The Haemodynamic and Neurohormonal Response to Initiation of Angiotensin Converting Enzyme Inhibitor Therapy in Heart Failure

The studies described in this thesis investigated the haemodynamic response to initiation of therapy with a number of angiotensin converting enzyme inhibitor agents in patients with heart failure. The studies were designed to: (i) define differences among agents in terms of the haemodynamic response to initiation of therapy (ii) investigate possible mechanisms for observed differences among agents in this regard (iii) investigate the relationship between plasma concentration of ACE inhibitor agent and the blood pressure response, and (iv) investigate the relationship between baseline clinical and physiological variables and the blood pressure response. Differences were observed among ACE inhibitor agents in terms of the blood pressure response to initiation of therapy. While similar blood pressure responses were observed to single oral doses of the ester prodrug ACE inhibitors enalapril and quinapril, the blood pressure response to oral perindopril did not differ from that seen with placebo. Two possible mechanisms, steric hindrance and "slow, tight binding", for the observed differences were explored using assay of both plasma ACE inhibition and relative concentrations of angiotensin I and angiotensin II. No evidence for either mechanism was gained from these studies. Using pharmacodynamic/pharmacokinetic modelling a direct linear relationship between the pharmacodynamic effect and plasma drug concentration was derived. Marked interindividual variability was apparent in the blood pressure response to oral initiation of ACE inhibitor therapy. The blood response was more consistent when interindividual pharmacokinetic differences were minimised by intravenous dosing. No consistent relationship could be identified between any single baseline physiological variable and the blood pressure response. The strongest relationship was with baseline mean arterial blood pressure. Forward stepwise regression analysis was used to identify the best combinations of predictive variables. The best of these, containing the variables, mean arterial pressure, plasma renin activity, 1/creatinine concentration, age and the ACE inhibitor agent, could explain approximately 25% of the variability in blood pressure response. In conclusion, differences in the individual blood pressure responses to initiation of ACE inhibitor therapy in CHF appear to be largely dependent upon interindividual pharmacokinetic differences. Accurate prediction of the blood pressure response to initiation of therapy is not possible using readily available laboratory and clinical criteria

In-hospital worsening heart failure: a clinically relevant endpoint?

Outcome measures used for the clinical evaluation of patients with acute heart failure differ between studies and may neither adequately address the characteristic presenting symptoms and signs nor reflect the pathophysiological processes involved. In‐hospital worsening of heart failure (WHF) is associated with poor outcomes and thus a potential endpoint conveying clinically meaningful prognostic information.Current definitions of WHF are based on the combination of worsening symptoms and signs and the intensification of treatment during admission. Definitions vary across studies and do not fully account for baseline therapy or circumstances in which there is failure to respond to treatment. Further, there are limited data to inform healthcare professionals as to which patients are most at risk of developing in‐hospital WHF.In this opinion piece, we review the definitions for WHF used in recent and ongoing clinical trials and propose a novel definition, which captures failure to respond to treatment as well as clinical worsening (deterioration of symptoms and signs) of the patient's condition. Such a definition, applied consistently across studies, would help clarify the characteristics of patients likely to develop in‐hospital WHF, allow comparative assessments of the effectiveness of interventions, and help guide appropriate patient management in order to improve outcomes

Relation of microvascular dysfunction to exercise capacity and symptoms in patients with severe aortic stenosis

Objective: The aim of this study was to assess the impact of left ventricular hypertrophy, myocardial fibrosis, myocardial perfusion reserve (MPR) and diastolic dysfunction on objectively measured aerobic exercise capacity (peak VO$_{2}$) in severe aortic stenosis (AS). Background: The management of asymptomatic patients with severe AS remains controversial and clinical practice varies. Echocardiographic measures of severity do not discriminate between symptomatic status or predict exercise capacity. The purpose of this study was to investigate the mechanisms contributing to symptom generation and exercise intolerance. This needs to be fully understood to optimise the management of asymptomatic AS. Methods: Patients were prospectively enrolled from a single cardiac surgical centre. Inclusion criteria: age 18-85, isolated severe AS referred for valve replacement. Exclusion criteria: syncope; other moderate/severe valve disease, previous valve surgery, obstructive coronary artery disease (>50% luminal stenosis on invasive angiography), chronic obstructive pulmonary disease, atrial fibrillation, estimated glomerular filtration rate <30mL/min. Investigations and primary outcome measures; cardiac magnetic resonance (CMR) - left ventricular mass index (LVMI), MPR (calculated from absolute myocardial blood flow during adenosine hyperaemia and rest determined by model-independent deconvolution of signal intensity curves with an arterial input function), late gadolinium enhancement (LGE); echocardiography - AS severity, tissue Doppler-derived diastolic function; symptom-limited bicycle ergometer cardiopulmonary exercise testing (CPEX) - peak VO$_{2}$. Linear regression investigated possible predictors of continuous outcome measures. Stepwise selection methods were used to determine the most important predictors of outcome. Results: Four patients with variable LVMI, LGE and MPR are shown, Figure 1. Univariate analyses and results from the stepwise model selection for peak VO$_{2}$ are summarised in Table 1. Only MPR was of independent significance in predicting age and sex corrected peak VO$_{2}$. The relationship between peak VO$_{2}$ and MPR is shown, Figure 2. Patients with higher NYHA Class had lower MPR (p=0.001). Examining predictors of MPR the best stepwise model contained LVMI and LGE category as independent predictors, Table 2. Conclusions: MPR is a novel independent predictor of peak VO$_{2}$ and is inversely related to NYHA functional class in severe AS. Microvascular dysfunction is determined by a combination of factors including AS severity, LVMI, diastolic perfusion time, myocardial fibrosis and LV filling pressure. Further work is required to determine the clinical significance of microvascular dysfunction in AS

Risk related to pre–diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction: insights from prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial

Background—The prevalence of pre–diabetes mellitus and its consequences in patients with heart failure and reduced ejection fraction are not known. We investigated these in the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. Methods and Results—We examined clinical outcomes in 8399 patients with heart failure and reduced ejection fraction according to history of diabetes mellitus and glycemic status (baseline hemoglobin A1c [HbA1c]: &lt;6.0% [&lt;42 mmol/mol], 6.0%–6.4% [42–47 mmol/mol; pre–diabetes mellitus], and ≥6.5% [≥48 mmol/mol; diabetes mellitus]), in Cox regression models adjusted for known predictors of poor outcome. Patients with a history of diabetes mellitus (n=2907 [35%]) had a higher risk of the primary composite outcome of heart failure hospitalization or cardiovascular mortality compared with those without a history of diabetes mellitus: adjusted hazard ratio, 1.38; 95% confidence interval, 1.25 to 1.52;P&lt;0.001. HbA1c measurement showed that an additional 1106 (13% of total) patients had undiagnosed diabetes mellitus and 2103 (25%) had pre–diabetes mellitus. The hazard ratio for patients with undiagnosed diabetes mellitus (HbA1c, &gt;6.5%) and known diabetes mellitus compared with those with HbA1c&lt;6.0% was 1.39 (1.17–1.64); P&lt;0.001 and 1.64 (1.43–1.87); P&lt;0.001, respectively. Patients with pre–diabetes mellitus were also at higher risk (hazard ratio, 1.27 [1.10–1.47];P&lt;0.001) compared with those with HbA1c&lt;6.0%. The benefit of LCZ696 (sacubitril/valsartan) compared with enalapril was consistent across the range of HbA1c in the trial. Conclusions—In patients with heart failure and reduced ejection fraction, dysglycemia is common and pre–diabetes mellitus is associated with a higher risk of adverse cardiovascular outcomes (compared with patients with no diabetes mellitus and HbA1c &lt;6.0%). LCZ696 was beneficial compared with enalapril, irrespective of glycemic status

Community screening for left ventricular systolic dysfunction using plasma and urinary natriuretic peptides

ObjectivesWe sought to compare urinary and plasma N-terminal pro-brain natriuretic peptide (N-BNP) in left ventricular systolic dysfunction (LVSD) diagnosis.BackgroundPlasma N-BNP is elevated in LVSD. Renal tubule cells produce BNP. We tested the incremental value of urinary N-BNP in LVSD diagnosis.MethodsIn this prospective, community-screening study of undiagnosed LVSD, 1,360 subjects (45 to 80 years of age) were invited, and 1,308 had analyzable echocardiographic scans and urine and plasma specimens. The criterion standard for LVSD was defined as a wall motion score over 1.8 (ejection fraction ≤40%).ResultsTwenty-eight patients with LVSD had elevated urinary and plasma N-BNP levels compared with normal subjects (p < 0.0005). Receiver-operating characteristic (ROC) areas under the curve (AUCs) for urinary and plasma N-BNP were 0.831 and 0.840, respectively. Both tests had high negative predictive values (>99%) for excluding LVSD. Urinary N-BNP was more specific (67.2%) than plasma N-BNP (41%). The plasma/urinary N-BNP product yielded a higher ROC-AUC (0.923) and specificity (78%), reducing the number of cases to scan to detect one case of LVSD to 11.4 (compared with 16.6 [urinary N-BNP] and 29.0 [plasma N-BNP]). Sequential application of tests (urinary N-BNP, then plasma N-BNP in the urine-“positive” cases) achieved similar reductions in the number of cases to scan (10.8), while limiting the number of N-BNP tests to be performed. Urinary N-BNP performed poorly in detection of other cardiac abnormalities with preserved systolic function. It was less costly to test urinary N-BNP in the whole population as compared with other strategies, including scanning high-risk cases with N-BNP testing in the remainder.ConclusionsUrinary N-BNP used together with plasma N-BNP could reduce the echocardiographic burden in screening programs

Patient, health service factors and variation in mortality following resuscitated out-of-hospital cardiac arrest in acute coronary syndrome : analysis of the Myocardial Ischaemia National Audit Project

Aims To determine patient and health service factors associated with variation in hospital mortality among resuscitated cases of out-of-hospital cardiac arrest (OHCA) with acute coronary syndrome (ACS). Methods In this cohort study, we used the Myocardial Ischaemia National Audit Project database to study outcomes in patients hospitalised with resuscitated OHCA due to ACS between 2003 and 2015 in the United Kingdom. We analysed variation in inter-hospital mortality and used hierarchical multivariable regression models to examine the association between patient and health service factors with hospital mortality. Results We included 17604 patients across 239 hospitals. Overall hospital mortality was 28.7%. In 94 hospitals that contributed at least 60 cases, mortality by hospital ranged from 10.7% to 66.3% (median 28.6%, IQR 23.2% to 39.1%)). Patient and health service factors explained 36.1% of this variation. After adjustment for covariates, factors associated with higher hospital mortality included increasing serum glucose, ST-Elevation myocardial infarction (STEMI) diagnosis, and initial admission to a primary percutaneous coronary intervention (pPCI) capable hospital. Hospital OHCA volume was not associated with mortality. The key modifiable factor associated with lower mortality was early reperfusion therapy in STEMI patients. Conclusion There was wide variation in inter-hospital mortality following resuscitated OHCA due to ACS that was only partially explained by patient and health service factors. Hospital OHCA volume and pPCI capability were not associated with lower mortality. Early reperfusion therapy was associated with lower mortality in STEMI patients

Variation in outcome of hospitalised patients with out-of-hospital cardiac arrest from acute coronary syndrome : a cohort study

Background Each year, approximately 30,000 people have an out-of-hospital cardiac arrest (OHCA) that is treated by UK ambulance services. Across all cases of OHCA, survival to hospital discharge is less than 10%. Acute coronary syndrome (ACS) is a common cause of OHCA. Objectives To explore factors that influence survival in patients who initially survive an OHCA attributable to ACS. Data source Data collected by the Myocardial Ischaemia National Audit Project (MINAP) between 2003 and 2015. Participants Adult patients who had a first OHCA attributable to ACS and who were successfully resuscitated and admitted to hospital. Main outcome measures Hospital mortality, neurological outcome at hospital discharge, and time to all-cause mortality. Methods We undertook a cohort study using data from the MINAP registry. MINAP is a national audit that collects data on patients admitted to English, Welsh and Northern Irish hospitals with myocardial ischaemia. From the data set, we identified patients who had an OHCA. We used imputation to address data missingness across the data set. We analysed data using multilevel logistic regression to identify modifiable and non-modifiable factors that affect outcome. Results Between 2003 and 2015, 1,127,140 patient cases were included in the MINAP data set. Of these, 17,604 OHCA cases met the study inclusion criteria. Overall hospital survival was 71.3%. Across hospitals with at least 60 cases, hospital survival ranged from 34% to 89% (median 71.4%, interquartile range 60.7–76.9%). Modelling, which adjusted for patient and treatment characteristics, could account for only 36.1% of this variability. For the primary outcome, the key modifiable factors associated with reduced mortality were reperfusion treatment [primary percutaneous coronary intervention (pPCI) or thrombolysis] and admission under a cardiologist. Admission to a high-volume cardiac arrest hospital did not influence survival. Sensitivity analyses showed that reperfusion was associated with reduced mortality among patients with a ST elevation myocardial infarction (STEMI), but there was no evidence of a reduction in mortality in patients who did not present with a STEMI. Limitations This was an observational study, such that unmeasured confounders may have influenced study findings. Differences in case identification processes at hospitals may contribute to an ascertainment bias. Conclusions In OHCA patients who have had a cardiac arrest attributable to ACS, there is evidence of variability in survival between hospitals, which cannot be fully explained by variables captured in the MINAP data set. Our findings provide some support for the current practice of transferring resuscitated patients with a STEMI to a hospital that can deliver pPCI. In contrast, it may be reasonable to transfer patients without a STEMI to the nearest appropriate hospital. Future work There is a need for clinical trials to examine the clinical effectiveness and cost-effectiveness of invasive reperfusion strategies in resuscitated OHCA patients of cardiac cause who have not had a STEMI. Funding The National Institute for Health Research Health Services and Delivery Research programme