Aircraft noise exposure and risk for recurrent cardiovascular events after acute coronary syndrome: A prospective patient cohort study.

In several population based cohort studies associations between aircraft noise and various diagnoses of cardiovascular disease were observed. However, no study has yet addressed the risk of recurrences in relation to transportation noise in patients with acute coronary heart disease. We conducted a prospective patient cohort study of 737 individuals recruited from eleven cardiac centers in the Rhine-Main region in the vicinity of Frankfurt Airport. All patients had an angiographically confirmed acute coronary syndrome diagnosed between July 2013 and November 2018. Individual aircraft noise exposure at the place of residence was calculated using Soundplan software, and exposure to road traffic and railway noise was obtained from noise maps provided by the Hessian State Agency. Data was analyzed by means of Cox regression adjusted for relevant confounders. Recurrent event as non-fatal endpoint was defined as myocardial infarction, stroke, bypass surgery or percutaneous coronary intervention with stent implantation. In addition, all-cause mortality was evaluated. Follow-up data including socioeconomic and confounder information was obtained from 663 (90%) patients covering a mean follow-up period of 42 (range: 1-80) months. Mean Lden aircraft noise exposure was 48.1 dB. Adjusted hazard ratio (HR) for recurrence was 1.24 (95%-CI: 0.97-1.58) per 10 dB increase in Lden aircraft noise exposure. A combined analysis of recurrence and all-cause mortality yielded a HR of 1.31 (95%-CI: 1.03-1.66). Similar HRs were found for Lday and Lnight aircraft noise exposure. HRs for road traffic and railway noise were above unity but less pronounced and not significant. Observed exposure-response associations for aircraft noise were more pronounced than previously observed in population-based cohort studies suggesting that acute coronary heart disease patients are particularly vulnerable to effects from transportation noise. Measures to reduce environmental noise exposure may thus be helpful in improving clinical outcome of patients with coronary heart disease.

Culprit lesion location and outcome in patients with cardiogenic shock complicating myocardial infarction: a substudy of the IABP-SHOCK II-trial.

BACKGROUND: In myocardial infarction without cardiogenic shock (CS), the affected coronary vessel has significant influence on the final infarct size and patient prognosis. CS data on this relation are scarce. The objective of this study was to determine the prognostic relevance of the culprit lesion location in patients with CS complicating acute myocardial infarction. METHODS: In the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial patients with CS were randomized to therapy with intraaortic balloon pump or control. Additional CS patients not eligible for the randomized trial were included in a registry. We compared the location of the culprit lesions in these patients with regard to the affected coronary vessel [left main (LM), left anterior descending (LAD), left circumflex (LCX) and right coronary artery (RCA)] and location within the vessel (proximal, mid or distal) regarding short- and long-term outcome. RESULTS: Of 758 patients, the majority had the culprit lesion in the LAD (44 %) compared to RCA (27 %), LCX (19 %) or LM (10 %). Proximal lesions were more frequent than mid or distal culprit lesions (60 vs. 27 vs. 13 %, p < 0.001). No differences were observed for mortality with respect to either culprit vessel (log-rank p value = 0.54). In contrast, a higher mortality was observed for patients with distal culprit lesions after 1 year (log-rank p value = 0.04). This difference persisted after multivariable adjustment (hazard ratio for distal lesions 1.40; 95 % confidential interval 1.03-1.90; p = 0.03). CONCLUSION: For patients with CS complicating myocardial infarction, the culprit vessel seems to be unrelated with mortality whereas distal culprit lesions may have a worse outcome.

ADP receptor antagonists in patients with acute myocardial infarction complicated by cardiogenic shock: a post hoc IABP-SHOCK II trial subgroup analysis.

AIMS: The aim of this post hoc subgroup analysis of the Intraaortic Balloon Pump in Cardiogenic Shock II trial was to compare the clinical outcome of patients treated with either clopidogrel or the newer, more potent P2Y12 receptor inhibitors prasugrel or ticagrelor. METHODS AND RESULTS: The primary endpoint was one-year mortality with respect to different P2Y12 receptor inhibitors. Secondary safety endpoints were GUSTO bleedings until hospital discharge. After exclusion of 117 patients (patients who died before or during PCI, patients with unavailable information on P2Y12 receptor inhibitor treatment, patients not receiving or receiving a combination of different P2Y12 receptor inhibitors as acute antiplatelet therapy), 483 patients were analysed. Of these, 373 patients (77.2%) received clopidogrel and 110 patients (22.8%) either prasugrel or ticagrelor as acute antiplatelet therapy. The adjusted rate of mortality did not differ between prasugrel/ticagrelor and clopidogrel treated patients (HR: 0.83, 95% CI: 0.59-1.19, padj=0.31). GUSTO bleedings did not differ between groups (14.3% for prasugrel/ticagrelor and 16.4% for clopidogrel, HR: 0.91, 95% CI: 0.55-1.5, padj=0.7). CONCLUSIONS: This IABP-SHOCK II trial subgroup analysis shows that the use of potent P2Y12 receptor inhibitors like prasugrel or ticagrelor is feasible and might not be harmful in selected patients with cardiogenic shock complicating acute myocardial infarction. However, the superiority in comparison to clopidogrel remains to be proven.

Gender differences in patients with cardiogenic shock complicating myocardial infarction: a substudy of the IABP-SHOCK II-trial.

BACKGROUND: Cardiogenic shock (CS) complicating acute myocardial infarction (AMI) is associated with high mortality. Previous studies regarding gender-specific differences in CS are conflicting and there are insufficient data for the presence of gender-associated differences in the contemporary percutaneous coronary intervention era. Aim of this study was therefore to investigate gender-specific differences in a large cohort of AMI patients with CS undergoing contemporary treatment. METHODS: In the randomized Intra-aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial, 600 patients with CS complicating AMI undergoing early revascularization were assigned to therapy with or without intra-aortic balloon pump. We compared sex-specific differences in these patients with regard to baseline and procedural characteristics as well as short- and long-term clinical outcome. RESULTS: Of 600 patients 187 (31%) were female. Women were significantly older than men and had a significantly lower systolic and diastolic blood pressure at presentation (p < 0.05 for all). Diabetes mellitus and hypertension were more frequent in women, whereas smoking was more frequent in men (p < 0.05 for all). Women showed a higher mortality within the first day after randomization (p = 0.004). However, after multivariable adjustment this numerical difference was no longer statistically significant. No gender-related differences in clinical outcome were observed after 1, 6 and 12 months of follow-up. CONCLUSION: In this large-scale multicenter study in patients with CS complicating AMI, women had a worse-risk profile in comparison to men. No significant gender-related differences in treatment as well as short- and long-term outcome were observed.

Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial.

BACKGROUND: In current international guidelines the recommendation for intra-aortic balloon pump (IABP) use has been downgraded in cardiogenic shock complicating acute myocardial infarction on the basis of registry data. In the largest randomised trial (IABP-SHOCK II), IABP support did not reduce 30 day mortality compared with control. However, previous trials in cardiogenic shock showed a mortality benefit only at extended follow-up. The present analysis therefore reports 6 and 12 month results. METHODS: The IABP-SHOCK II trial was a randomised, open-label, multicentre trial. Patients with cardiogenic shock complicating acute myocardial infarction who were undergoing early revascularisation and optimum medical therapy were randomly assigned (1:1) to IABP versus control via a central web-based system. The primary efficacy endpoint was 30 day all-cause mortality, but 6 and 12 month follow-up was done in addition to quality-of-life assessment for all survivors with the Euroqol-5D questionnaire. A masked central committee adjudicated clinical outcomes. Patients and investigators were not masked to treatment allocation. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00491036. FINDINGS: Between June 16, 2009, and March 3, 2012, 600 patients were assigned to IABP (n=301) or control (n=299). Of 595 patients completing 12 month follow-up, 155 (52%) of 299 patients in the IABP group and 152 (51%) of 296 patients in the control group had died (relative risk [RR] 1·01, 95% CI 0·86-1·18, p=0·91). There were no significant differences in reinfarction (RR 2·60, 95% CI 0·95-7·10, p=0·05), recurrent revascularisation (0·91, 0·58-1·41, p=0·77), or stroke (1·50, 0·25-8·84, p=1·00). For survivors, quality-of-life measures including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression did not differ significantly between study groups. INTERPRETATION: In patients undergoing early revascularisation for myocardial infarction complicated by cardiogenic shock, IABP did not reduce 12 month all-cause mortality. FUNDING: German Research Foundation; German Heart Research Foundation; German Cardiac Society; Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte; University of Leipzig--Heart Centre; Maquet Cardiopulmonary; Teleflex Medical.

Intraaortic balloon support for myocardial infarction with cardiogenic shock.

BACKGROUND: In current international guidelines, intraaortic balloon counterpulsation is considered to be a class I treatment for cardiogenic shock complicating acute myocardial infarction. However, evidence is based mainly on registry data, and there is a paucity of randomized clinical trials. METHODS: In this randomized, prospective, open-label, multicenter trial, we randomly assigned 600 patients with cardiogenic shock complicating acute myocardial infarction to intraaortic balloon counterpulsation (IABP group, 301 patients) or no intraaortic balloon counterpulsation (control group, 299 patients). All patients were expected to undergo early revascularization (by means of percutaneous coronary intervention or bypass surgery) and to receive the best available medical therapy. The primary efficacy end point was 30-day all-cause mortality. Safety assessments included major bleeding, peripheral ischemic complications, sepsis, and stroke. RESULTS: A total of 300 patients in the IABP group and 298 in the control group were included in the analysis of the primary end point. At 30 days, 119 patients in the IABP group (39.7%) and 123 patients in the control group (41.3%) had died (relative risk with IABP, 0.96; 95% confidence interval, 0.79 to 1.17; P=0.69). There were no significant differences in secondary end points or in process-of-care measures, including the time to hemodynamic stabilization, the length of stay in the intensive care unit, serum lactate levels, the dose and duration of catecholamine therapy, and renal function. The IABP group and the control group did not differ significantly with respect to the rates of major bleeding (3.3% and 4.4%, respectively; P=0.51), peripheral ischemic complications (4.3% and 3.4%, P=0.53), sepsis (15.7% and 20.5%, P=0.15), and stroke (0.7% and 1.7%, P=0.28). CONCLUSIONS: The use of intraaortic balloon counterpulsation did not significantly reduce 30-day mortality in patients with cardiogenic shock complicating acute myocardial infarction for whom an early revascularization strategy was planned. (Funded by the German Research Foundation and others; IABP-SHOCK II ClinicalTrials.gov number, NCT00491036.).

Intraaortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock: design and rationale of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial.

BACKGROUND: In current guidelines, intraaortic balloon pumping (IABP) is considered a class 1 indication in cardiogenic shock complicating acute myocardial infarction. However, evidence is mainly based on retrospective or prospective registries with a lack of randomized clinical trials. Therefore, IABP is currently only used in 20% to 40% of cardiogenic shock cases. The hypothesis of this trial is that IABP in addition to early revascularization by either percutaneous coronary intervention or coronary artery bypass grafting will improve clinical outcome of patients in cardiogenic shock. STUDY DESIGN: The IABP-SHOCK II study is a 600-patient, prospective, multicenter, randomized, open-label, controlled trial. The study is designed to compare the efficacy and safety of IABP versus optimal medical therapy on the background of early revascularization by either percutaneous coronary intervention or coronary artery bypass grafting. Patients will be randomized in a 1:1 fashion to 1 of the 2 treatments. The primary efficacy end point of IABP-SHOCK II is 30-day all-cause mortality. Secondary outcome measures, such as hemodynamic, laboratory, and clinical parameters, will serve as surrogate end points for prognosis. Furthermore, an intermediate and long-term follow-up at 6 and 12 months will be performed. Safety will be assessed, by the GUSTO bleeding definition, peripheral ischemic complications, sepsis, and stroke. CONCLUSIONS: The IABP-SHOCK II trial addresses important questions regarding the efficacy and safety of IABP in addition to early revascularization in patients with cardiogenic shock complicating myocardial infarction.

Incidence of atrial tachyarrhythmias in pacemaker patients: results from the Balanced Evaluation of Atrial Tachyarrhythmias in Stimulated patients (BEATS) study.

OBJECTIVES: The prospective Balanced Evaluation of Atrial Tachyarrhythmias in Stimulated patients (BEATS) study compared atrial tachyarrhythmia (AT) detection by means of serial ECG recordings versus device detection. BACKGROUND: The annual incidence of AT in patients with dual-chamber pacemakers may be significantly underestimated based on ECG and Holter recordings. METHODS: A DDD(R) device capable of AT-triggered dual-channel electrogram (EGM) storage was implanted in 254 patients (70 +/- 11 years, 159 men) with a class I pacing indication. Patients were seen at 6, 26, and 52 weeks after pacemaker implantation. At all visits, symptoms were checked, surface ECGs were recorded including a 24-hour Holter recording at 6 weeks, and the pacemakers were interrogated. Primary study endpoint was AT documentation by surface ECG/Holter versus stored EGMs. Secondary endpoints consisted of the association between patients' symptoms and AT documentation, and of the AT incidence depending on pacing indication and a history of AT. RESULTS: ATs were documented by ECG/Holter recordings in 37 patients (15%) and by stored EGMs in 137 patients (54%) (P < 0.0001). Symptoms were absent in 108 of 137 patients (79%) with device-documented AT but present in 70 of 117 patients (60%) without AT documentation. AT documentation was more frequent in patients with a history of AT but not in patients with sinus node compared to AV node disease. CONCLUSION: ATs occur in pacemaker patients significantly more frequently than estimated by ECG/Holter recordings. Only the analysis of device-stored EGMs allows reliable assessment of the AT burden.

Reduction of ICAM-1 and LFA-1-positive leukocytes in the perivascular space of arteries under mycophenolate mofetil therapy reduces rat heart transplant vasculopathy.

BACKGROUND: The interaction of lymphocyte function-associated antigen-1 (LFA-1)-positive host leukocytes with intercellular adhesion molecule-1 (ICAM-1) on graft endothelium may play a key role in allograft recognition, triggering the development of transplant vasculopathy (TVP). We investigated the correlation between TVP and ICAM-1 expression and accumulation of LFA-1-positive leukocytes in the perivascular space (PVS) of arteries under different immunosuppressive drugs. METHODS: After cardiac transplantation (Lewis to Fisher) animals were randomized 4 groups: cyclosporine (CsA), 3 mg/kg/day (n=74); mycophenolate mofetil (MMF), 40 mg/kg/day (n=96); FK 506, 0.3 mg/kg/day (n=96); and control, no therapy (n=74). Three or 4 animals from each group were harvested at intervals of 1 to 4 days within the study period of 60 days. Using immunohistochemistry, LFA-1-positive leukocytes were analyzed in intra- and epicardial arteries. ICAM-1 expression was scored histologically. TVP was assessed by digitizing morphometry and expressed as mean vascular occlusion. RESULTS: Accumulation of LFA-1-positive leukocytes in the PVS of arteries and the myocardium correlated with expression of ICAM-1 on graft endothelium. The severity of TVP in arteries correlated with the accumulation of LFA-1-positive leukocytes in PVS. All immunosuppressive drugs significantly reduced ICAM-1 expression, LFA-1 accumulation and extent of TVP, compared with controls. In MMF-treated animals, we also found a significant reduction of ICAM-1 expression, LFA-1 accumulation and extent of TVP compared with the groups treated with CsA and FK 506 (p <0.005). CONCLUSION: These data support an essential role of LFA-1/ICAM-1 interaction in the genesis of TVP that may be abrogated, especially by the use of MMF.

Mycophenolate mofetil significantly reduces leukocyte graft infiltration after heterotopic cardiac transplantation in a rat model: comparative study with cyclosporine and FK 506.

BACKGROUND: The purpose of the study was to evaluate the effects of cyclosporine (CsA), FK 506 and mycophenolate mofetil (MMF) on graft-infiltrating leukocytes (CD4, CD8, CD11a, CD18) after cardiac transplantation in rats. METHODS: Three hundred forty animals were transplanted and randomly divided into 4 groups: CsA, 3 mg/kg/d (n = 74); MMF, 40 mg/kg/d (n = 96); FK 506, 0.3 mg/kg/d (n = 96); and a control group receiving no immunosuppressive therapy (n = 74). Three or 4 animals from each group were killed at intervals of 1 to 4 days up to Day 60. Immunohistochemistry was performed using monoclonal antibodies (MAb) against CD4, CD8, CD11a and CD18. Positively stained cells were analyzed in the perivascular space (PVS) of intra- and epicardial arteries. Statistical analysis was performed using area-under-the-curve assessment with an extended t-test. RESULTS: CsA and FK 506 reduced the presence graft-infiltrating leukocytes (CD4, CD8, CD11a, CD18) in the PVS of intra- and epicardial arteries when compared with control animals. MMF therapy resulted in a further significant reduction in infiltrating leukocytes when compared with the 2 calcineurin inhibitors. MMF had a faster onset of action than the calcineurin inhibitors. CsA and FK 506 required 12 to 20 additional days to achieve the reducing effect of graft infiltration seen in MMF-treated animals. CONCLUSION: MMF possesses potent infiltration-blocking properties and its application leads to a greater reduction of cellular infiltration in the course of transplant rejection when compared with calcineurin inhibitors.

Two good reasons for an angiotensin-II type 1 receptor blockade with losartan after cardiac transplantation: reduction of incidence and severity of transplant vasculopathy.

Despite considerable progress in immunosuppressive therapy, the incidence and severity of transplant vasculopathy (TVP) after cardiac transplantation have not declined. The renin-angiotensin system (RAS) plays a pivotal role in the proliferation of vascular smooth muscle cells (VSMCs) contributing to TVP. We compared the effects of an angiotensin-II blocker, losartan (AT(1) blocker), and an angiotensin-converting enzyme (ACE) inhibitor, enalapril, on the incidence of diseased vessels and the severity of experimental TVP in the Lewis-to-Fischer rat heterotopic heart transplantation model. Recipients were randomly divided into six groups, group 1: no therapy, group 2: 3 mg/kg per day cyclosporine (CyA) s.c., group 3: CyA and 10 mg/kg per day losartan p.o., group 4: CyA and 40 mg/kg per day enalapril p.o., and groups 5 and 6: as groups 3 and 4, but additionally pre-treated with losartan or enalapril 7 days prior to transplantation. Eighty days after grafting, we assessed the incidence and severity of TVP, expressed as percentage of diseased vessels and mean vessel occlusion (MVO), by digitizing morphometry. CyA and CyA/enalapril post-treatment significantly reduced MVO, compared with controls, but not the incidence. Additional reduction of MVO was achieved in CyA/enalapril pre-treatment and both CyA/losartan pre- and post-treatment groups when compared with CyA and untreated controls. However, only losartan post-treatment in combination with CyA reduced both incidence and MVO. Our results validate the important role of the RAS in neointimal proliferation after cardiac transplantation. Losartan appears to be superior to enalapril in preventing TVP after experimental cardiac transplantation. Therefore, AT(1) blockade with losartan might be a therapeutic option for the prevention of TVP in human heart recipients.

Cyclosporine does not enhance the development of accelerated coronary artery disease: experimental study in a rat cardiac transplant model.

BACKGROUND: Among other factors, cyclosporine (CsA) is linked with the development of accelerated coronary artery disease (ACAD) after transplantation. The objective of this study was to assess the influence of different CsA regimens on ACAD after rat heart transplantation. METHODS: After heterotopic cardiac transplantation (Lewis to Fisher), animals were treated with 3 or 12 mg/kg per day of CsA, administered subcutaneously. The control group received no therapy. CsA blood levels were determined every 10 days. Twenty and 80 days after grafting, the incidence of ACAD was determined and the extent of ACAD was assessed as mean vessel occlusion (mvo). RESULTS: In the 12-mg group, CsA levels were nearly 10-fold higher than in the 3-mg group. Only in the 12-mg CsA group was the incidence of ACAD significantly reduced at Days 20 and 80 when compared with controls. Continuous therapy with 3 mg and 12 mg of CsA significantly reduced the mvo at Days 20 and 80 when compared with control animals (p <.05). However, comparing the two dosages, there were no significant differences. When the 20-day-limited course of CsA application was used we did not observe significant differences in mvo at Day 80 upon comparison of 3-mg and 12-mg CsA treatment versus untreated animals. CONCLUSIONS: Despite the excessive increase in CsA blood levels we observed neither a further reduction nor an increase of ACAD in the high-dose group compared with the low-dose group. Therefore, CsA did not enhance the development of chronic rejection in this experiment.