Colm McCabe

Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock

BACKGROUND Myocardial failure has a central role in the complex pathophysiology of septic shock and contributes to organ failure and death. During the sepsis-induced inflammatory process, specific factors are released that depress myocardial contractile function. We aimed to identify these mediators of myocardial depression in meningococcal septic shock. METHODS We combined gene-expression profiling with protein and cellular methods to identify a serum factor causing cardiac dysfunction in meningococcal septic shock. We identified genes that were significantly upregulated in blood after exposure to meningococci. We then selected for further analysis those genes whose protein products had properties of a myocardial depressant factor--specifically a 12-25 kDa heat-stable protein that is released into serum shortly after onset of meningococcal infection. FINDINGS We identified 174 significantly upregulated genes in meningococcus-infected blood: six encoded proteins that were of the predicted size and had characteristics of a myocardial depressant factor. Of these, interleukin 6 caused significant myocardial depression in vitro. Removal of interleukin 6 from serum samples of patients with meningococcaemia and from supernatants of inflammatory cells stimulated by meningococci in vitro abolished the negative inotropic activity. Furthermore, concentrations in serum of interleukin 6 strongly predicted degree of myocardial dysfunction and severity of disease in children with meningococcal septic shock. INTERPRETATION Interleukin 6 is a mediator of myocardial depression in meningococcal disease. This cytokine and its downstream mediators could be a target for future treatment strategies.

Right ventricular dysfunction in chronic thromboembolic obstruction of the pulmonary artery: a pressure-volume study using the conductance catheter

Pressure-volume loops describe dynamic ventricular performance, relevant to patients with and at risk of pulmonary hypertension. We used conductance catheter-derived pressure-volume loops to measure right ventricular (RV) mechanics in patients with chronic thromboembolic pulmonary arterial obstruction at different stages of pathological adaptation. Resting conductance catheterization was performed in 24 patients: 10 with chronic thromboembolic pulmonary hypertension (CTEPH), 7 with chronic thromboembolic disease without pulmonary hypertension (CTED), and 7 controls. To assess the validity of conductance measurements, RV volumes were compared in a subset of 8 patients with contemporaneous cardiac magnetic resonance (CMR). Control, CTED, and CTEPH groups showed different pressure-volume loop morphology, most notable during systolic ejection. Prolonged diastolic relaxation was seen in patients with CTED and CTEPH [tau = 56.2 ± 6.7 (controls) vs. 69.7 ± 10.0 (CTED) vs. 67.9 ± 6.2 ms (CTEPH), P = 0.02]. Control and CTED groups had lower afterload (Ea) and contractility (Ees) compared with the CTEPH group (Ea = 0.30 ± 0.10 vs. 0.52 ± 0.24 vs. 1.92 ± 0.70 mmHg/ml, respectively, P < 0.001) (Ees = 0.44 ± 0.20 vs. 0.59 ± 0.15 vs. 1.13 ± 0.43 mmHg/ml, P < 0.01) with more efficient ventriculoarterial coupling (Ees/Ea = 1.46 ± 0.30 vs. 1.27 ± 0.36 vs. 0.60 ± 0.18, respectively, P < 0.001). Stroke volume assessed by CMR and conductance showed closest agreement (mean bias +9 ml, 95% CI -1 to +19 ml) compared with end-diastolic volume (+48 ml, -16 to 111 ml) and end-systolic volume (+37 ml, -21 to 94 ml). RV conductance catheterization detects novel alteration in pressure-volume loop morphology and delayed RV relaxation in CTED, which distinguish this group from controls. The observed agreement in stroke volume assessed by CMR and conductance suggests RV mechanics are usefully measured by conductance catheter in chronic thromboembolic obstruction.

Inefficient exercise gas exchange identifies pulmonary hypertension in chronic thromboembolic obstruction following pulmonary embolism

INTRODUCTION Persistent obstruction in the pulmonary artery following acute pulmonary embolism (PE) can give rise to both chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease without PH (CTED). We hypothesised that cardiopulmonary exercise testing (CPET) may be able to differentiate patients with CTEPH and CTED following unresolved PE which may help guide patient assessment. MATERIALS AND METHODS Fifteen patients with CTEPH and 15 with CTED all diagnosed after PE underwent CT pulmonary angiography, CPET and resting right heart catheterisation. Exercise variables were compared between patients with CTEPH, CTED and 10 sedentary controls and analysed as predictors of a CTEPH diagnosis. Proximal thrombotic burden in CTEPH and CTED was quantified using CT criteria. RESULTS Physiological dead space (Vd/Vt) (34.5±11.4 vs 50.8±6.6 %, p<0.001) and alveolar-arterial oxygen gradient (29±16 vs 46±12mmHg, p <0.001) at peak exercise strongly differentiated CTED and CTEPH groups respectively. Resting ventilatory efficiency also differed from control subjects. In both univariate and multivariate analyses, peak exercise Vd/Vt predicted a diagnosis of CTEPH (ROC AUC>0.88, 0.67 - 0.97) despite a similar degree of proximal thrombotic obstruction to the CTED group (67.5, 55 - 70% and 72.5, 60 - 80% respectively, p=0.08). CONCLUSIONS Gas exchange at peak exercise differentiates CTED and CTEPH after PE that can present with no apparent relation to the degree of proximal thrombotic burden. A potential role for CPET exists in guiding further clinical investigations in this setting.

Patient-Reported Outcomes Assessed by the CAMPHOR Questionnaire Predict Clinical Deterioration in Idiopathic Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension

BACKGROUND The Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) is a disease-specific assessment tool used for the evaluation and follow-up of patients with pulmonary hypertension (PH). We describe a novel use for this questionnaire in its potential to predict clinical deterioration (CD) in two patient cohorts with subtypes of PH, idiopathic pulmonary arterial hypertension (IPAH), and chronic thromboembolic pulmonary hypertension (CTEPH) during an 8-year period. METHODS We retrospectively analyzed CAMPHOR scores obtained at baseline and at follow-up visits in patients under the care of our unit over an 8-year period to assess CD and survival, as well as 6-min walk distance (6MWD) and New York Heart Association (NYHA) class. RESULTS Using Cox regression, we demonstrated a significant predictive effect of CD from total CAMPHOR scores at study enrollment in IPAH and CTEPH (hazard ratios, 1.03 [95% CI, 1.01-1.05] and 1.04 [95% CI, 1.02-1.06] per unit score increase, respectively), as well as from CAMPHOR subscales as independent predictors. This predictive effect is diluted after adjusting for the prognostic effect of 6MWD and NYHA class. Repeated CAMPHOR assessment over time appears not to add predictive value of CD to that obtained at diagnosis, although it still informs physicians of important changes in self-reported symptoms. CONCLUSIONS When emphasis is placed on the evaluation of patient perceptions, CAMPHOR may represent an alternative method of estimating the likelihood of CD.

Platelet count and mean platelet volume predict outcome in adults with Eisenmenger syndrome

Objectives Although a significant proportion of patients with cyanotic congenital heart disease are thrombocytopaenic, its prevalence and clinical significance in adults with Eisenmenger syndrome (ES) is not well studied. Accordingly, we examined the relationship of thrombocytopaenia and mean platelet volume (MPV) to bleeding or thrombotic complications and survival in a contemporary cohort of patients with ES, including patients with Down syndrome. Methods Demographics, laboratory and clinical data were analysed from 226 patients with ES under active follow-up over 11 years. Results Age at baseline was 34.6±11.4 years and 34.1% were men. Mean platelet count and MPV were 152.6±73.3×109/L and 9.6±1.2 fL, respectively. A strong inverse correlation was found between platelet count and haemoglobin concentration and MPV. During the study, there were 39 deaths, and 21 thrombotic and 43 bleeding events. On univariate Cox regression analysis, patients with a platelet count <100×109/L had a twofold increased mortality (HR 2.10, 95% CI 1.10 to 4.01, p=0.024). Platelet count was not associated with an increased risk of thrombosis. However, there was a threefold increased thrombotic risk with MPV >9.5 fL (HR 3.50, 95% CI 1.28 to 9.54, p=0.015). Patients with either severe secondary erythrocytosis (>220g/L) or anaemia (<130g/L) were at higher risk of thrombotic events (HR 3.93, 95% CI 1.60 to 9.67, p=0.003; and HR 4.75, 95% CI 1.03 to 21.84, p=0.045, respectively). Conclusions Thrombocytopaenia significantly increased the risk of mortality in ES. Furthermore, raised MPV, severe secondary erythrocytosis and anaemia, but not platelet count, were associated with an increased risk of thrombotic events in our adult cohort.

Cardiopulmonary Exercise Testing Suggests a Beneficial Response to Pulmonary Endarterectomy in a Patient with Chronic Thromboembolic Obstruction and Normal Preoperative Pulmonary Hemodynamics

Pulmonary endarterectomy offers a symptomatic and survival benefit in patients with chronic thromboembolic pulmonary hypertension through sustained improvement in right ventricular function. However, its role in patients with symptom limitation, chronic thrombotic obstruction, and a normal pulmonary hemodynamic profile is less clear. Cardiopulmonary exercise testing (CPET) stresses the cardiopulmonary system and has a characteristic response in pulmonary hypertension. CPET may therefore reveal abnormalities in patients with chronic thrombotic obstruction where hemodynamic investigations conducted at rest are reassuring. Using incremental CPET, we demonstrated improvements in right ventricular performance and ventilatory efficiency following pulmonary endarterecomy in a patient with preoperative exercise limitation and normal pulmonary hemodynamics. Careful evaluation of exercise responses may extend the potential benefit offered by pulmonary endarterectomy in patients with chronic thromboembolic obstruction irrespective of their resting hemodynamic profile.

Ventriculo‐arterial coupling detects occult RV dysfunction in chronic thromboembolic pulmonary vascular disease

Chronic thromboembolic disease (CTED) is suboptimally defined by a mean pulmonary artery pressure (mPAP) <25 mmHg at rest in patients that remain symptomatic from chronic pulmonary artery thrombi. To improve identification of right ventricular (RV) pathology in patients with thromboembolic obstruction, we hypothesized that the RV ventriculo‐arterial (Ees/Ea) coupling ratio at maximal stroke work (Ees/Eamax sw) derived from an animal model of pulmonary obstruction may be used to identify occult RV dysfunction (low Ees/Ea) or residual RV energetic reserve (high Ees/Ea). Eighteen open chested pigs had conductance catheter RV pressure‐volume (PV)‐loops recorded during PA snare to determine Ees/Eamax sw. This was then applied to 10 patients with chronic thromboembolic pulmonary hypertension (CTEPH) and ten patients with CTED, also assessed by RV conductance catheter and cardiopulmonary exercise testing. All patients were then restratified by Ees/Ea. The animal model determined an Ees/Eamax sw = 0.68 ± 0.23 threshold, either side of which cardiac output and RV stroke work fell. Two patients with CTED were identified with an Ees/Ea well below 0.68 suggesting occult RV dysfunction whilst three patients with CTEPH demonstrated Ees/Ea ≥ 0.68 suggesting residual RV energetic reserve. Ees/Ea > 0.68 and Ees/Ea < 0.68 subgroups demonstrated constant RV stroke work but lower stroke volume (87.7 ± 22.1 vs. 60.1 ± 16.3 mL respectively, P = 0.006) and higher end‐systolic pressure (36.7 ± 11.6 vs. 68.1 ± 16.7 mmHg respectively, P < 0.001). Lower Ees/Ea in CTED also correlated with reduced exercise ventilatory efficiency. Low Ees/Ea aligns with features of RV maladaptation in CTED both at rest and on exercise. Characterization of Ees/Ea in CTED may allow for better identification of occult RV dysfunction.

Right ventricle functional assessment: have new techniques supplanted the old faithful conductance catheter?

This review explores the historical development of conductance catheterization of the human right ventricle (RV) and its current diagnostic role in assessing RV function in an era of contemporary noninvasive imaging. Significant advances in echocardiography, cardiothoracic computed tomography, and cardiac magnetic resonance in the last decade have led a paradigm shift away from invasive hemodynamic assessment toward noninvasive measurement of RV function. However, imaging modalities are not without some disadvantages. For example, they do not provide the beat-to-beat pressure-volume assessment that is obtained by conductance catheterization, which is still arguably the gold standard for measuring cardiac performance. Right heart catheterization remains an integral part of the assessment of patients with RV dysfunction, and a burgeoning interest in early RV insufficiency in a range of cardiopulmonary diseases has brought the detailed interrogation of RV function back into focus. Although conductance volume assessment of the RV is more limited than the left ventricle, the scope for improving the understanding of RV adaptation to pulmonary and valvular pathologies and RV myocardial disease by using a conductance catheter still exists. We review the up-to-date functional applications of echocardiography and computed tomography/cardiac magnetic resonance to assess the RV and illustrate the potential of contemporary conductance catheter techniques to complement noninvasive imaging in the assessment of RV function.

Incidence, mortality and bleeding rates associated with pulmonary embolism in England between 1997 and 2015

BACKGROUND Improvements in availability and accuracy of diagnostic testing in pulmonary embolism (PE) in the last 20 years have more recently been paralleled by the introduction of additional anticoagulation agents and treatment strategies. These developments are likely to shape potentially important changes in PE incidence, associated mortality and treatment complications. METHODS We investigated trends in PE incidence, PE-related mortality and bleeding risk by analysing Hospital Episodes Statistics for England. RESULTS Between 1997 and 2015, 464,046 patients (53.9% female) were hospitalized with PE in England. The annual number of hospitalizations with an associated diagnosis of PE more than doubled over this period (24,366 in 1998 vs. 53,108 in 2014), with a corresponding increase in PE hospitalization rate (50.2 to 97.8 per 100,000 population/year), evident in all age categories. Mortality at 1 and 3 months decreased over the study period and was significantly associated with age, treatment era and comorbidities. The risk of bleeding resulting in hospitalization or death within 3 and 12 months after the index PE admission increased over the study period (4.3%/5.1% for 1998-2004 versus 6.1%/7.2% for 2010-2014, p < 0.001 for both comparisons). CONCLUSIONS The incidence of PE doubled in England between 1997 and 2015, likely attributable to raised awareness and ability to diagnose less severe cases. While PE-associated mortality decreased, there was an increase in bleeding risk. Renewed efforts directed at reducing the incidence of bleeding, including consideration of anticoagulation regimens and investigation of anticoagulation requirement in patients with low-risk features, are needed.

Arrhythmias in adult patients with congenital heart disease and pulmonary arterial hypertension

Objectives Approximately 5%–10% of adults with congenital heart disease (CHD) develop pulmonary arterial hypertension (PAH), which affects life expectancy and quality of life. Arrhythmias are common among these patients, but their incidence and impact on outcome remains uncertain. Methods All adult patients with PAH associated with CHD (PAH-CHD) seen in a tertiary centre between 2007 and 2015 were followed for new-onset atrial or ventricular arrhythmia. Clinical variables associated with arrhythmia and their relation to mortality were assessed using Cox analysis. Results A total of 310 patients (mean age 34.9±12.3 years, 36.8% male) were enrolled. The majority had Eisenmenger syndrome (58.4%), 15.2% had a prior defect repair and a third had Down syndrome. At baseline, 14.2% had a prior history of arrhythmia, mostly supraventricular arrhythmia (86.4%). During a median follow-up of 6.1 years, 64 patients developed at least one new arrhythmic episode (incidence 3.47% per year), mostly supraventricular tachycardia or atrial fibrillation (78.1% of patients). Arrhythmia was associated with symptoms in 75.0% of cases. The type of PAH-CHD, markers of disease severity and prior arrhythmia were associated with arrhythmia during follow-up. Arrhythmia was a strong predictor of death, even after adjusting for demographic and clinical variables (HR 3.41, 95% CI 2.10 to 5.53, p<0.0001). Conclusions Arrhythmia is common in PAH-CHD and is associated with an adverse long-term outcome, even when managed in a specialist centre.