vasodilatation, platelet function, endothelial progenitor cells, markers of the renin-angiotensin system, inflammation, and oxidative stress were determined at baseline and after each treatment period. Treatment with acetaminophen resulted in a significant increase in mean systolic (from 122.4±11.9 to 125.3±12.0 mm Hg P=0.02 versus placebo) and diastolic (from 73.2±6.9 to 75.4±7.9 mm Hg P=0.02 versus placebo) ambulatory blood pressures. On the other hand, heart rate, endothelial function, early endothelial progenitor cells, and platelet function did not change. Conclusions— This study demonstrates for the first time that acetaminophen induces a significant increase in ambulatory blood pressure in patients with coronary artery disease. Thus, the use of acetaminophen should be evaluated as rigorously as traditional nonsteroidal antiinflammatory drugs and cyclooxygenase-2 inhibitors, particularly in patients at increased cardiovascular risk. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00534651.

Prognostic value of cardiac hybrid imaging integrating single-photon emission computed tomography with coronary computed tomography angiography

Aims Although cardiac hybrid imaging, fusing single-photon emission computed tomography (SPECT) myocardial perfusion imaging with coronary computed tomography angiography (CCTA), provides important complementary diagnostic information for coronary artery disease (CAD) assessment, no prognostic data exist on the predictive value of cardiac hybrid imaging. Hence, the aim of this study was to assess the prognostic value of hybrid SPECT/CCTA images. Methods and results Of 335 consecutive patients undergoing a 1-day stress/rest (99m)Tc-tetrofosmin SPECT and a CCTA, acquired on stand-alone scanners and fused to obtain cardiac hybrid images, follow-up was obtained in 324 patients (97%). Survival free of all-cause death or non-fatal myocardial infarction (MI) and free of major adverse cardiac events (MACE: death, MI, unstable angina requiring hospitalization, coronary revascularizations) was determined using the Kaplan-Meier method for the following groups: (i) stenosis by CCTA and matching reversible SPECT defect; (ii) unmatched CCTA and SPECT finding; and (iii) normal finding by CCTA and SPECT. Coxs proportional hazard regression was used to identify independent predictors for cardiac events. At a median follow-up of 2.8 years (25th-75th percentile: 1.9-3.6), 69 MACE occurred in 47 patients, including 20 death/MI. A corresponding matched hybrid image finding was associated with a significantly higher death/MI incidence (P < 0.005) and proved to be an independent predictor for MACE. The annual death/MI rate was 6.0, 2.8, and 1.3% for patients with matched, unmatched, and normal findings. Conclusion Cardiac hybrid imaging allows risk stratification in patients with known or suspected CAD. A matched defect on hybrid image is a strong predictor of MACE.

Loss of AngiomiR-126 and 130a in Angiogenic Early Outgrowth Cells From Patients With Chronic Heart Failure Role for Impaired In Vivo Neovascularization and Cardiac Repair Capacity

Background— MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34+ cells has been suggested to improve cardiac function after ischemic injury, in particular by promoting neovascularization. The present study therefore examines regulation of angiomiRs, microRNAs involved in angiogenesis, in angiogenic EOCs and circulating CD34+ cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity. Methods and Results— Angiogenic EOCs and CD34+ cells were isolated from patients with CHF caused by ischemic cardiomyopathy (n=45) and healthy subjects (n=35). In flow cytometry analyses, angiogenic EOCs were largely myeloid and positive for alternatively activated M2 macrophage markers. In vivo cardiac neovascularization and functional repair capacity were examined after transplantation into nude mice with myocardial infarction. Cardiac transplantation of angiogenic EOCs from healthy subjects markedly increased neovascularization and improved cardiac function, whereas no such effect was observed after transplantation of angiogenic EOCs from patients with CHF. Real-time polymerase chain reaction analysis of 14 candidate angiomiRs, expressed in angiogenic EOCs, revealed a pronounced loss of angiomiR-126 and -130a in angiogenic EOCs from patients with CHF that was also observed in circulating CD34+ cells. Anti–miR-126 transfection markedly impaired the capacity of angiogenic EOCs from healthy subjects to improve cardiac function. miR-126 mimic transfection increased the capacity of angiogenic EOCs from patients with CHF to improve cardiac neovascularization and function. Conclusions— The present study reveals a loss of angiomiR-126 and -130a in angiogenic EOCs and circulating CD34+ cells from patients with CHF. Reduced miR-126 expression was identified as a novel mechanism limiting their capacity to improve cardiac neovascularization and function that can be targeted by miR-126 mimic transfection.Background— MicroRNAs are key regulators of angiogenic processes. Administration of angiogenic early outgrowth cells (EOCs) or CD34+ cells has been suggested to improve cardiac function after ischemic injury, in particular by promoting neovascularization. The present study therefore examines regulation of angiomiRs, microRNAs involved in angiogenesis, in angiogenic EOCs and circulating CD34+ cells from patients with chronic heart failure (CHF) and the role for their cardiac repair capacity. Methods and Results— Angiogenic EOCs and CD34+ cells were isolated from patients with CHF caused by ischemic cardiomyopathy (n=45) and healthy subjects (n=35). In flow cytometry analyses, angiogenic EOCs were largely myeloid and positive for alternatively activated M2 macrophage markers. In vivo cardiac neovascularization and functional repair capacity were examined after transplantation into nude mice with myocardial infarction. Cardiac transplantation of angiogenic EOCs from healthy subjects markedly increased neovascularization and improved cardiac function, whereas no such effect was observed after transplantation of angiogenic EOCs from patients with CHF. Real-time polymerase chain reaction analysis of 14 candidate angiomiRs, expressed in angiogenic EOCs, revealed a pronounced loss of angiomiR-126 and -130a in angiogenic EOCs from patients with CHF that was also observed in circulating CD34+ cells. Anti–miR-126 transfection markedly impaired the capacity of angiogenic EOCs from healthy subjects to improve cardiac function. miR-126 mimic transfection increased the capacity of angiogenic EOCs from patients with CHF to improve cardiac neovascularization and function. Conclusions— The present study reveals a loss of angiomiR-126 and -130a in angiogenic EOCs and circulating CD34+ cells from patients with CHF. Reduced miR-126 expression was identified as a novel mechanism limiting their capacity to improve cardiac neovascularization and function that can be targeted by miR-126 mimic transfection. # Clinical Perspective {#article-title-54}

Cardiovascular effects of flavanol-rich chocolate in patients with heart failure

AIMS Flavanol-rich chocolate (FRC) is beneficial for vascular and platelet function by increasing nitric oxide bioavailability and decreasing oxidative stress. Congestive heart failure (CHF) is characterized by impaired endothelial and increased platelet reactivity. As statins are ineffective in CHF, alternative therapies are a clinical need. We therefore investigated whether FRC might improve cardiovascular function in patients with CHF. METHODS AND RESULTS Twenty patients with CHF were enrolled in a double-blind, randomized placebo-controlled trial, comparing the effect of commercially available FRC with cocoa-liquor-free control chocolate (CC) on endothelial and platelet function in the short term (2 h after ingestion of a chocolate bar) and long term (4 weeks, two chocolate bars/day). Endothelial function was assessed non-invasively by flow-mediated vasodilatation of the brachial artery. Flow-mediated vasodilatation significantly improved from 4.98 ± 1.95 to 5.98 ± 2.32% (P = 0.045 and 0.02 for between-group changes) 2h after intake of FRC to 6.86 ± 1.76% after 4 weeks of daily intake (P = 0.03 and 0.004 for between groups). No effect on endothelial-independent vasodilatation was observed. Platelet adhesion significantly decreased from 3.9 ± 1.3 to 3.0 ± 1.3% (P = 0.03 and 0.05 for between groups) 2 h after FRC, an effect that was not sustained at 2 and 4 weeks. Cocoa-liquor-free CC had no effect, either on endothelial function or on platelet function. Blood pressure and heart rate did not change in either group. CONCLUSION Flavanol-rich chocolate acutely improves vascular function in patients with CHF. A sustained effect was seen after daily consumption over a 4-week period, even after 12 h abstinence. These beneficial effects were paralleled by an inhibition of platelet function in the presence of FRC only.

Stroke prevention by percutaneous closure of patent foramen ovale: a systematic review and meta-analysis

Context The role of percutaneous closure of patent foramen oval (PFO) in patients with cryptogenic stroke has been very controversial for years due to a lack of clear evidence. Objective Systematic review and meta-analysis of the effect of percutaneous PFO closure for secondary prevention of cryptogenic strokes as compared to best medical therapy (BMT). Data sources Trials were identified through a literature search until 28 May 2013. Study selection Controlled clinical trials (randomised and non-randomised) comparing percutaneous PFO closure with BMT. Data extraction and synthesis Main end point of interest was stroke. A random effects model was used to calculate the pooled relative risks (RR) with 95% CIs. Results A total of 14 studies (three randomised controlled trials (RCT) and 11 non-randomised observational studies (non-RCT)), and a total of 4335 patients were included for this analysis. There was no significant treatment effect of PFO closure regarding stroke among the RCT (RR 0.66, 95% CI 0.37 to 1.19, p=0.171). However, among non-RCT stroke was reduced (RR 0.37, 95% CI 0.20 to 0.67, p<0.001) after PFO closure. A time-to-event (stroke) analysis, combining all three RCT and the two non-RCT which applied strict multivariate adjustments, showed a borderline significant risk reduction after PFO closure (HR 0.58, 95% CI 0.33 to 0.99, p=0.047). Neither risk of bleeding nor mortality differed significantly between the groups. However, there was a higher incidence of new onset atrial fibrillation in the closure group (RR 3.50, 95% CI 1.47 to 8.35, p=0.005). Conclusions Percutaneous closure of PFO in patients with cryptogenic stroke does not appear superior to medical therapy according to currently available randomised data. Furthermore, it is associated with an increased incidence of atrial fibrillation. However, there are signals pointing towards a potential benefit and more research should be strongly encouraged.

Improved Outcome Prediction by SPECT Myocardial Perfusion Imaging After CT Attenuation Correction

The aim of this study was to determine the impact of attenuation correction with CT (CT-AC) on the prognostic value of SPECT myocardial perfusion imaging (SPECT MPI). Methods: The summed stress score (SSS; 20-segment model) was obtained from filtered backprojection (FBP) and iterative reconstruction with CT-AC in 876 consecutive patients undergoing a 1-d stress–rest 99mTc-tetrofosmin SPECT MPI study for the evaluation of known or suspected coronary artery disease. Survival free of major adverse cardiac events (MACEs; cardiac death or nonfatal myocardial infarction) and survival free of any adverse cardiac events (including cardiac hospitalization, unstable angina, and late coronary revascularization) were analyzed by Kaplan–Meier analysis. Results: At a mean follow-up of 2.3 ± 0.6 y, a total of 184 adverse events occurred in 145 patients, including 35 MACEs (16 cardiac deaths [rate, 1.8%] and 19 nonfatal myocardial infarctions [rate, 2.2%]). With FBP, an SSS of 0–3 best distinguished patients with a low MACE rate (0.6%), followed by an SSS of 4–8 (4.3%), with increased MACE rate, and an SSS of 9–13 (3.8%), which was comparable. By contrast, with CT-AC the discrimination of low from intermediate MACE rate was best observed between an SSS of 0 (0%) and an SSS of 1–3 (3.7%), with a plateau at an SSS of 4–8 (3.2%). Conclusion: CT-AC for SPECT MPI allows improved risk stratification. The prognostically relevant SSS cutoff is shifted toward lower values.

Impact of cardiac hybrid single-photon emission computed tomography/computed tomography imaging on choice of treatment strategy in coronary artery disease

Aims Cardiac hybrid imaging by fusing single-photon emission computed tomography (SPECT) myocardial perfusion imaging with coronary computed tomography angiography (CCTA) provides important complementary diagnostic information for coronary artery disease (CAD) assessment. We aimed at assessing the impact of cardiac hybrid imaging on the choice of treatment strategy selection for CAD. Methods and results Three hundred and eighteen consecutive patients underwent a 1 day stress/rest 99mTc-tetrofosmin SPECT and a CCTA on a separate scanner for evaluation of CAD. Patients were divided into one of the following three groups according to findings in the hybrid images obtained by fusing SPECT and CCTA: (i) matched finding of stenosis by CCTA and corresponding reversible SPECT defect; (ii) unmatched CCTA and SPECT finding; (iii) normal finding by both CCTA and SPECT. Follow-up was confined to the first 60 days after hybrid imaging as this allows best to assess treatment strategy decisions including the revascularization procedure triggered by its findings. Hybrid images revealed matched, unmatched, and normal findings in 51, 74, and 193 patients. The revascularization rate within 60 days was 41, 11, and 0% for matched, unmatched, and normal findings, respectively (P< 0.001 for all inter-group comparisons). Conclusion Cardiac hybrid imaging with SPECT and CCTA provides an added clinical value for decision making with regard to treatment strategy for CAD.

Validation of CT Attenuation Correction for High-Speed Myocardial Perfusion Imaging Using a Novel Cadmium-Zinc-Telluride Detector Technique

The aim of this study was to validate attenuation correction (AC) using low-dose standard CT for myocardial perfusion imaging (MPI) on a novel ultra fast γ-camera with cadmium-zinc-telluride (CZT) detector technology. Methods: Sixty-six patients (body mass index ± SD, 27.2 ± 3.5 kg/m2; range, 19.1–36.0 kg/m2) underwent a 1-d 99mTc-tetrofosmin adenosine stress–rest imaging protocol with 15-min acquisitions on a standard dual-head SPECT camera. All scans were repeated within minutes on the CZT camera, with 3-min acquisitions for stress (low dose) and 2-min acquisitions for rest (high dose) as recently established. We compared maximum myocardial uptake (20-segment model) from CZT versus standard SPECT MPI by intraclass correlation without and with CT AC. In addition, clinical agreement for each coronary territory for all scans from both devices was assessed, and Bland–Altmann (BA) limits of agreement for percentage uptake were calculated. Results: The clinical agreement between CZT and standard SPECT cameras was 96% for noncorrected low- and high-dose images (r = 0.90 and BA = −18 to 15, and r = 0.91 and BA = −15 to 16, respectively), and agreement after AC was 96% for low- and 99% for high-dose images (r = 0.87 and BA = −16 to 14, and r = 0.88 and BA = −16 to 14, respectively). Conclusion: Our results support that AC of MPI on the novel CZT camera, compared with AC MPI on a conventional SPECT camera, is feasible because it provides a high correlation of segmental tracer uptake and an excellent clinical agreement.

Statins and the Risk of Cancer After Heart Transplantation

Background— Although newer immunosuppressive agents, such as mTOR (mammalian target of rapamycin) inhibitors, have lowered the occurrence of malignancies after transplantation, cancer is still a leading cause of death late after heart transplantation. Statins may have an impact on clinical outcomes beyond their lipid-lowering effects. The aim of the present study was to delineate whether statin therapy has an impact on cancer risk and total mortality after heart transplantation. Methods and Results— A total of 255 patients who underwent heart transplantation at the University Hospital Zurich between 1985 and 2007 and survived the first year were included in the present study. The primary outcome measure was the occurrence of any malignancy; the secondary end point was overall survival. During follow-up, a malignancy was diagnosed in 108 patients (42%). The cumulative incidence of tumors 8 years after transplantation was reduced in patients receiving a statin (34% versus 13%; 95% confidence interval, 0.25–0.43 versus 0.07–0.18; P<0.003). Statin use was associated with improved cancer-free and overall survival (both P<0.0001). A Cox regression model that analyzed the time to tumor formation with or without statin therapy, adjusted for age, male sex, type of cardiomyopathy, and immunosuppressive therapy (including switch to mTOR inhibitors or tacrolimus), demonstrated a superior survival in the statin group. Statins reduced the hazard of occurrence of any malignancy by 67% (hazard ratio, 0.33; 95% confidence interval, 0.21–0.51; P<0.0001). Conclusions— Although it is not possible to adjust for all potential confounders because of the very long follow-up period, this registry suggests that statin use is associated with improved cancer-free and overall survival after cardiac transplantation. These data will need to be confirmed in a prospective trial.

Effects of Pycnogenol on endothelial function in patients with stable coronary artery disease: a double-blind, randomized, placebo-controlled, cross-over study

AIMS Extracts from pine tree bark containing a variety of flavonoids have been used in traditional medicine. Pycnogenol is a proprietary bark extract of the French maritime pine tree (Pinus pinaster ssp. atlantica) that exerts antioxidative, anti-inflammatory, and anti-platelet effects. However, the effects of Pycnogenol on endothelial dysfunction, a precursor of atherosclerosis and cardiovascular events, remain still elusive. METHODS AND RESULTS Twenty-three patients with coronary artery disease (CAD) completed this randomized, double-blind, placebo-controlled cross-over study. Patients received Pycnogenol (200 mg/day) for 8 weeks followed by placebo or vice versa on top of standard cardiovascular therapy. Between the two treatment periods, a 2-week washout period was scheduled. At baseline and after each treatment period, endothelial function, non-invasively assessed by flow-mediated dilatation (FMD) of the brachial artery using high-resolution ultrasound, biomarkers of oxidative stress and inflammation, platelet adhesion, and 24 h blood pressure monitoring were evaluated. In CAD patients, Pycnogenol treatment was associated with an improvement of FMD from 5.3 ± 2.6 to 7.0 ± 3.1 (P < 0.0001), while no change was observed with placebo (5.4 ± 2.4 to 4.7 ± 2.0; P = 0.051). This difference between study groups was significant [estimated treatment effect 2.75; 95% confidence interval (CI): 1.75, 3.75, P < 0.0001]. 15-F(2t)-Isoprostane, an index of oxidative stress, significantly decreased from 0.71 ± 0.09 to 0.66 ± 0.13 after Pycnogenol treatment, while no change was observed in the placebo group (mean difference 0.06 pg/mL with an associated 95% CI (0.01, 0.11), P = 0.012]. Inflammation markers, platelet adhesion, and blood pressure did not change after treatment with Pycnogenol or placebo. CONCLUSION This study provides the first evidence that the antioxidant Pycnogenol improves endothelial function in patients with CAD by reducing oxidative stress.