Publications by authors named "Iain B Squire"

107 Publications

The Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients with Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction.

Circulation 2021 May 13. Epub 2021 May 13.

Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.

Patients with left ventricular systolic dysfunction (LVSD) following myocardial infarction (MI) are at high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system (RAS) inhibition may result in greater attenuation of adverse LV remodeling due to increased levels of substrates for neprilysin with vasodilatory, anti-hypertrophic, anti-fibrotic and sympatholytic effects. We performed a prospective, multi-center, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103mg twice daily with valsartan 160mg twice daily in patients ≥3 months following MI with a LV ejection fraction (LVEF) ≤40% who were taking a RAS inhibitor (equivalent dose of ramipril ≥2.5mg twice daily), and a beta-blocker unless contraindicated or intolerant. Patients in New York Heart Association functional classification ≥II or with signs and symptoms of HF were excluded. The primary outcome was change from baseline to 52-weeks in LV end-systolic volume index (LVESVI) measured using cardiac magnetic resonance imaging (MRI). Secondary outcomes included other MRI measurements of LV remodeling, change in N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-TnI), and a patient global assessment of change questionnaire. From July 2018 to June 2019, 93 patients were randomized: mean age 60.7±10.4 years, median time from MI 3.6 years (IQR 1.2-7.2), mean LVEF 36.8%±7.1, median NT-proBNP 230pg/mL (124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LVESVI; adjusted between-group difference -1.9mL/m (95%CI -4.9, 1.0); p=0.19. There were no significant between-group differences in NT-proBNP, hs-TnI, LV end-diastolic volume index, left atrial volume index, LVEF, LV mass index, or patient global assessment of change. In patients with asymptomatic LVSD following MI, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. URL: https://www.clinicaltrials.gov Unique identifier: NCT03552575.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.054892DOI Listing
May 2021

Benefits of sodium glucose cotransporter 2 inhibitors across the spectrum of cardiovascular diseases.

Heart 2021 May 10. Epub 2021 May 10.

Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester, UK.

Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a class of medications with positive cardiovascular (CV) effects across a spectrum of patients with and without type 2 diabetes (T2D). In heart failure with reduced ejection fraction, there is clear evidence that SGLT2i reduce hospitalisations and mortality regardless of the presence of diabetes, and they are now recognised as the fourth pillar of pharmacological management. Recent trial data also indicate promising effects in heart failure with preserved ejection fraction. In patients with T2D and atherosclerotic CV diseases, multiple CV outcomes trials have shown reductions in major adverse CV events. Meta-analysis of these trials also shows lower rates of incident and recurrent atrial fibrillation with SGLT2i. Concerns regarding utilisation in patients with chronic kidney disease have been allayed in trials showing SGLT2i in fact have renoprotective effects. Questions still remain regarding the safety of SGLT2i in the acute heart failure setting and immediately post myocardial infarction, as well as in patients with more advanced stages of chronic kidney disease. Furthermore, studies are underway evaluating SGLT2i in patients with heart valve disease, where positive effects on left ventricular remodelling may, for example, improve functional mitral regurgitation. In this review, we summarise the available evidence of recent CV outcomes trials of SGLT2i, focusing particularly on the application of these agents across various CV diseases. We detail evidence to support increased utilisation of these drugs, which in many cases will reduce mortality and improve quality of life in patients routinely encountered by the CV specialist physician.
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http://dx.doi.org/10.1136/heartjnl-2021-319185DOI Listing
May 2021

Non-adherence to heart failure medications predicts clinical outcomes: assessment in a single spot urine sample by liquid chromatography-tandem mass spectrometry (results of a prospective multicentre study).

Eur J Heart Fail 2021 Mar 23. Epub 2021 Mar 23.

Department of Cardiovascular Science, University of Leicester, NIHR Leicester Biomedical Research Centre, Cardiovascular Unit and University Hospitals of Leicester NHS Trust, Leicester, UK.

Aims: Liquid chromatography-mass spectrometry (LC-MS/MS) is an objective new technique to assess non-adherence to medications. We used this method to study the prevalence, predictors and outcomes of non-adherence in patients with heart failure with reduced left ventricular ejection fraction (HFrEF).

Methods And Results: This study included 1296 patients with HFrEF from BIOSTAT-CHF, a study that aimed to optimise guideline-recommended therapies. Angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, β-blockers and loop diuretics were measured in a single spot urine sample at 9 months using LC-MS/MS. The relationship between medication non-adherence and the composite endpoint of all-cause death or heart failure hospitalisation, over a median follow-up of 21 months, was evaluated. Non-adherence to at least one prescribed medication was observed in 45.9% of patients. The strongest predictor of non-adherence was non-adherence to any of the other medication classes (P < 0.0005). Regional differences within Europe were observed. On multivariable analyses, non-adherence to ACEi/ARBs and β-blockers was associated with an increased risk of the composite endpoint [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.09-1.95, P = 0.008 and HR 1.48, 95% CI 1.12-1.96, P = 0.006, respectively). Non-adherence to β-blockers was also associated with an increased risk of death (HR 2.48, 95% CI 1.67-3.68, P < 0.0005). Patients who were non-adherent to loop diuretics were healthier and had a decreased risk of the composite endpoint (HR 0.69, 95% CI 0.51-0.93, P = 0.014). Non-adherence to mineralocorticoid receptor antagonists was not related to any clinical outcome.

Conclusion: Non-adherence to medications, assessed by a single urine test, is common and predicts clinical outcomes in patients with HFrEF.
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http://dx.doi.org/10.1002/ejhf.2160DOI Listing
March 2021

Plasma P-selectin is a predictor of mortality in heart failure with preserved ejection fraction.

ESC Heart Fail 2021 Jun 10;8(3):2328-2333. Epub 2021 Mar 10.

Department of Cardiovascular Sciences, University of Leicester, National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Leicester, UK.

Aims: The aim of the study was to assess the association of P-selectin with outcomes in heart failure with preserved ejection fraction (HFpEF).

Methods And Results: This is a prospective, observational study of 130 HFpEF patients who underwent clinical profiling, blood sampling, 6 min walk testing, Minnesota Living with Heart Failure Questionnaire evaluation, echocardiography, cardiovascular magnetic resonance imaging, calculation of the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk scores, and blinded plasma P-selectin measurement. Patients were followed up for the endpoint of all-cause mortality. The HFpEF subgroup with higher P-selectin levels [overall median 26 372, inter-quartile range (19 360-34 889) pg/mL] was associated with lower age, higher heart rate, less prevalent atrial fibrillation, more frequent current smoking status, and lower right ventricular end-diastolic volumes. During follow-up (median 1428 days), there were 38 deaths. Following maximal sensitivity and specificity receiver operating characteristic curve analysis, P-selectin levels above 35 506 pg/mL were associated with greater risk of all-cause mortality [hazard ratio (HR) 2.700; 95% confidence interval (CI) 1.416-5.146; log-rank P = 0.002]. Following multivariable Cox proportional hazards regression analysis and when added to MAGGIC scores, only P-selectin (adjusted HR 1.707; 95% CI 1.099-2.650; P < 0.017) and myocardial infarction detected by cardiovascular magnetic resonance imaging (HR 2.377; 95% CI 1.114-5.075; P < 0.025) remained significant predictors. In a final model comprising all three parameters, only P-selectin (HR 1.447; 95% CI 1.130-1.853; P < 0.003) and MAGGIC scores (HR 1.555; 95% CI 1.136-2.129; P < 0.006) remained independent predictors of death. Adding P-selectin (0.618, P = 0.035) improved the area under the receiver operating characteristic curve for mortality prediction for MAGGIC scores (0.647, P = 0.009) to 0.710, P < 0.0001.

Conclusions: Plasma P-selectin is an independent predictor of mortality and provides incremental prognostic information beyond MAGGIC scores in HFpEF.
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http://dx.doi.org/10.1002/ehf2.13280DOI Listing
June 2021

Biomarkers in Heart Failure: Clinical Insights.

Heart Fail Clin 2021 Apr 10;17(2):223-243. Epub 2021 Feb 10.

Department of Translational Medical Sciences, Federico II University, Naples, Italy.

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http://dx.doi.org/10.1016/j.hfc.2021.01.002DOI Listing
April 2021

Are heart failure observational studies still useful? 'No need to argue'.

Eur J Prev Cardiol 2020 Jun 25. Epub 2020 Jun 25.

Department of Translational Medical Sciences, Federico II University, Italy.

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http://dx.doi.org/10.1177/2047487320932258DOI Listing
June 2020

Frailty and mortality in patients with COVID-19.

Lancet Public Health 2020 11;5(11):e581

Department of Respiratory Sciences, University of Leicester, Leicester LE1 7RH, UK; Department of Infectious Diseases and HIV Medicine, Leicester Royal Infirmary, University of Leicester Hospitals NHS Trust, Leicester, UK. Electronic address:

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http://dx.doi.org/10.1016/S2468-2667(20)30229-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588174PMC
November 2020

The need for improved discharge criteria for hospitalised patients with COVID-19-implications for patients in long-term care facilities.

Age Ageing 2021 01;50(1):16-20

Department of Respiratory Sciences, University of Leicester, Leicester, UK.

In the COVID-19 pandemic, patients who are older and residents of long-term care facilities (LTCF) are at greatest risk of worse clinical outcomes. We reviewed discharge criteria for hospitalised COVID-19 patients from 10 countries with the highest incidence of COVID-19 cases as of 26 July 2020. Five countries (Brazil, Mexico, Peru, Chile and Iran) had no discharge criteria; the remaining five (USA, India, Russia, South Africa and the UK) had discharge guidelines with large inter-country variability. India and Russia recommend discharge for a clinically recovered patient with two negative reverse transcription polymerase chain reaction (RT-PCR) tests 24 h apart; the USA offers either a symptom based strategy-clinical recovery and 10 days after symptom onset, or the same test-based strategy. The UK suggests that patients can be discharged when patients have clinically recovered; South Africa recommends discharge 14 days after symptom onset if clinically stable. We recommend a unified, simpler discharge criteria, based on current studies which suggest that most SARS-CoV-2 loses its infectivity by 10 days post-symptom onset. In asymptomatic cases, this can be taken as 10 days after the first positive PCR result. Additional days of isolation beyond this should be left to the discretion of individual clinician. This represents a practical compromise between unnecessarily prolonged admissions and returning highly infectious patients back to their care facilities, and is of particular importance in older patients discharged to LTCFs, residents of which may be at greatest risk of transmission and worse clinical outcomes.
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http://dx.doi.org/10.1093/ageing/afaa206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543250PMC
January 2021

Fibroblast-growth-factor-23 in heart failure with preserved ejection fraction: relation to exercise capacity and outcomes.

ESC Heart Fail 2020 Sep 16. Epub 2020 Sep 16.

Department of Cardiovascular Sciences, University of Leicester, National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Leicester, UK.

Aims: This study aimed to assess plasma fibroblast growth factor 23 (FGF23) in patients with heart failure with preserved ejection fraction (HFpEF) and its relation to inflammation, renal function, clinical and imaging characteristics, exercise capacity, and prognosis.

Methods And Results: We performed a prospective, observational study of 172 age-matched and sex-matched subjects (HFpEF n = 130; controls n = 42, age 73 ± 9, female 50%) who underwent plasma biomarker sampling, echocardiography, cardiac magnetic resonance imaging, and 6 min walk testing (6MWT). The primary endpoint was the composite of all-cause death or HF hospitalization. FGF23 was higher in HFpEF compared with controls (62 [42-105] vs. 34 [22-41] pg/mL, P < 0.0001). In HFpEF, FGF23 correlated with greater symptom burden (New York Heart Association class: r = 0.308), poorer exercise capacity (6MWT distance: r = -0.345), and plasma biomarkers reflecting inflammation (highly sensitive C-reactive protein: r = 0.207, myeloperoxidase: r = 0.311), bone metabolism (osteoprotegerin: r = 0.446), renal dysfunction (urea: r = 0.267, creatinine: r = 0.351, estimated glomerular filtration rate: r = -0.367), and echocardiographic E/e' (r = 0.298); P < 0.05. Following multivariable linear regression modelling, FGF23 remained independently associated with shorter 6MWT distance (P = 0.012) in addition to age, body mass index, and lower haemoglobin. During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations) in patients with HFpEF. In multivariable Cox regression analysis, FGF23 [adjusted hazard ratio (HR) 1.665; 95% confidence interval (CI) (1.284-2.160; P < 0.0001)], B-type natriuretic peptide (HR 1.433; CI 1.053-1.951; P = 0.022), and prior HF hospitalization (HR 2.058; CI 1.074-3.942; P = 0.030) were independent predictors of the composite endpoint.

Conclusions: Plasma FGF23 is higher in HFpEF compared with age-matched and sex-matched controls and is strongly associated with exercise incapacity and prognosis. FGF23 correlates with plasma markers of inflammation and renal impairment.
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http://dx.doi.org/10.1002/ehf2.13020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755022PMC
September 2020

Plasma Tenascin-C: a prognostic biomarker in heart failure with preserved ejection fraction.

Biomarkers 2020 Nov 28;25(7):556-565. Epub 2020 Aug 28.

Department of Cardiovascular Sciences and the National Institute for Health Research (NIHR) Leicester, Biomedical Research Centre, Leicester, UK.

Introduction: Tenascin-C is a marker of interstitial fibrosis. We assessed whether plasma Tenascin-C differed between heart failure with preserved ejection fraction (HFpEF) and asymptomatic controls and related to clinical outcomes.

Materials And Methods: Prospective, observational study of 172 age- and sex-matched subjects (HFpEF  = 130; controls  = 42, age 73 ± 9, males 50%) who underwent phenotyping with 20 plasma biomarkers, echocardiography, cardiac MRI and 6-minute-walk-testing. The primary endpoint was the composite of all-cause death/HF hospitalisation.

Results: Tenascin-C was higher in HFpEF compared to controls (13.7 [10.8-17.3] vs (11.1 [8.9-12.9] ng/ml,  < 0.0001). Tenascin-C correlated positively with markers of clinical severity (NYHA, E/E', BNP) and plasma biomarkers reflecting interstitial fibrosis (ST-2, Galectin-3, GDF-15, TIMP-1, TIMP-4, MMP-2, MMP-3, MMP-7, MMP-8), cardiomyocyte stress (BNP, NTpro-ANP), inflammation (MPO, hs-CRP, TNFR-1, IL6) and renal dysfunction (urea, cystatin-C, NGAL);  < 0.05 for all. During follow-up (median 1428 days), there were 61 composite events (21 deaths, 40 HF hospitalizations). In multivariable Cox regression analysis, Tenascin-C (adjusted hazard ratio [HR] 1.755, 95% confidence interval [CI] 1.305-2.360;  < 0.0001) and indexed extracellular volume (HR 1.465, CI 1.019-2.106;  = 0.039) were independently associated with adverse outcomes.

Conclusions: In HFpEF, plasma Tenascin-C is higher compared to age- and sex-matched controls and a strong predictor of adverse outcomes. : ClinicalTrials.gov: NCT03050593.
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http://dx.doi.org/10.1080/1354750X.2020.1810319DOI Listing
November 2020

Prevalence of right ventricular dysfunction and prognostic significance in heart failure with preserved ejection fraction.

Int J Cardiovasc Imaging 2021 Jan 31;37(1):255-266. Epub 2020 Jul 31.

Department of Cardiovascular Sciences, National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, University of Leicester, Leicester, UK.

There is a paucity of data characterizing right ventricular performance in heart failure with preserved ejection fraction (HFpEF) using the gold standard of cardiovascular magnetic resonance imaging (CMR). We aimed to assess the proportion of right ventricular systolic dysfunction (RVD) in HFpEF and the relation to clinical outcomes. As part of a single-centre, prospective, observational study, 183 subjects (135 HFpEF, and 48 age- and sex-matched controls) underwent extensive characterization with CMR. transthoracic echocardiography, blood sampling and six-minute walk testing. Patients were followed for the composite endpoint of death or HF hospitalization. RVD (defined as right ventricular ejection fraction < 47%) controls was present in 19% of HFpEF. Patients with RVD presented more frequently with lower systolic blood pressure, atrial fibrillation, radiographic evidence of pulmonary congestion and raised cardiothoracic ratio and larger right ventricular volumes. During median follow-up of 1429 days, 47% (n = 64) of HFpEF subjects experienced the composite endpoint of death (n = 22) or HF hospitalization (n = 42). RVD was associated with an increased risk of composite events (Log-Rank p = 0.001). In multivariable Cox regression analysis, RVD was an independent predictor of adverse outcomes (adjusted Hazard Ratio [HR] 3.946, 95% CI 1.878-8.290, p = 0.0001) along with indexed extracellular volume (HR 1.742, CI 1.176-2.579, p = 0.006) and E/E' (HR 1.745, CI 1.230-2.477, p = 0.002). RVD as assessed by CMR is prevalent in nearly one-fifth of HFpEF patients and is independently associated with death and/or hospitalization with HF.The trial was registered retrospectively on ClinicalTrials.gov (Identifier: NCT03050593). The date of registration was February 06, 2017.
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http://dx.doi.org/10.1007/s10554-020-01953-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878207PMC
January 2021

Forty-six year old man with palpitations.

Heart 2020 Aug;106(16):1235-1282

Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.

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http://dx.doi.org/10.1136/heartjnl-2020-316902DOI Listing
August 2020

The impact of ethnicity on clinical outcomes in COVID-19: A systematic review.

EClinicalMedicine 2020 Jun 3;23:100404. Epub 2020 Jun 3.

Department of Respiratory Sciences, University of Leicester, United Kingdom.

Background: The relationship between ethnicity and COVID-19 is uncertain. We performed a systematic review to assess whether ethnicity has been reported in patients with COVID-19 and its relation to clinical outcomes.

Methods: We searched EMBASE, MEDLINE, Cochrane Library and PROSPERO for English-language citations on ethnicity and COVID-19 (1 December 2019-15 May 2020). We also reviewed: COVID-19 articles in , clinical trial protocols, grey literature, surveillance data and preprint articles on COVID-19 in to evaluate if the association between ethnicity and clinical outcomes were reported and what they showed. PROSPERO:180654.

Findings: Of 207 articles in the database search, five reported ethnicity; two reported no association between ethnicity and mortality. Of 690 articles identified from medical journals, 12 reported ethnicity; three reported no association between ethnicity and mortality. Of 209 preprints, 34 reported ethnicity - 13 found Black, Asian and Minority Ethnic (BAME) individuals had an increased risk of infection with SARS-CoV-2 and 12 reported worse clinical outcomes, including ITU admission and mortality, in BAME patients compared to White patients. Of 12 grey literature reports, seven with original data reported poorer clinical outcomes in BAME groups compared to White groups.

Interpretation: Data on ethnicity in patients with COVID-19 in the published medical literature remains limited. However, emerging data from the grey literature and preprint articles suggest BAME individuals are at an increased risk of acquiring SARS-CoV-2 infection compared to White individuals and also worse clinical outcomes from COVID-19. Further work on the role of ethnicity in the current pandemic is of urgent public health importance.

Funding: NIHR.
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http://dx.doi.org/10.1016/j.eclinm.2020.100404DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267805PMC
June 2020

Are heart failure observational studies still useful? 'No need to argue'.

Eur J Prev Cardiol 2020 Jun 24:2047487320932258. Epub 2020 Jun 24.

Department of Translational Medical Sciences, Federico II University, Italy.

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http://dx.doi.org/10.1177/2047487320932258DOI Listing
June 2020

Characterizing heart failure with preserved and reduced ejection fraction: An imaging and plasma biomarker approach.

PLoS One 2020 29;15(4):e0232280. Epub 2020 Apr 29.

National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Leicester, England, United Kingdom.

Introduction: The pathophysiology of heart failure with preserved ejection fraction (HFpEF) remains incompletely defined. We aimed to characterize HFpEF compared to heart failure with reduced ejection fraction (HFrEF) and asymptomatic hypertensive or non-hypertensive controls.

Materials And Methods: Prospective, observational study of 234 subjects (HFpEF n = 140; HFrEF n = 46, controls n = 48, age 73±8, males 49%) who underwent echocardiography, cardiovascular magnetic resonance imaging (CMR), plasma biomarker analysis (panel of 22) and 6-minute walk testing (6MWT). The primary end-point was the composite of all-cause mortality and/or HF hospitalization.

Results: Compared to controls both HF groups had lower exercise capacity, lower left ventricular (LV) EF, higher LV filling pressures (E/E', B-type natriuretic peptide [BNP], left atrial [LA] volumes), more right ventricular (RV) systolic dysfunction, more focal and diffuse fibrosis and higher levels of all plasma markers. LV remodeling (mass/volume) was different between HFpEF (concentric, 0.68±0.16) and HFrEF (eccentric, 0.47±0.15); p<0.0001. Compared to controls, HFpEF was characterized by (mild) reductions in LVEF, more myocardial fibrosis, LA remodeling/dysfunction and RV dysfunction. HFrEF patients had lower LVEF, increased LV volumes, greater burden of focal and diffuse fibrosis, more RV remodeling, lower LAEF and higher LA volumes compared to HFpEF. Inflammatory/fibrotic/renal dysfunction plasma markers were similarly elevated in both HF groups but markers of cardiomyocyte stretch/damage (BNP, pro-BNP, N-terminal pro-atrial natriuretic peptide and troponin-I) were higher in HFrEF compared to HFpEF; p<0.0001. Focal fibrosis was associated with galectin3, GDF-15, MMP-3, MMP-7, MMP-8, BNP, pro-BNP and NTproANP; p<0.05. Diffuse fibrosis was associated with GDF-15, Tenascin-C, MMP-2, MMP-3, MMP-7, BNP, proBNP and NTproANP; p<0.05. Composite event rates (median 1446 days follow-up) did not differ between HFpEF and HFrEF (Log-Rank p = 0.784).

Conclusions: HFpEF is a distinct pathophysiological entity compared to age- and sex-matched HFrEF and controls. HFpEF and HFrEF are associated with similar adverse outcomes. Inflammation is common in both HF phenotypes but cardiomyocyte stretch/stress is greater in HFrEF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232280PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190371PMC
July 2020

Intra-study and inter-technique validation of cardiovascular magnetic resonance imaging derived left atrial ejection fraction as a prognostic biomarker in heart failure with preserved ejection fraction.

Int J Cardiovasc Imaging 2020 May 6;36(5):921-928. Epub 2020 Feb 6.

Department of Cardiovascular Sciences, University of Leicester, National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Leicester, UK.

The aim of this study was to assess the agreements of both biplane and short-axis Simpson's (SAX) methods for left atrial ejection fraction (LAEF) calculation utilising cardiovascular magnetic resonance imaging (CMR) in heart failure with preserved ejection fraction (HFpEF) and evaluate their relation to clinical outcomes. One hundred and thirty six subjects (HFpEF n = 97, controls n = 39) underwent CMR, six-minute walk tests and blood sampling in our prospective, observational, single-centre study. Overall, LAEF (%) was lower in HFpEF patients compared to controls (SAX 34 ± 13 vs 47 ± 8, biplane 34 ± 16 vs 51 ± 11; p < 0.0001 for both). Atrial fibrillation (AF) was present in 24% of HFpEF and was associated with higher LA volumes and lower LAEF compared to sinus rhythm (p < 0.0001) with both methods. Biplane LAEF correlated strongly with SAX measurements (overall Pearson's r = 0.851, sinus rhythm r = 0.651, AF r = 0.882; p < 0.0001). Biplane LAEF did not differ significantly compared to SAX LAEF (overall 34 ± 16 vs 34 ± 13%; p = 0.307) except in AF subjects in whom biplane LAEF was lower (mean difference 2 ± 4%, p = 0.013). There were 44 composite events (25 deaths, 19 HF hospitalizations) in HFpEF during median follow-up of 1429 days. LAEF below the median was associated with increased risk of composite endpoints (Log-Rank biplane p < 0.0001; SAX p = 0.009). In multivariable Cox proportional hazards regression analysis, both biplane LAEF (hazard ratio [HR] 0.604; 95% confidence interval [CI] (0.406-0.900); p = 0.013) and SAX LAEF (HR 0.636; CI 0.441-0.918; p = 0.016) remained independent predictors along with indexed extracellular volume. CMR LAEF, derived from either the short-axis or biplane method is lower in HFpEF compared to healthy controls and remains a strong marker of prognosis.
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http://dx.doi.org/10.1007/s10554-020-01785-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174265PMC
May 2020

Regulatory RNAs in Heart Failure.

Circulation 2020 01 27;141(4):313-328. Epub 2020 Jan 27.

Cardiovascular Research Unit, Luxembourg Institute of Health, Strassen, Luxembourg (C.P.d.C.G., Y.D.).

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042474DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012349PMC
January 2020

Combined use of trimethylamine N-oxide with BNP for risk stratification in heart failure with preserved ejection fraction: findings from the DIAMONDHFpEF study.

Eur J Prev Cardiol 2020 12 14;27(19):2159-2162. Epub 2019 Aug 14.

Department of Cardiovascular Sciences and NIHR Leicester Cardiovascular Biomedical Research Centre, University of Leicester, UK.

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http://dx.doi.org/10.1177/2047487319870355DOI Listing
December 2020

Left atrial ejection fraction and outcomes in heart failure with preserved ejection fraction.

Int J Cardiovasc Imaging 2020 Jan 10;36(1):101-110. Epub 2019 Aug 10.

Department of Cardiovascular Sciences, University of Leicester, National Institute for Health Research (NIHR) Leicester Biomedical Research Centre, Leicester, UK.

The aim of this study was to determine whether left atrial ejection fraction (LAEF) quantified with cardiovascular magnetic resonance (CMR) was different between heart failure with preserved ejection fraction (HFpEF) and controls, and its relation to prognosis. As part of our single-centre, prospective, observational study, 188 subjects (HFpEF n = 140, controls n = 48) underwent phenotyping with contrast-enhanced CMR, transthoracic echocardiography, blood sampling and six-minute walk testing. LAEF was calculated using the biplane method. Atrial fibrillation (AF) was present in 43 (31%) of HFpEF subjects. Overall, LAEF (%) was lower in HFpEF patients inclusive of AF (32 ± 16) or those in sinus rhythm alone (41 ± 12) compared to controls (51 ± 11), p < 0.0001. LAEF correlated inversely with maximal and minimal left atrial volumes indexed (r =  - 0.602, r =  - 0.762), and plasma N-terminal pro-atrial natriuretic peptide (r =  - 0.367); p < 0.0001. During median follow-up (1429 days), there were 67 composite events of all-cause death or hospitalization for heart failure (22 deaths, 45 HF hospitalizations) in HFpEF. Lower LAEF (below median) was associated with an increased risk of composite endpoints (Log-Rank: all p = 0.028; sinus p = 0.036). In multivariable Cox regression analysis, LAEF (adjusted hazard ratio [HR] 0.767, 95% confidence interval [CI] 0.591-0.996; p = 0.047) and indexed extracellular volume (HR 1.422, CI 1.015-1.992; p = 0.041) were the only parameters that remained significant when added to a base prognostic model comprising age, prior HF hospitalization, diastolic blood pressure, lung disease, NYHA, six-minute-walk-test-distance, haemoglobin, creatinine and B-type natriuretic peptide. CMR-derived LAEF is lower in HFpEF compared to healthy controls and is a strong prognostic biomarker.
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http://dx.doi.org/10.1007/s10554-019-01684-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942575PMC
January 2020

Differential left ventricular and left atrial remodelling in heart failure with preserved ejection fraction patients with and without diabetes.

Ther Adv Endocrinol Metab 2019 5;10:2042018819861593. Epub 2019 Jul 5.

Department of Cardiovascular Sciences, University of Leicester and the Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester LE3 9QP, UK.

Background: Attempts to characterize cardiac structure in heart failure with preserved ejection fraction (HFpEF) in people with type 2 diabetes (T2D) have yielded inconsistent findings. We aimed to determine whether patients with HFpEF and T2D have a distinct pattern of cardiac remodelling compared with those without diabetes and whether remodelling was related to circulating markers of inflammation and fibrosis and clinical outcomes.

Methods: We recruited 140 patients with HFpEF (75 with T2D and 65 without). Participants underwent comprehensive cardiovascular phenotyping, including echocardiography, cardiac magnetic resonance imaging and plasma biomarker profiling.

Results: Patients with T2D were younger (age 70 ± 9 75 ± 9y,  = 0.002), with evidence of more left ventricular (LV) concentric remodelling (LV mass/volume ratio 0.72 ± 0.15 0.62 ± 0.16,  = 0.024) and smaller indexed left atrial (LA) volumes (maximal LA volume index 48 ± 20 59 ± 29 ml/m,  = 0.004) than those without diabetes. Plasma biomarkers of inflammation and extracellular matrix remodelling were elevated in those with T2D. Overall, there were 45 hospitalizations for HF and 22 deaths over a median follow-up period of 47 months [interquartile range (IQR) 38-54]. There was no difference in the primary composite endpoint of hospitalization for HF and mortality between groups. On multivariable Cox regression analysis, age, prior HF hospitalization, history of pulmonary disease and LV mass/volume were independent predictors of the primary endpoint.

Conclusions: Patients with HFpEF and T2D have increased concentric LV remodelling, smaller LA volumes and evidence of increased systemic inflammation compared with those without diabetes. This suggests the underlying pathophysiology for the development of HFpEF is different in patients with and without T2D.

Clinicaltrialsgov Identifier: NCT03050593.
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http://dx.doi.org/10.1177/2042018819861593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613057PMC
July 2019

A novel form of glycolytic metabolism-dependent cardioprotection revealed by PKCα and β inhibition.

J Physiol 2019 09 26;597(17):4481-4501. Epub 2019 Jul 26.

Department of Cardiovascular Sciences, University of Leicester, Glenfield General Hospital, Leicester, UK.

Key Points: Acute hyperglycaemia at the time of a heart attack worsens the outcome for the patient. Acute hyperglycaemia is not limited to diabetic patients and can be due to a stress response in non-diabetics. This study suggests that the damaging cardiac effects of hyperglycaemia can be reversed by selective PKC inhibition. If PKCα/β isoforms are inhibited, then high glucose itself becomes protective against ischaemic damage. Selective PKC inhibition may therefore be a useful therapeutic tool to limit the damage that can occur during a heart attack by stress-induced hyperglycaemia.

Abstract: Hyperglycaemia has a powerful association with adverse prognosis for patients with acute coronary syndromes (ACS). Previous work shows that high glucose prevents ischaemic preconditioning and causes electrical and mechanical disruption via protein kinase C α/β (PKCα/β) activation. The present study aimed to: (i) determine whether the adverse clinical association of hyperglycaemia in ACS can be replicated in preclinical cellular models of ACS and (ii) determine the importance of PKCα/β activation to the deleterious effect of glucose. Freshly isolated rat, guinea pig or rabbit cardiomyocytes were exposed to simulated ischaemia after incubation in the presence of normal (5 mm) or high (20 mm) glucose in the absence or presence of small molecule or tat-peptide-linked PKCαβ inhibitors. In each of the four conditions, the following hallmarks of cardioprotection were recorded using electrophysiology or fluorescence imaging: cardiomyocyte contraction and survival, action potential stability and time to failure, intracellular calcium and ATP, mitochondrial depolarization, ischaemia-sensitive leak current, and time to K 6.2 opening. High glucose alone resulted in decreased cardiomyocyte contraction and survival; however, it also imparted cardioprotection in the presence of PKCα/β inhibitors. This cardioprotective phenotype displayed improvements in all of the measured parameters and decreased myocardium damage during whole heart coronary ligation experiments. High glucose is deleterious to cellular and whole-heart models of simulated ischaemia, in keeping with the clinical association of hyperglycaemia with an adverse outcome in ACS. PKCαβ inhibition revealed high glucose to show a cardioprotective phenotype in this setting. The results of the present study suggest the potential for the therapeutic application of PKCαβ inhibition in ACS associated with hyperglycaemia.
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http://dx.doi.org/10.1113/JP278332DOI Listing
September 2019

Global lessons from deaths from heart failure in UK hospitals.

Heart 2019 06 2;105(12):902-903. Epub 2019 Mar 2.

National Heart and Lung Institute, Imperial College London, London, UK.

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http://dx.doi.org/10.1136/heartjnl-2018-314641DOI Listing
June 2019

Relationship Between Focal and Diffuse Fibrosis Assessed by CMR and Clinical Outcomes in Heart Failure With Preserved Ejection Fraction.

JACC Cardiovasc Imaging 2019 11 13;12(11 Pt 2):2291-2301. Epub 2019 Feb 13.

Department of Cardiovascular Sciences, University of Leicester, National Institute for Health Research, Leicester Biomedical Research Centre, Leicester, United Kingdom.

Objectives: This study sought to assess the presence and extent of focal and diffuse fibrosis in heart failure in patients with preserved ejection fraction (HFpEF) compared to asymptomatic control subjects, and the relationship of fibrosis to clinical outcome.

Background: Myocardial fibrosis has been implicated in the pathophysiology of HFpEF.

Methods: In this prospective, observational study, 140 subjects of similar age and sex (HFpEF: n = 96; control subjects: n = 44; 73 ± 8 years of age; 49% males) underwent cardiac magnetic resonance imaging. Late gadolinium-enhanced (LGE) imaging and T1 mapping to calculate myocardial extracellular volume indexed to body surface area (iECV) were used to assess fibrosis.

Results: Patients with HFpEF had more concentric remodeling and worse diastolic function. Focal fibrosis was more frequent in HFpEF subjects (overall: n = 49; infarction: n = 17; nonischemic cases: n = 36; mixed patterns: n = 4) than in control subjects (overall: n = 3). Diffuse fibrosis was also greater in HFpEF subjects than control subjects (iECV: 13.7 ± 4.4 ml/m versus 10.9 ± 2.8 ml/m; p < 0.0001). During median follow-up (1,429 days), there were 42 composite events (14 deaths; 28 heart failure hospitalizations) in cases of HFpEF. Myocardial infarction revealed on LGE imaging was a predictor of outcomes on univariate analysis only. With multivariate analysis, iECV (hazard ratio [HR]: 1.689; 95% confidence interval [CI]: 1.141 to 2.501; p = 0.009) was an independent predictor of outcome along with mitral peak velocity of early filling (E)-to-early diastolic mitral annular velocity (E') (E/E') ratio (HR: 1.716; 95% CI: 1.191 to 2.472; p = 0.004) and prior HF hospitalization (HR: 2.537; 95% CI: 1.090 to 5.902; p = 0.031). iECV was also significantly associated with ventricular/left atrial remodeling and renal dysfunction: right ventricular end-diastolic volume indexed (r = 0.456; p < 0.0001), left ventricular mass/volume (r = 0.348; p = 0.001), maximal left atrial volume indexed (r = 0. 269; p = 0.009), and creatinine (r = 0.271; p = 0.009).

Conclusions: Both focal and diffuse myocardial fibrosis are more prevalent in HFpEF subjects than in control subjects of similar age and sex. iECV significantly correlates with indices of ventricular/left atrial remodeling and renal dysfunction and is an independent predictor of adverse outcome in HFpEF. (Developing Imaging And plasMa biOmarkers iN Describing Heart Failure With Preserved Ejection Fraction [DIAMONDHFpEF]; NCT03050593).
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http://dx.doi.org/10.1016/j.jcmg.2018.11.031DOI Listing
November 2019

Proenkephalin and prognosis in heart failure with preserved ejection fraction: a GREAT network study.

Clin Res Cardiol 2019 Aug 14;108(8):940-949. Epub 2019 Feb 14.

Department of Cardiovascular Sciences, Clinical Sciences Wing, NIHR Leicester Biomedical Research Centre, Glenfield Hospital, University of Leicester, Leicester, LE3 9QP, UK.

Background: Proenkephalin (PENK), a stable endogenous opioid biomarker related to renal function, has prognostic utility in acute and chronic heart failure. We investigated the prognostic utility of PENK in heart failure with preserved ejection fraction (HFpEF), and its relationship to renal function, Body Mass Index (BMI), and imaging measures of diastolic dysfunction.

Methods: In this multicentre study, PENK was measured in 522 HFpEF patients (ejection fraction > 50%, 253 male, mean age 76.13 ± 10.73 years) and compared to 47 age and sex-matched controls. The primary endpoint was 2-years composite of all-cause mortality and/or heart failure rehospitalisation (HF). A subset (n = 163) received detailed imaging studies.

Results: PENK levels were raised in HFpEF (median [interquartile range] 88.9 [62.1-132.0]) compared to normal controls (56.3 [47.9-70.5]). PENK was correlated to urea, eGFR, Body Mass Index and E/e' (r 0.635, - 0.741, - 0.275, 0.476, respectively, p < 0.0005). During 2 years follow-up 144 patients died and 220 had death/HF endpoints. Multivariable Cox regression models showed PENK independently predicted 2 year death/HF [hazard ratio (for 1 SD increment of log-transformed biomarker) HR 1.45 [95% CI 1.12-1.88, p = 0.005]], even after adjustment for troponin (HR 1.59 [1.14-2.20, p = 0.006]), and Body Mass Index (HR 1.63 [1.13-2.33, p = 0.009]). PENK showed no interaction with ejection fraction status for prediction of poor outcomes. Net reclassification analyses showed PENK significantly improved classification of death/HF outcomes for multivariable models containing natriuretic peptide, troponin and Body Mass Index (p < 0.05 for all).

Conclusions: In HFpEF, PENK levels are related to BMI, and measures of diastolic dysfunction and are prognostic for all-cause mortality and heart failure rehospitalisation.
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http://dx.doi.org/10.1007/s00392-019-01424-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652170PMC
August 2019

Correction to: does stress perfusion imaging improve the diagnostic accuracy of late gadolinium enhanced cardiac magnetic resonance for establishing the etiology of heart failure?

BMC Cardiovasc Disord 2019 Jan 21;19(1):24. Epub 2019 Jan 21.

Department of Cardiovascular Sciences, University of Leicester, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK.

Following publication of the original article [1], the author reported his name has erroneously spelled as Abishek Shetye. The correct name is Abhishek Shetye.
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http://dx.doi.org/10.1186/s12872-019-1001-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6340168PMC
January 2019

Evidence for reduced susceptibility to cardiac bradycardias in South Asians compared with Caucasians.

Heart 2018 08 20;104(16):1350-1355. Epub 2018 Feb 20.

Department of Cardiovascular Sciences, University of Leicester, and NIHR Leicester Biomedical Research Centre, Glenfield Hospital Leicester, Leicester, UK.

Objectives: To investigate ethnic differences in susceptibility to bradycardias in South Asian and white European patients in the UK by determining rates of permanent pacemaker (PPM) implantation for sinus node dysfunction (SND) and atrioventricular block (AVB) in each ethnic group.

Methods: We carried out a retrospective cohort study into new PPM implantation during the period from 1 May 2006 to 31 March 2014, in patients of South Asian and Caucasian ethnicity resident in Leicestershire, UK. Numbers of individuals at risk in each ethnic group were derived from UK National Census data of 2011. Crude, and age-standardised incidence rates and risk ratios per 1000 population of PPM implantation were calculated for Caucasians and South Asians.

Results: During the study period, 4883 individuals from the Leicestershire population of 980 328 underwent PPM implantation, a cumulative implantation rate of 4.98/1000 population. The population cumulative PPM implantation rate for SND was 1.74/1000, AVB 2.83/1000 and other indications 0.38/1000 population. The crude incidence in Caucasians (6.15/1000 population) was higher than in South Asians (1.07/1000 population) and remained higher after age standardisation (5.60/1000 vs 2.03/1000, P<0.001). The age-standardised cumulative PPM implantation rates were lower in South Asians for both SND (0.53/1000 in South Asians; 1.97/1000 in Caucasians, P<0.001) and AVB (1.30/1000 in South Asians; 3.17/1000 in Caucasians, P<0.001). Standardised risk ratios (95% CI) for PPM implantation in South Asians compared with Caucasians for all pacing indications, SND and AVB were 0.36 (95% CI 0.36 to 0.37), 0.27 (95% CI 0.27 to 0.28) and 0.41 (95% CI 0.41 to 0.42), respectively.

Conclusions: Rates of PPM implantation are lower in South Asians residing in the UK, compared with Caucasians. This observation raises the possibility of lower inherent susceptibility to bradycardias in South Asians compared with Caucasians. Studies aimed at identifying underlying mechanisms, including possible genetic differences, are warranted.
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http://dx.doi.org/10.1136/heartjnl-2017-312374DOI Listing
August 2018

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

ESC Heart Fail 2018 02 18;5(1):9-18. Epub 2017 Jul 18.

Department of Cardiovascular Sciences, University of Leicester, NIHR Cardiovascular Biomedical Research Unit, Glenfield General Hospital, Leicester, UK.

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.
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http://dx.doi.org/10.1002/ehf2.12195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5793965PMC
February 2018

Diagnostic and prognostic utility of cardiovascular magnetic resonance imaging in heart failure with preserved ejection fraction - implications for clinical trials.

J Cardiovasc Magn Reson 2018 01 11;20(1). Epub 2018 Jan 11.

Department of Cardiovascular Sciences and National Institute for Health Research (NIHR), University of Leicester, Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK.

Background: Heart failure with preserved ejection fraction (HFpEF) is a poorly characterized condition. We aimed to phenotype patients with HFpEF using multiparametric stress cardiovascular magnetic resonance imaging (CMR) and to assess the relationship to clinical outcomes.

Methods: One hundred and fifty four patients (51% male, mean age 72 ± 10 years) with a diagnosis of HFpEF underwent transthoracic echocardiography and CMR during a single study visit. The CMR protocol comprised cine, stress/rest perfusion and late gadolinium enhancement imaging on a 3T scanner. Follow-up outcome data (death and heart failure hospitalization) were captured after a minimum of 6 months.

Results: CMR detected previously undiagnosed pathology in 42 patients (27%), who had similar baseline characteristics to those without a new diagnosis. These diagnoses consisted of: coronary artery disease (n = 20, including 14 with 'silent' infarction), microvascular dysfunction (n = 11), probable or definite hypertrophic cardiomyopathy (n = 10) and constrictive pericarditis (n = 5). Four patients had dual pathology. During follow-up (median 623 days), patients with a new CMR diagnosis were at higher risk of adverse outcome for the composite endpoint (log rank test: p = 0.047). In multivariate Cox proportional hazards analysis, a new CMR diagnosis was the strongest independent predictor of adverse outcome (hazard ratio: 1.92; 95% CI: 1.07 to 3.45; p = 0.03).

Conclusions: CMR diagnosed new significant pathology in 27% of patients with HFpEF. These patients were at increased risk of death and heart failure hospitalization.

Trial Registration: ClinicalTrials.gov Identifier: NCT03050593 . Retrospectively registered; Date of registration: February 06, 2017.
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http://dx.doi.org/10.1186/s12968-017-0424-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5763769PMC
January 2018