Characterisation of infantile cardiomyopathy in Alström syndrome using ALMS1 knockout induced pluripotent stem cell derived cardiomyocyte model.

Alström syndrome (AS) is an inherited rare ciliopathy characterised by multi-organ dysfunction and premature cardiovascular disease. This may manifest as an infantile-onset dilated cardiomyopathy with significant associated mortality. An adult-onset restrictive cardiomyopathy may also feature later in life. Loss of function pathogenic variants in ALMS1 have been identified in AS patients, leading to a lack of ALMS1 protein. The biological role of ALMS1 is unknown, particularly in a cardiovascular context. To understand the role of ALMS1 in infantile cardiomyopathy, the reduction of ALMS1 protein seen in AS patients was modelled using human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), in which ALMS1 was knocked out. MuscleMotion analysis and calcium optical mapping experiments suggest that ALMS1 knockout (KO) cells have increased contractility, with altered calcium extrusion and impaired calcium handling dynamics compared to wildtype (WT) counterparts. Seahorse metabolic assays showed ALMS1 knockout iPSC-CMs had increased glycolytic and mitochondrial respiration rates, with ALMS1 knockout cells portraying increased energetic demand and respiratory capacity than WT counterparts. Using senescence associated ß-galactosidase (SA-ß gal) staining assay, we identified increased senescence of ALMS1 knockout iPSC-CMs. Overall, this study provides insights into the molecular mechanisms in AS, particularly the role of ALMS1 in infantile cardiomyopathy in AS, using iPSC-CMs as a 'disease in a dish' model to provide insights into multiple aspects of this complex disease.

Arrhythmogenesis in Fabry Disease.

PURPOSE OF REVIEW: Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate. RECENT FINDINGS: There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual's risk of arrhythmia in FD. In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.

Adipose tissue function and insulin sensitivity in syndromic obesity of Bardet-Biedl syndrome.

BACKGROUND: Bardet-Biedl syndrome (BBS) is a rare autosomal recessive syndromic obesity of childhood onset among many other features. To date, the excess risk of metabolic complications of severe early-onset obesity in BBS remains controversial. In-depth investigation of adipose tissue structure and function with detailed metabolic phenotype has not been investigated yet. OBJECTIVE: To investigate adipose tissue function in BBS. DESIGN: A prospective cross-sectional study. MAIN OUTCOME MEASURE: To determine if there are differences in insulin resistance, metabolic profile, adipose tissue function and gene expression in patients with BBS compared to BMI-matched polygenic obese controls. METHOD: 9 adults with BBS and 10 controls were recruited from the national centre for BBS, Birmingham, UK. An in-depth study of adipose tissue structure and function along with insulin sensitivity was performed using hyperinsulinemic-euglycemic clamp studies, adipose tissue microdialysis, histology and RNA sequencing, and measurement of circulating adipokines and inflammatory biomarkers. RESULTS: Adipose tissue structure, gene expression and in vivo functional analysis between BBS and polygenic obesity cohorts were similar. Using hyperinsulinemic-euglycemic clamp and surrogate markers of insulin resistance, we found no significant differences in insulin sensitivity between BBS and obese controls. Furthermore, no significant changes were noted in an array of adipokines, cytokines, pro-inflammatory markers and adipose tissue RNA transcriptomic. CONCLUSION: Although childhood-onset extreme obesity is a feature of BBS, detailed studies of insulin sensitivity and adipose tissue structure and function are similar to common polygenic obesity. This study adds to the literature by suggesting that it is the quality and quantity of adiposity not the duration that drives the metabolic phenotype.

Management of heart failure in patients with kidney disease-updates from the 2021 ESC guidelines.

The wide overlap between the syndromes of chronic kidney disease (CKD) and chronic heart failure (HF) means that familiarity with the 2021 European Society of Cardiology guidelines is of importance to nephrologists. The common risk factors for the two syndromes together with the adverse cardiac structural remodelling associated with CKD means that many kidney disease patients experience breathlessness and fall within the HF phenotypes categorized in the guidelines. The management of HF is evolving rapidly leading to significant changes in the latest guideline iteration. The 2021 guidelines have changed from the 2016 version firstly by an increased focus on identifying the three phenotypes of HF to guide appropriate evidence-based management. Secondly, a new and simplified treatment algorithm for HF with reduced ejection fraction involving the rapid sequential initiation and up-titration of four 'pillars' of drug treatment-angiotensin-converting enzyme inhibitors or angiotensin-neprilysin inhibitors, beta blockers, mineralocorticoid receptor antagonists and now, thanks to convincing trial data, sodium-glucose co-transporter 2 inhibitors. Thirdly, guidelines for device therapy have been changed with down-graded advice on indications for primary prevention implantable cardioverter defibrillator therapy for patients with non-ischaemic HF and for cardiac resynchronization therapy with left bundle branch block (LBBB) and a QRS duration <150 ms. There are updated treatment plans for HF associated with non-cardiovascular comorbidities including CKD.

Prognostic value of coronary risk factors, exercise capacity and single photon emission computed tomography in liver transplantation candidates: A 5-year follow-up study.

BACKGROUND: Although consensus-based guidelines support noninvasive stress testing prior to orthotopic liver transplantation (OLT), the optimal screening strategy for assessment of coronary artery disease in patients with end-stage liver disease (ESLD) is unclear. This study sought to determine the relative predictive value of coronary risk factors, functional capacity, and single photon emission computed tomography (SPECT) on major adverse cardiovascular events and all-cause mortality in liver transplantation candidates. METHODS: Prior to listing for transplantation, 404 consecutive ESLD patients were referred to a University hospital for cardiovascular (CV) risk stratification. All subjects met at least one of the following criteria: inability to perform > 4 METs by history (62%), insulin-treated diabetes mellitus (53%), serum creatinine > 1.72 mg/dL (8%), history of MI, PCI or CABG (5%), stable angina (3%), cerebrovascular disease (1%), peripheral vascular disease (1%). Subjects underwent Technetium-99m SPECT with multislice coronary artery calcium scoring (CACS) using exercise treadmill or standard adenosine stress in those unable to achieve 85% maximal heart rate (Siemens Symbia T16). Abnormal perfusion was defined as a summed stress score (SSS) ≥ 4. RESULTS: Of the 404 patients, 158 (age 59 ± 9 years; male 68%) subsequently underwent transplantation and were included in the primary analysis. Of those, 50 (32%) died after a mean duration follow-up of 5.4 years (maximal 10.9 years). Most deaths (78%) were attributed to noncardiovascular causes (malignancy, sepsis, renal failure). Of the 32 subjects with abnormal perfusion (20%), nine (6%) had a high-risk perfusion abnormality defined as a total perfusion defect size (PDS) ≥ 15% and/or an ischemic PDS ≥ 10%. Kaplan-Meier survival curves demonstrated abnormal perfusion was associated with increased CV mortality (generalized Wilcoxon, P = 0.014) but not all-cause death. Subjects with both abnormal perfusion and an inability to exercise > 4 METs had the lowest survival from all-cause death (P = 0.038). Abnormal perfusion was a strong independent predictor of CV death (adjusted HR 4.2; 95% CI 1.4 to 12.3; P = 0.019) and MACE (adjusted HR 7.7; 95% CI 1.4 to 42.4; P = 0.018) in a multivariate Cox regression model that included age, sex, diabetes, smoking and the ability to exercise > 4 METs. There was no association between CACS and the extent of perfusion abnormality, nor with outcomes. CONCLUSIONS: Most deaths following OLT are noncardiovascular. Nonetheless, abnormal perfusion is prevalent in this high-risk population and a stronger predictor of cardiovascular morbidity and mortality than functional status. A combined assessment of functional status and myocardial perfusion identifies those at highest risk of all-cause death. (Exercise Capacity and Single Photon Emission Computed Tomography in Liver Transplantation Candidates [ExSPECT]; ClinicalTrials.gov Identifier: NCT03864497).

Coronary microvascular dysfunction is associated with degree of anaemia in end-stage renal disease.

BACKGROUND: Coronary microvascular dysfunction (CMD) is common in end-stage renal disease (ESRD) and is an adverse prognostic marker. Coronary flow velocity reserve (CFVR) is a measure of coronary microvascular function and can be assessed using Doppler echocardiography. Reduced CFVR in ESRD has been attributed to factors such as diabetes, hypertension and left ventricular hypertrophy. The contributory role of other mediators important in the development of cardiovascular disease in ESRD has not been studied. The aim of this study was to examine the prevalence of CMD in a cohort of kidney transplant candidates and to look for associations of CMD with markers of anaemia, bone mineral metabolism and chronic inflammation. METHODS: Twenty-two kidney transplant candidates with ESRD were studied with myocardial contrast echocardiography, Doppler CFVR assessment and serum multiplex immunoassay analysis. Individuals with diabetes, uncontrolled hypertension or ischaemic heart disease were excluded. RESULTS: 7/22 subjects had CMD (defined as CFVR < 2). Demographic, laboratory and echocardiographic parameters and serum biomarkers were similar between subjects with and without CMD. Subjects with CMD had significantly lower haemoglobin than subjects without CMD (102 g/L ± 12 vs. 117 g/L ± 11, p = 0.008). There was a positive correlation between haemoglobin and CFVR (r = 0.7, p = 0.001). Similar results were seen for haematocrit. In regression analyses, haemoglobin was an independent predictor of CFVR (ß = 0.041 95% confidence interval 0.012-0.071, p = 0.009) and of CFVR < 2 (odds ratio 0.85 95% confidence interval 0.74-0.98, p = 0.022). CONCLUSIONS: Among kidney transplant candidates with ESRD, there is a high prevalence of CMD, despite the absence of traditional risk factors. Anaemia may be a potential driver of microvascular dysfunction in this population and requires further investigation.

Defining renal phenotype in Alström syndrome.

BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone-rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. METHOD: Prospective observational cohort study. SETTING AND PARTICIPANTS: Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. OUTCOMES: First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. ANALYTICAL APPROACH: Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. RESULTS: The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of -16.7 and -10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo-interstitial and glomerular disease. CONCLUSIONS: This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases.

Myocardial fibrosis in asymptomatic and symptomatic chronic severe primary mitral regurgitation and relationship to tissue characterisation and left ventricular function on cardiovascular magnetic resonance.

BACKGROUND: Myocardial fibrosis occurs in end-stage heart failure secondary to mitral regurgitation (MR), but it is not known whether this is present before onset of symptoms or myocardial dysfunction. This study aimed to characterise myocardial fibrosis in chronic severe primary MR on histology, compare this to tissue characterisation on cardiovascular magnetic resonance (CMR) imaging, and investigate associations with symptoms, left ventricular (LV) function, and exercise capacity. METHODS: Patients with class I or IIa indications for surgery underwent CMR and cardiopulmonary exercise testing. LV biopsies were taken at surgery and the extent of fibrosis was quantified on histology using collagen volume fraction (CVFmean) compared to autopsy controls without cardiac pathology. RESULTS: 120 consecutive patients (64 ± 13 years; 71% male) were recruited; 105 patients underwent MV repair while 15 chose conservative management. LV biopsies were obtained in 86 patients (234 biopsy samples in total). MR patients had more fibrosis compared to 8 autopsy controls (median: 14.6% [interquartile range 7.4-20.3] vs. 3.3% [2.6-6.1], P < 0.001); this difference persisted in the asymptomatic patients (CVFmean 13.6% [6.3-18.8], P < 0.001), but severity of fibrosis was not significantly higher in NYHA II-III symptomatic MR (CVFmean 15.7% [9.9-23.1] (P = 0.083). Fibrosis was patchy across biopsy sites (intraclass correlation 0.23, 95% CI 0.08-0.39, P = 0.001). No significant relationships were identified between CVFmean and CMR tissue characterisation [native T1, extracellular volume (ECV) or late gadolinium enhancement] or measures of LV function [LV ejection fraction (LVEF), global longitudinal strain (GLS)]. Although the range of ECV was small (27.3 ± 3.2%), ECV correlated with multiple measures of LV function (LVEF: Rho = - 0.22, P = 0.029, GLS: Rho = 0.29, P = 0.003), as well as NTproBNP (Rho = 0.54, P < 0.001) and exercise capacity (%PredVO2max: R = - 0.22, P = 0.030). CONCLUSIONS: Patients with chronic primary MR have increased fibrosis before the onset of symptoms. Due to the patchy nature of fibrosis, CMR derived ECV may be a better marker of global myocardial status. Clinical trial registration Mitral FINDER study; Clinical Trials NCT02355418, Registered 4 February 2015, https://clinicaltrials.gov/ct2/show/NCT02355418.

Effect of Digoxin vs Bisoprolol for Heart Rate Control in Atrial Fibrillation on Patient-Reported Quality of Life: The RATE-AF Randomized Clinical Trial.

Importance: There is little evidence to support selection of heart rate control therapy in patients with permanent atrial fibrillation, in particular those with coexisting heart failure. Objective: To compare low-dose digoxin with bisoprolol (a ß-blocker). Design, Setting, and Participants: Randomized, open-label, blinded end-point clinical trial including 160 patients aged 60 years or older with permanent atrial fibrillation (defined as no plan to restore sinus rhythm) and dyspnea classified as New York Heart Association class II or higher. Patients were recruited from 3 hospitals and primary care practices in England from 2016 through 2018; last follow-up occurred in October 2019. Interventions: Digoxin (n = 80; dose range, 62.5-250 µg/d; mean dose, 161 µg/d) or bisoprolol (n = 80; dose range, 1.25-15 mg/d; mean dose, 3.2 mg/d). Main Outcomes and Measures: The primary end point was patient-reported quality of life using the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) at 6 months (higher scores are better; range, 0-100), with a minimal clinically important difference of 0.5 SD. There were 17 secondary end points (including resting heart rate, modified European Heart Rhythm Association [EHRA] symptom classification, and N-terminal pro-brain natriuretic peptide [NT-proBNP] level) at 6 months, 20 end points at 12 months, and adverse event (AE) reporting. Results: Among 160 patients (mean age, 76 [SD, 8] years; 74 [46%] women; mean baseline heart rate, 100/min [SD, 18/min]), 145 (91%) completed the trial and 150 (94%) were included in the analysis for the primary outcome. There was no significant difference in the primary outcome of normalized SF-36 PCS at 6 months (mean, 31.9 [SD, 11.7] for digoxin vs 29.7 [11.4] for bisoprolol; adjusted mean difference, 1.4 [95% CI, -1.1 to 3.8]; P = .28). Of the 17 secondary outcomes at 6 months, there were no significant between-group differences for 16 outcomes, including resting heart rate (a mean of 76.9/min [SD, 12.1/min] with digoxin vs a mean of 74.8/min [SD, 11.6/min] with bisoprolol; difference, 1.5/min [95% CI, -2.0 to 5.1/min]; P = .40). The modified EHRA class was significantly different between groups at 6 months; 53% of patients in the digoxin group reported a 2-class improvement vs 9% of patients in the bisoprolol group (adjusted odds ratio, 10.3 [95% CI, 4.0 to 26.6]; P < .001). At 12 months, 8 of 20 outcomes were significantly different (all favoring digoxin), with a median NT-proBNP level of 960 pg/mL (interquartile range, 626 to 1531 pg/mL) in the digoxin group vs 1250 pg/mL (interquartile range, 847 to 1890 pg/mL) in the bisoprolol group (ratio of geometric means, 0.77 [95% CI, 0.64 to 0.92]; P = .005). Adverse events were less common with digoxin; 20 patients (25%) in the digoxin group had at least 1 AE vs 51 patients (64%) in the bisoprolol group (P < .001). There were 29 treatment-related AEs and 16 serious AEs in the digoxin group vs 142 and 37, respectively, in the bisoprolol group. Conclusions and Relevance: Among patients with permanent atrial fibrillation and symptoms of heart failure treated with low-dose digoxin or bisoprolol, there was no statistically significant difference in quality of life at 6 months. These findings support potentially basing decisions about treatment on other end points. Trial Registration: ClinicalTrials.gov Identifier: NCT02391337 and clinicaltrialsregister.eu Identifier: 2015-005043-13.

Variation in cardiovascular magnetic resonance myocardial contouring: Insights from an international survey.

LEVEL OF EVIDENCE: 5 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:1336-1338.

Myocardial characterization in pre-dialysis chronic kidney disease: a study of prevalence, patterns and outcomes.

BACKGROUND: Late gadolinium enhancement (LGE) using cardiac magnetic resonance (CMR) characterizes myocardial disease and predicts an adverse cardiovascular (CV) prognosis. Myocardial abnormalities, are present in early chronic kidney disease (CKD). To date there are no data defining prevalence, pattern and clinical implications of LGE-CMR in CKD. METHODS: Patients with pre-dialysis CKD (stage 2-5) attending specialist renal clinics at University Hospital Birmingham (UK) who underwent gadolinium enhanced CMR (1.5 T) between 2005 and 2017 were included. The patterns and presence (LGEpos) / absence (LGEneg) of LGE were assessed by two blinded observers. Association between LGE and CV outcomes were assessed. RESULTS: In total, 159 patients received gadolinium (male 61%, mean age 55 years, mean left ventricular ejection fraction 69%, left ventricular hypertrophy 5%) with a median follow up period of 3.8 years [1.04-11.59]. LGEpos was present in 55 (34%) subjects; the patterns were: right ventricular insertion point n = 28 (51%), mid wall n = 18 (33%), sub-endocardial n = 5 (9%) and sub-epicardial n = 4 (7%). There were no differences in left ventricular structural or functional parameters with LGEpos. There were 12 adverse CV outcomes over follow up; 7 of 55 with LGEpos and 5 of 104 LGEneg. LGEpos was not predicted by age, gender, glomerular filtration rate or electrocardiographic abnormalities. CONCLUSIONS: In a selected cohort of subjects with moderate CKD but low CV risk, LGE was present in approximately a third of patients. LGE was not associated with adverse CV outcomes. Further studies in high risk CKD cohorts are required to assess the role of LGE with multiplicative risk factors.

Ventricular arrhythmia and sudden cardiac death in Fabry disease: a systematic review of risk factors in clinical practice.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A enzyme. Cardiovascular (CV) disease is a common cause of mortality in FD, in particular as a result of heart failure and arrhythmia, with a significant proportion of events categorized as sudden. There are no clear models for risk prediction in FD. This systematic review aims to identify the risk factors for ventricular arrhythmia (VA) and sudden cardiac deaths (SCD) in FD. A systematic search was performed following PRISMA guidelines of EMBASE, Medline, PubMed, Web of Science, and Cochrane from inception to August 2016, focusing on identification of risk factors for the development of VA or SCD. Thirteen studies were included in the review (n = 4185 patients) from 1189 articles, with follow-up of 1.2-10 years. Weighted average age was 37.6 years, and 50% were male. Death from any cause was reported in 8.3%. Of these, 75% was due to CV problems, with the majority being SCD events (62% of reported deaths). Ventricular tachycardia was reported in 7 studies, with an average prevalence of 15.3%. Risk factors associated with SCD events were age, male gender, left ventricular hypertrophy, late gadolinium enhancement on CV magnetic resonance imaging, and non-sustained ventricular tachycardia. Although a multi-system disease, FD is a predominantly cardiac disease from a mortality perspective, with death mainly from SCD events. Limited evidence highlights the importance of clinical and imaging risk factors that could contribute to improved decision-making in the management of FD.

Treatment with PBI-4050 in patients with Alström syndrome: study protocol for a phase 2, single-Centre, single-arm, open-label trial.

BACKGROUND: Alström syndrome (ALMS) is a very rare autosomal recessive monogenic disorder caused by a mutation in the ALMS1 gene and characterised by childhood onset obesity, dyslipidaemia, advanced non-alcoholic fatty liver disease, diabetes and extreme insulin resistance. There is evidence of multi-organ fibrosis in ALMS and severity of the disease often leads to organ failure with associated morbidities, resulting in reduced life expectancy. There are no specific treatments for this disease, and current management consists of only symptomatic therapies. PBI-4050 is a new molecular entity with demonstrated anti-inflammatory and anti-fibrotic activities in preclinical models, including animal models of human diseases characterized by progressive fibrosis in the kidney, heart, liver and lungs. Moreover, completed Phase 2 studies in type 2 diabetes mellitus with metabolic syndrome and idiopathic pulmonary fibrosis further support the anti-inflammatory and anti-fibrotic activity of PBI-4050. Together, these data suggest that PBI-4050 has the potential to treat the pathological inflammatory and fibrotic features of ALMS. The aim of this study is to evaluate the safety and anti-inflammatory & anti-fibrotic activities of PBI-4050 in subjects with ALMS. METHODS: This is a Phase 2, single-centre, single-arm, open-label trial. A total of 18 patients with ALMS will be enrolled to receive PBI-4050 at a total daily oral dose of 800 mg for an initial 24 weeks with continuation for an additional 36 or 48 weeks. Standard assessments of safety include adverse events, clinical laboratory tests, vital signs, physical examination and electrocardiograms. Efficacy assessments include adipose tissue biopsy, hyperinsulinaemic-euglycaemic glucose clamp, adipose tissue microdialysis, liver transient elastography, liver and cardiac magnetic resonance imaging, and laboratory blood tests. DISCUSSION: This is the first clinical study of PBI-4050 in subjects with ALMS. Given the rarity and complexity of the disease, a single-centre, single-arm, open-label design has been chosen to maximise subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable safety and preliminary evidence of the effects of PBI-4050 in ALMS, a rare heterogeneous disease associated with progressive fibrosis and premature mortality. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (Identifier; NCT02739217 , February 2016) and European Union Drug Regulating Authorities Clinical Trials (EudraCT Number 2015-001625-16, Sept 2015).

Comparison of exercise testing and CMR measured myocardial perfusion reserve for predicting outcome in asymptomatic aortic stenosis: the PRognostic Importance of MIcrovascular Dysfunction in Aortic Stenosis (PRIMID AS) Study.

AIMS: To assess cardiovascular magnetic resonance (CMR) measured myocardial perfusion reserve (MPR) and exercise testing in asymptomatic patients with moderate-severe AS. METHODS AND RESULTS: Multi-centre, prospective, observational study, with blinded analysis of CMR data. Patients underwent adenosine stress CMR, symptom-limited exercise testing (ETT) and echocardiography and were followed up for 12-30 months. The primary outcome was a composite of: typical AS symptoms necessitating referral for AVR, cardiovascular death and major adverse cardiovascular events. 174 patients were recruited: mean age 66.2 ± 13.34 years, 76% male, peak velocity 3.86 ± 0.56 m/s and aortic valve area index 0.57 ± 0.14 cm2/m2. A primary outcome occurred in 47 (27%) patients over a median follow-up of 374 (IQR 351-498) days. The mean MPR in those with and without a primary outcome was 2.06 ± 0.65 and 2.34 ± 0.70 (P = 0.022), while the incidence of a symptom-limited ETT was 45.7% and 27.0% (P = 0.020), respectively. MPR showed moderate association with outcome area under curve (AUC) = 0.61 (0.52-0.71, P = 0.020), as did exercise testing (AUC = 0.59 (0.51-0.68, P = 0.027), with no significant difference between the two. CONCLUSIONS: MPR was associated with symptom-onset in initially asymptomatic patients with AS, but with moderate accuracy and was not superior to symptom-limited exercise testing. ClinicalTrials.gov (NCT01658345).

Is echocardiography valid and reproducible in patients with atrial fibrillation? A systematic review.

AIMS: Echocardiography is vital in the routine assessment and management of atrial fibrillation (AF). We performed a systematic review of the validity and reproducibility of echocardiographic left ventricular systolic and diastolic function in AF, and optimal acquisition methods. METHODS AND RESULTS: Online databases were searched for studies in patients with AF at the time of echocardiography (1960 to August 2015), prospectively registered with PROSPERO (CRD42015025297). The systematic review included 32 studies from 3 066 search results (1 968 patients with AF). Average age was 67 years, 33% were women, mean LVEF 53% (±10%), and average E/e' 11.7 (±2.7). Data on the validity and reproducibility of systolic indices were extremely limited. In contrast, diastolic parameters demonstrated correlation with invasive filling pressure and adequate reproducibility: E/e' (n = 444) r = 0.47 to 0.79; IVRT (n = 177) r = -0.70 to -0.95; E/Vp` (n = 55) r = 0.63 and 0.65; pulmonary vein diastolic flow (n = 67) r = -0.80 and -0.91. Elevated E/e' (>15) was associated with functional capacity, quality of life, and impaired prognosis. For optimal acquisition in AF patients, cardiac cycles with controlled heart rate (<100 beats/min) and similar preceding and pre-preceding RR intervals are required. Cardiac cycle length and equivalence were more important than the number of beats averaged. CONCLUSION: With careful selection of appropriate cardiac cycles, echocardiography is a valid tool to identify diastolic dysfunction in AF, and E/e' is an independent marker of clinical status and adverse prognosis. However, data on systolic function was extremely limited and requires further prospective study and assessment of variability in clinical practice.

Quality of care assessment and improvement in aortic stenosis - rationale and design of a multicentre registry (IMPULSE).

BACKGROUND: Severe aortic stenosis (AS) is a common, serious valve disease in which no effective medical therapy is available and, if not treated by intervention, has a 5-year survival of only 40-60%. Despite the availability of guidelines supporting the effective use of surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVI) to treat the majority of these patients, adherence to these guidelines in clinical practice is still unsatisfactory. Several recent studies have emphasised the necessity for improved communication between multidisciplinary teams, with the aim to ensure that severe AS patients receive appropriate treatment. METHODS/DESIGN: IMPULSE is a prospective, multicentre, European registry designed to gather data over 12 months on the treatment decisions made by referring physicians for patients newly diagnosed with severe AS. Each patient has a follow-up of 3 months. The study will consist of two observational phases to assess the appropriateness and rate of referral based on current guidelines prior to and after an interventional phase aiming to determine whether a simple quality of care intervention improves patient management. DISCUSSION: Data will be analysed firstly, to determine the appropriateness of treatment decisions for the management of severe AS in current European clinical practice, and secondly, to evaluate the effectiveness of facilitated data relay from a designated echocardiography department nurse to the referring physician early after diagnosis in improving quality of care. Additionally, variables will be identified that are associated with inappropriate decision-making. Collectively, the aim will be to design a clinical pathway that will improve the timely management of patients with newly diagnosed severe AS.

A prospective study examining the role of myocardial Fibrosis in outcome following mitral valve repair IN DEgenerative mitral Regurgitation: rationale and design of the mitral FINDER study.

BACKGROUND: The optimal management of chronic severe primary degenerative mitral regurgitation (MR) is to repair the valve but identification of the optimal timing of surgery remains challenging. Current guidelines suggest 'watchful waiting' until the onset of symptoms or left ventricular (LV) dysfunction but these have been challenged as promoting 'rescue surgery'. Better predictors are required to inform decision-making in relation to the necessity and timing of surgery. Chronic volume overload is a stimulus for adverse adaptive LV remodelling. Subclinical reduction in LV strain before mitral repair predicts a fall in LV ejection fraction following surgery and is thought to reflect the development of myocardial fibrosis in response to chronic volume overload. Myocardial fibrosis can be detected non-invasively using cardiac magnetic resonance (CMR) imaging techniques as an expansion of the extracellular volume (ECV). METHODS/DESIGN: This study investigates whether: 1) patients with above median ECV will have smaller reduction in end-systolic volume index (as a measure of the degree of reverse LV remodelling) on CMR following mitral valve repair, compared to those with below median ECV; and 2) higher ECV on CMR, validated through histology, adversely impacts upon post-operative complications and symptomatic improvement following surgery. This is a multi-centre, prospective, cross-sectional comparison of patients prior to and 9 months following surgery for chronic severe primary degenerative MR. To establish the natural history of ECV in MR, an additional cohort of patients with asymptomatic MR who do not wish to consider early repair will be followed. Investigations include CMR, cardiopulmonary exercise test, stress echocardiography, signal-averaged electrocardiogram, 24-h electrocardiogram monitoring, laboratory tests and patient-reported outcome measures. Patients undergoing surgery will have cardiac biopsies performed at the time of mitral valve repair for histological quantification of fibrosis. DISCUSSION: This study will advance our understanding of ventricular remodelling in MR, its impact on patient symptoms and ventricular response following surgery. Establishing the link between myocardial fibrosis (measured on CMR and validated through histology), with early ventricular dysfunction, will offer physicians a novel non-invasive biomarker that can further inform the timing of surgery. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov ( NCT02355418 ) on 30th November 2015.

Caveolin-1 single-nucleotide polymorphism and arterial stiffness in non-dialysis chronic kidney disease.

BACKGROUND: Arteriosclerosis is an independent predictor of increased cardiovascular mortality in chronic kidney disease (CKD). Histologically it is characterized by hypertrophy and fibrosis of the arterial media wall leading to increased arterial stiffness and end-organ damage. Caveolin-1 acts as an intracellular signalling pathway chaperone in human fibrotic and vascular diseases. The purpose of this study was to assess the association between caveolin-1 (CAV1) single-nucleotide polymorphism (SNP) rs4730751 and arterial stiffness as measured by arterial pulse wave velocity (PWV) in an early-stage CKD cohort and in a cohort with more severe CKD. METHODS: Two prospectively maintained patient cohorts with non-dialysis CKD were studied: 144 patients in the Chronic Renal Impairment in Birmingham (CRIB) cohort and 147 patients in the Renal Impairment in Secondary Care (RIISC) cohort, with matched exclusion criteria and DNA sampling availability. At entry to each cohort database, each patient's initial arterial PWV was measured, as well as their anthropomorphic and biochemical data. CAV1 rs4730751 SNP genotyping was performed using Taqman technology. RESULTS: The CAV1 rs4730751 SNP CC genotype was associated with lower arterial PWV in both CRIB early stage CKD patients [8.1 versus 8.6 m/s; coefficient -0.780 (-1.412, -0.149); P = 0.016] and RIISC more advanced stage CKD patients [8.7 versus 9.4 m/s; coefficient -0.695 (-1.288, -0.102); P = 0.022]; these relationships held following adjustment for other important confounders. CONCLUSIONS: This replicated study suggests potential utility of the studied CAV1 SNP as a genetic biomarker in CKD and a role for CAV1 in the development of arteriosclerosis in this setting. Further studies are warranted to further explore the basic science driving these clinical observations.

Mechanical effects of left ventricular midwall fibrosis in non-ischemic cardiomyopathy.

BACKGROUND: Left ventricular (LV) mid-wall fibrosis (MWF), which occurs in about a quarter of patients with non-ischemic cardiomyopathy (NICM), is associated with high risk of pump failure. The mid LV wall is the site of circumferential myocardial fibers. We sought to determine the effect of MWF on LV myocardial mechanics. METHODS: Patients with NICM (n = 116; age: 62.8 ± 13.2 years; 67% male) underwent late gadolinium enhancement cardiovascular magnetic resonance (CMR) and were categorized according to the presence (+) or absence (-) of MWF. Feature tracking (FT) CMR was used to assess myocardial deformation. RESULTS: Despite a similar LVEF (24.3 vs. 27.5%, p = 0.20), patients with MWF (32 [24%]) had lower global circumferential strain (Ɛcc: -6.6% vs. -9.4 %, P = 0.004), but similar longitudinal (Ɛll: -7.6 % vs. -9.4 %, p = 0.053) and radial (Ɛrr: 14.6% vs. 17.8% p = 0.18) strain. Compared with - MWF, + MWF was associated with reduced LV systolic, circumferential strain rate (-0.38 ± 0.1 vs. -0.56 ± 0.3 s(-1), p = 0.005) and peak LV twist (4.65 vs. 6.31°, p = 0.004), as well as rigid LV body rotation (64 % vs. 28 %, P <0.001). In addition, +MWF was associated with reduced LV diastolic strain rates (DSRcc: 0.34 vs. 0.46 s(-1); DSRll: 0.38 vs. 0.50s(-1); DSRrr: -0.55 vs. -0.75 s(-1); all p <0.05). CONCLUSIONS: MWF is associated with reduced LV global circumferential strain, strain rate and torsion. In addition, MWF is associated with rigid LV body rotation and reduced diastolic strain rates. These systolic and diastolic disturbances may be related to the increased risk of pump failure observed in patients with NICM and MWF.

The clinical outcome of cardiac resynchronization therapy in post-surgical valvular cardiomyopathy.

AIMS: Trials have shown that cardiac resynchronization therapy (CRT) is effective in patients with 'non-ischaemic cardiomyopathy'. Patients with post-surgical valvular cardiomyopathy (PSVCM) have been excluded from such trials. We sought to compare the clinical outcome of CRT in patients with PSVCM, idiopathic dilated cardiomyopathy (IDCM), or ischaemic cardiomyopathy (ICM). METHODS AND RESULTS: Clinical events and response to CRT were quantified in 556 patients (PSVCM = 38; IDCM = 165; ICM = 353) over 4.52 years [median, inter-quartile range (IQR): 4.42]. Response to CRT was defined as survival for ≥1 year free of hospitalizations plus improvement by ≥1 NYHA class or ≥25% in 6-min walking distance. Cardiac resynchronization therapy was initiated at 5.86 years (median, IQR: 9.86) after aortic valve replacement (73.7%) or mitral valve replacement/repair (44.7%). Compared with PSVCM, IDCM was associated with a lower total mortality [hazards ratio, HR: 0.54 (95% confidence interval, CI 0.34-0.84)], cardiac mortality [HR: 0.43 (95% CI 0.26-0.70)], and total mortality or major adverse cardiovascular events [HR: 0.57 (95% CI 0.37-0.87)], independent of known confounders. Compared with PSVCM, ICM was associated with a similar risk of death from pump failure [HR: 0.83 (95% CI 0.50-1.37)] and IDCM was associated with a lower risk [HR: 0.46 (95% CI 0.26-0.82)]. Response to CRT was similar across the groups. CONCLUSIONS: Compared with IDCM, PSVCM was associated with a worse outcome after CRT. Outcomes from PSVCM were similar to ICM. These findings indicate that PSVCM behaves very differently to IDCM after CRT.