Acute and Chronic Cardiopulmonary Effects of High Dose Interleukin-2 Therapy: An Observational Magnetic Resonance Imaging Study.

High dose interleukin-2 (IL-2) is known to be associated with cardiopulmonary toxicity. The goal of this study was to evaluate the effects of high dose IL-2 therapy on cardiopulmonary structure and function. Combined cardiopulmonary magnetic resonance imaging (MRI) was performed in 7 patients in the acute period following IL-2 therapy and repeated in 4 patients in the chronic period. Comparison was made to 10 healthy volunteers. IL-2 therapy was associated with myocardial and pulmonary capillary leak, tissue oedema and cardiomyocyte injury, which resulted in acute significant left ventricular (LV) dilatation, a reduction in LV ejection fraction (EF), an increase in LV mass and a prolongation of QT interval. The acute effects occurred irrespective of symptoms. In the chronic period many of the effects resolved, but LV hypertrophy ensued, driven by focal replacement and diffuse interstitial myocardial fibrosis and increased cardiomyocyte mass. In conclusion, IL-2 therapy is ubiquitously associated with acute cardiopulmonary inflammation, irrespective of symptoms, which leads to acute LV dilatation and dysfunction, increased LV mass and QT interval prolongation. Most of these effects are reversible but IL-2 therapy is associated with chronic LV hypertrophy, driven by interstitial myocardial fibrosis and increased cardiomyocyte mass. The findings have important implications for the monitoring and long term impact of newer immunotherapies. Future studies are needed to improve risk stratification and develop cardiopulmonary-protective strategies.

The Diagnostic and Prognostic Utility of Contemporary Cardiac Magnetic Resonance in Suspected Acute Myocarditis.

Cardiovascular magnetic resonance (CMR) is used to investigate suspected acute myocarditis, however most supporting data is retrospective and few studies have included parametric mapping. We aimed to investigate the utility of contemporary multiparametric CMR in a large prospective cohort of patients with suspected acute myocarditis, the impact of real-world variations in practice, the relationship between clinical characteristics and CMR findings and factors predicting outcome. 540 consecutive patients we recruited. The 113 patients diagnosed with myocarditis on CMR performed within 40 days of presentation were followed-up for 674 (504-915) days. 39 patients underwent follow-up CMR at 189 (166-209) days. CMR provided a positive diagnosis in 72% of patients, including myocarditis (40%) and myocardial infarction (11%). In multivariable analysis, male sex and shorter presentation-to-scan interval were associated with a diagnosis of myocarditis. Presentation with heart failure (HF) was associated with lower left ventricular ejection fraction (LVEF), higher LGE burden and higher extracellular volume fraction. Lower baseline LVEF predicted follow-up LV dysfunction. Multiparametric CMR has a high diagnostic yield in suspected acute myocarditis. CMR should be performed early and include parametric mapping. Patients presenting with HF and reduced LVEF require closer follow-up while those with normal CMR may not require it.

Cardiac involvement in cystic fibrosis evaluated using cardiopulmonary magnetic resonance.

Cystic fibrosis (CF) transmembrane conductance regulator is expressed in myocardium, but cardiac involvement in CF remains poorly understood. The recent development of a combined cardiopulmonary magnetic resonance imaging technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. The aim of this study was to investigate myocardial manifestations in adults with CF, both in a stable state and during an acute respiratory exacerbation, and to investigate the relationship between cardiac and pulmonary disease. Healthy adult volunteers (n = 12) and adults with CF (n = 10) were studied using a multiparametric cardiopulmonary magnetic resonance protocol. CF patients were scanned during an acute respiratory exacerbation and re-scanned when stable. Stable CF was associated with left ventricular dilatation and hypertrophy (LVH; left ventricular mass: CF 59 ± 9 g/m2 vs. control 50 ± 8 g/m2; p = 0.028). LVH was predominantly driven by extracellular myocardial matrix expansion (extracellular matrix mass: CF 27.5 ± 3.4 g vs. control 23.6 ± 5.2 g; p = 0.006; extracellular volume [ECV]: CF 27.6 [24.7-29.8]% vs. control 24.8 [22.9-26.0]%; p = 0.030). Acute CF was associated with an acute reduction in left ventricular function (ejection fraction: acute 57 ± 3% vs. stable 61 ± 5%; p = 0.025) and there was a suggestion of myocardial oedema. Myocardial oedema severity was strongly associated with the severity of airflow limitation (r = - 0.726, p = 0.017). Multiparametric cardiopulmonary magnetic resonance technology allows for a simultaneous interrogation of cardiac and pulmonary structure and function. Stable CF is associated with adverse myocardial remodelling, including left ventricular systolic dilatation and hypertrophy, driven by myocardial fibrosis. CF exacerbation is associated with acute myocardial contractile dysfunction. There is also a suggestion of myocardial oedema in the acute period which is related to pulmonary disease severity.

Mechanisms Underlying the Association of Chronic Obstructive Pulmonary Disease With Heart Failure.

OBJECTIVES: The purposes of this study were to determine why chronic obstructive pulmonary disease (COPD) is associated with heart failure (HF). Specific objectives included whether COPD is associated with myocardial fibrosis, whether myocardial fibrosis is associated with hospitalization for HF and death in COPD, and whether COPD and smoking are associated with myocardial inflammation. BACKGROUND: COPD is associated with HF independent of shared risk factors. The underlying pathophysiological mechanism is unknown. METHODS: A prospective, multicenter, longitudinal cohort study of 572 patients undergoing cardiac magnetic resonance (CMR), including 450 patients with COPD and 122 age- and sex-matched patients with a median: 726 days (interquartile range: 492 to 1,160 days) follow-up. Multivariate analysis was used to examine the relationship between COPD and myocardial fibrosis, measured using cardiac magnetic resonance (CMR). Cox regression analysis was used to examine the relationship between myocardial fibrosis and outcomes; the primary endpoint was composite of hospitalizations for HF or all-cause mortality; secondary endpoints included hospitalizations for HF and all-cause mortality. Fifteen patients with COPD, 15 current smokers, and 15 healthy volunteers underwent evaluation for myocardial inflammation, including ultrasmall superparamagnetic particles of iron oxide CMR. RESULTS: COPD was independently associated with myocardial fibrosis (p < 0.001). Myocardial fibrosis was independently associated with the primary outcome (hazard ratio [HR]: 1.14; 95% confidence interval [CI]: 1.08 to 1.20; p < 0.001), hospitalization for HF (HR: 1.25 [95% CI: 1.14 to 1.36]); p < 0.001), and all-cause mortality. Myocardial fibrosis was associated with outcome measurements more strongly than any other variable. Acute and stable COPD were associated with myocardial inflammation. CONCLUSIONS: The associations between COPD, myocardial inflammation and myocardial fibrosis, and the independent prognostic value of myocardial fibrosis elucidate a potential pathophysiological link between COPD and HF.

Substrate for the Myocardial Inflammation-Heart Failure Hypothesis Identified Using Novel USPIO Methodology.

OBJECTIVES: The purpose of this study was to identify where ultrasmall superparamagnetic particles of iron oxide (USPIO) locate to in myocardium, develop a methodology that differentiates active macrophage uptake of USPIO from passive tissue distribution; and investigate myocardial inflammation in cardiovascular diseases. BACKGROUND: Myocardial inflammation is hypothesized to be a key pathophysiological mechanism of heart failure (HF), but human evidence is limited, partly because evaluation is challenging. USPIO-magnetic resonance imaging (MRI) potentially allows specific identification of myocardial inflammation but it remains unclear what the USPIO-MRI signal represents. METHODS: Histological validation was performed using a murine acute myocardial infarction (MI) model. A multiparametric, multi-time-point MRI methodology was developed, which was applied in patients with acute MI (n = 12), chronic ischemic cardiomyopathy (n = 7), myocarditis (n = 6), dilated cardiomyopathy (n = 5), and chronic sarcoidosis (n = 5). RESULTS: USPIO were identified in myocardial macrophages and myocardial interstitium. R1 time-course reflected passive interstitial distribution whereas multi-time-point R2* was also sensitive to active macrophage uptake. R2*/R1 ratio provided a quantitative measurement of myocardial macrophage infiltration. R2* behavior and R2*/R1 ratio were higher in infarcted (p = 0.001) and remote (p = 0.033) myocardium in acute MI and in chronic ischemic cardiomyopathy (infarct: p = 0.008; remote p = 0.010), and were borderline higher in DCM (p = 0.096), in comparison to healthy controls, but were no different in myocarditis or sarcoidosis. An R2*/R1 threshold of 25 had a sensitivity and specificity of 90% and 83%, respectively, for detecting active USPIO uptake. CONCLUSIONS: USPIO are phagocytized by cardiac macrophages but are also passively present in myocardial interstitium. A multiparametric multi-time-point MRI methodology specifically identifies active myocardial macrophage infiltration. Persistent active macrophage infiltration is present in infarcted and remote myocardium in chronic ischemic cardiomyopathy, providing a substrate for HF.

Myocardial involvement in eosinophilic granulomatosis with polyangiitis evaluated with cardiopulmonary magnetic resonance.

Patients with eosinophilic granulomatosis with polyangiitis (EGPA) most commonly die from cardiac causes, however, cardiac involvement remains poorly characterised and the relationship between cardiac and pulmonary disease is not known. This study aimed to characterise myocardial and pulmonary manifestations of EGPA, and their relationship. Prospective comprehensive cardiopulmonary investigation, including a novel combined cardiopulmonary magnetic resonance imaging (MRI) technology, was performed in 13 patients with stable EGPA. Comparison was made with 11 prospectively recruited matched healthy volunteers. Stable EGPA was associated with focal replacement and diffuse interstitial myocardial fibrosis (myocardial extracellular volume 26.9% vs. 24.7%; p = 0.034), which drove a borderline increase in left ventricular mass (56  ±  9 g/m2 vs. 49  ±  8 g/m2; p = 0.065). Corrected QT interval was significantly prolonged and was associated with the severity of myocardial fibrosis (r = 0.582, p = 0.037). Stable EGPA was not associated with increased myocardial capillary permeability or myocardial oedema. Pulmonary tissue perfusion and capillary permeability were normal and there was no evidence of pulmonary tissue oedema or fibrosis. Forced expiratory volume in one second showed a strong inverse relationship with myocardial fibrosis (r = -0.783, p = 0.038). In this exploratory study, stable EGPA was associated with focal replacement and diffuse interstitial myocardial fibrosis, but no evidence of myocardial or pulmonary inflammation or pulmonary fibrosis. Myocardial fibrosis was strongly associated with airway obstruction and abnormal cardiac repolarisation. Further investigation is required to determine the mechanisms underlying the association between heart and lung disease in EGPA and whether an immediate immunosuppressive strategy could prevent myocardial fibrosis formation.

Non-invasive cardiac stress studies may not offer significant benefit in pre-kidney transplant evaluation: A retrospective cohort study.

BACKGROUND: Screening with cardiac non-invasive stress studies (NISS) prior to listing for kidney transplantation can help in identifying treatable coronary disease and is considered an integral part of pre-kidney transplant evaluation. However, few studies assessed their effectiveness in all patients evaluated for transplantation in clinical practice. To evaluate the role of NISS in pre-kidney transplant evaluation we analyzed their impact prior to waitlisting in 1053 adult CKD-5 patients consecutively evaluated in Greater Manchester, UK during a 6-year period. METHODS: 918 waitlisted patients were grouped based on presence or absence of Diabetes or Cardio-Vascular Disease (CVD): Group-1 (255 DM-/CVD-/NISS-), Group-2 (368 DM-/CVD-/NISS+) and Group-3 (295 with DM or CVD). RESULTS: Group-2 patients had longer 'time-to-listing' (5.5months in Group-1 vs 6.9months in 'Normal-NISS' vs 9.9months in 'Abnormal-NISS', p<0.01) but none with 'Abnormal-NISS' needed coronary revascularization before listing. NISS was followed by revascularization in 8 Group-3 patients (3%). In multi-variate analyses, there was no association of NISS on death or MACE in listed patients. During follow up, Transplantation was the most significant factor associated with improved outcomes in all subgroups (HR:0.97, p<0.001). 135 patients were considered unsuitable for waitlisting, with NISS influencing management in 11 of these patients (8%). CONCLUSIONS: Pre-kidney transplant evaluation with NISS influenced clinical management in 19 of 1053 (2%) patients. Screening with NISS added limited benefit but contributes to significant delays in listing and adding resource implications. Further studies are needed to assess clinical and cost effectiveness of NISS in pretransplant evaluation to optimize outcomes and resources.

Association of Cardiovascular Disease With Respiratory Disease.

BACKGROUND: The relationship between respiratory diseases and individual cardiovascular diseases, and the impact of cardiovascular diseases on mortality in patients with respiratory disease, are unclear. OBJECTIVES: This study sought to determine the relationship between chronic obstructive pulmonary disease (COPD), asthma and interstitial lung disease (ILD), and individual cardiovascular diseases, and evaluate the impact of individual cardiovascular diseases on all-cause mortality in respiratory conditions. METHODS: The authors conducted a cohort study of all patients admitted to 7 National Health Service hospitals across the North West of England, between January 1, 2000, and March 31, 2013, with relevant respiratory diagnoses, with age-matched and sex-matched control groups. RESULTS: A total of 31,646 COPD, 60,424 asthma, and 1,662 ILD patients were included. Control groups comprised 158,230, 302,120, and 8,310 patients, respectively (total follow-up 2,968,182 patient-years). COPD was independently associated with ischemic heart disease (IHD), heart failure (HF), atrial fibrillation, and peripheral vascular disease, all of which were associated with all-cause mortality (e.g., odds ratio for the association of COPD with HF: 2.18 [95% confidence interval (CI): 2.08 to 2.26]; hazard ratio for the contribution of HF to mortality in COPD: 1.65 [95% CI: 1.61 to 1.68]). Asthma was independently associated with IHD, and multiple cardiovascular diseases contributed to mortality (e.g., HF hazard ratio: 1.81 [95% CI: 1.75 to 1.87]). ILD was independently associated with IHD and HF, both of which were associated with mortality. Patients with lung disease were less likely to receive coronary revascularization. CONCLUSIONS: Lung disease is independently associated with cardiovascular diseases, particularly IHD and HF, which contribute significantly to all-cause mortality. However, patients with lung disease are less likely to receive coronary revascularization.

The effect of 1.5 T cardiac magnetic resonance on human circulating leucocytes.

Aims: Investigators have proposed that cardiovascular magnetic resonance (CMR) should have restrictions similar to those of ionizing imaging techniques. We aimed to investigate the acute effect of 1.5 T CMR on leucocyte DNA integrity, cell counts, and function in vitro, and in a large cohort of patients in vivo. Methods and results: In vitro study: peripheral blood mononuclear cells (PBMCs) were isolated from healthy volunteers, and histone H2AX phosphorylation (γ-H2AX) expression, leucocyte counts, and functional parameters were quantified using flow cytometry under the following conditions: (i) immediately following PBMC isolation, (ii) after standing on the benchside as a temperature and time control, (iii) after a standard CMR scan. In vivo study: blood samples were taken from 64 consecutive consenting patients immediately before and after a standard clinical scan. Samples were analysed for γ-H2AX expression and leucocyte counts. CMR was not associated with a significant change in γ-H2AX expression in vitro or in vivo, although there were significant inter-patient variations. In vitro cell integrity and function did not change with CMR. There was a significant reduction in circulating T cells in vivo following CMR. Conclusion: 1.5 T CMR was not associated with DNA damage in vitro or in vivo. Histone H2AX phosphorylation expression varied markedly between individuals; therefore, small studies using γ-H2AX as a marker of DNA damage should be interpreted with caution. Cardiovascular magnetic resonance was not associated with loss of leucocyte viability or function in vitro. Cardiovascular magnetic resonance was associated with a statistically significant reduction in viable leucocytes in vivo.