Contribution of NOTCH1 genetic variants to bicuspid aortic valve and other congenital lesions.

INTRODUCTION: Bicuspid aortic valve (BAV) affects 1% of the general population. NOTCH1 was the first gene associated with BAV. The proportion of familial and sporadic BAV disease attributed to NOTCH1 mutations has not been estimated. AIM: The aim of our study was to provide an estimate of familial and sporadic BAV disease attributable to NOTCH1 mutations. METHODS: The population of our study consisted of participants of the University of Leicester Bicuspid aoRtic vAlVe gEnetic research-8 pedigrees with multiple affected family members and 381 sporadic patients. All subjects underwent NOTCH1 sequencing. A systematic literature search was performed in the NCBI PubMed database to identify publications reporting NOTCH1 sequencing in context of congenital heart disease. RESULTS: NOTCH1 sequencing in 36 subjects from 8 pedigrees identified one variant c.873C>G/p.Tyr291* meeting the American College of Medical Genetics and Genomics criteria for pathogenicity. No pathogenic or likely pathogenic NOTCH1 variants were identified in 381 sporadic patients. Literature review identified 64 relevant publication reporting NOTCH1 sequencing in 528 pedigrees and 9449 sporadic subjects. After excluding families with syndromic disease pathogenic and likely pathogenic NOTCH1 variants were detected in 9/435 (2.1%; 95% CI: 0.7% to 3.4%) of pedigrees and between 0.05% (95% CI: 0.005% to 0.10%) and 0.08% (95% CI: 0.02% to 0.13%) of sporadic patients. Incomplete penetrance of definitely pathogenic NOTCH1 mutations was observed in almost half of reported pedigrees. CONCLUSIONS: Pathogenic and likely pathogenic NOTCH1 genetic variants explain 2% of familial and <0.1% of sporadic BAV disease and are more likely to associate with tetralogy of Fallot and hypoplastic left heart.

Short-term adverse remodeling progression in asymptomatic aortic stenosis.

OBJECTIVES: Aortic stenosis (AS) is characterised by a long and variable asymptomatic course. Our objective was to use cardiovascular magnetic resonance imaging (MRI) to assess progression of adverse remodeling in asymptomatic AS. METHODS: Participants from the PRIMID-AS study, a prospective, multi-centre observational study of asymptomatic patients with moderate to severe AS, who remained asymptomatic at 12 months, were invited to undergo a repeat cardiac MRI. RESULTS: Forty-three participants with moderate-severe AS (mean age 64.4 ± 14.8 years, 83.4% male, aortic valve area index 0.54 ± 0.15 cm2/m2) were included. There was small but significant increase in indexed left ventricular (LV) (90.7 ± 22.0 to 94.5 ± 23.1 ml/m2, p = 0.007) and left atrial volumes (52.9 ± 11.3 to 58.6 ± 13.6 ml/m2, p < 0.001), with a decrease in systolic (LV ejection fraction 57.9 ± 4.6 to 55.6 ± 4.1%, p = 0.001) and diastolic (longitudinal diastolic strain rate 1.06 ± 0.2 to 0.99 ± 0.2 1/s, p = 0.026) function, but no overall change in LV mass or mass/volume. Late gadolinium enhancement increased (2.02 to 4.26 g, p < 0.001) but markers of diffuse interstitial fibrosis did not change significantly (extracellular volume index 12.9 [11.4, 17.0] ml/m2 to 13.3 [11.1, 15.1] ml/m2, p = 0.689). There was also a significant increase in the levels of NT-proBNP (43.6 [13.45, 137.08] pg/ml to 53.4 [19.14, 202.20] pg/ml, p = 0.001). CONCLUSIONS: There is progression in cardiac remodeling with increasing scar burden even in asymptomatic AS. Given the lack of reversibility of LGE post-AVR and its association with long-term mortality post-AVR, this suggests the potential need for earlier intervention, before the accumulation of LGE, to improve the long-term outcomes in AS. KEY POINTS: • Current guidelines recommend waiting until symptom onset before valve replacement in severe AS. • MRI showed clear progression in cardiac remodeling over 12 months in asymptomatic patients with AS, with near doubling in LGE. • This highlights the need for potentially earlier intervention or better risk stratification in AS.

Symptom Onset in Aortic Stenosis: Relation to Sex Differences in Left Ventricular Remodeling.

OBJECTIVES: The aim of this study was to establish sex differences in remodeling and outcome in aortic stenosis (AS) and their associations with biomarkers of myocardial fibrosis. BACKGROUND: The remodeling response and timing of symptoms is highly variable in AS, and sex plays an important role. METHODS: A total of 174 patients (133 men, mean age 66.2 ± 13.3 years) with asymptomatic moderate to severe AS underwent comprehensive stress cardiac magnetic resonance imaging, transthoracic echocardiography, and biomarker analysis (matrix metalloproteinase [MMP]-2, -3, -7, -8, and -9; tissue inhibitor matrix metalloproteinases-1 and -4; syndecan-1 and -4; and N-terminal pro-B-type natriuretic peptide), and were followed up at 6-month intervals. A primary endpoint was a composite of typical AS symptoms necessitating referral for aortic valve replacement, cardiovascular death, or major adverse cardiovascular events. RESULTS: For a similar severity of AS, male patients demonstrated higher indexed left ventricular (LV) volumes and mass, more concentric remodeling (higher LV mass/volume), a trend to more late gadolinium enhancement (present in 51.1% men vs. 34.1% women; p = 0.057), and higher extracellular volume index than female patients (13.27 [interquartile range (IQR): 11.5 to 17.0] vs. 11.53 [IQR: 10.5 to 13.5] ml/m2, p = 0.017), with worse systolic and diastolic function and higher MMP-3 and syndecan-4 levels, whereas female patients had higher septal E/e'. Male sex was independently associated with indexed LV mass (ß = 13.32 [IQR: 9.59 to 17.05]; p < 0.001). During median follow-up of 374 (IQR: 351 to 498) days, a primary outcome, driven by spontaneous symptom onset, occurred in 21.8% of male and 43.9% of female patients (relative risk: 0.50 [95% confidence interval: 0.31 to 0.80]; p = 0.004). Measures of AS severity were associated with the primary outcome in both sexes, whereas N-terminal pro-B-type natriuretic peptide, MMP-3, and mass/volume were only associated in men. CONCLUSIONS: In AS, women tolerate pressure overload with less concentric remodeling and myocardial fibrosis but are more likely to develop symptoms. This may be related to higher wall stress and filling pressures in women.

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).

Point-of-care cardiac ultrasound in acute medicine--the quick scan.

The optimum management of acute medical patients requires prompt and accurate diagnosis, monitoring and treatment. The clinical history and physical examination remain central to diagnosis, but often need supplementation by laboratory testing or imaging. Echocardiographic assessment of cardiac structure and function provides valuable information that can aid diagnosis and assess clinical progress. It has many advantages as an imaging modality, and recent technological advances have resulted in hand-held, battery-powered ultrasound devices that provide high-quality images. Three broad applications of cardiac ultrasound now exist: conventional echocardiography, focussed echocardiography and the quick-scan. A quick-scan using a hand-held ultrasound device is readily integrated into the bedside clinical assessment, providing information that can be used immediately in diagnostic reasoning; it can also guide pericardiocentesis. Hand-held ultrasound devices can also be used in acute situations, as well as geographically remote areas or special situations (eg disaster zones) where other imaging is not available. However, the diagnostic yield of echocardiography is user dependent, and training is required for its benefits to be realised, adding to the hardware costs. More data are needed on the incremental value of hand-held ultrasonography and a quick-scan over conventional methods of assessment, their impact on clinical outcomes, and cost effectiveness.

Successful low-dose thrombolysis of submassive pulmonary embolus in a pregnant patient.

Low-dose thrombolysis was effective and safe in a pregnant woman with acute pulmonary embolism causing severe right ventricular dysfunction. This is the first reported case of successful thrombolysis for pulmonary embolus in pregnancy in the absence of shock.

A study of role expansion: a new GP role in cardiology care.

BACKGROUND: The National Health Service is reconfiguring health care services in order to meet the increasing challenge of providing care for people with long-term conditions and to reduce the demand on specialised outpatient hospital services by enhancing primary care. A review of cardiology referrals to specialised care and the literature on referral management inspired the development of a new GP role in Cardiology. This new extended role was developed to enable GPs to diagnose and manage patients with mild to moderate heart failure or atrial fibrillation and to use a range of diagnostics effectively in primary care. This entailed GPs participating in a four-session short course with on-going clinical supervision. The new role was piloted in a small number of GP practices in one county in England for four months. This study explores the impact of piloting the Extended Cardiology role on the GP's role, patients' experience, service delivery and quality. METHODS: A mixed methods approach was employed including semi-structured interviews with GPs, a patient experience survey, a quality review of case notes, and analysis on activity and referral data. RESULTS: The participating GPs perceived the extended GP role as a professional development opportunity that had the potential to reduce healthcare utilisation and costs, through a reduction in referrals, whilst meeting the patient's wishes for the provision of care closer to home. Patient experience of the new GP service was positive. The standard of clinical practice was judged acceptable. There was a fall in referrals during the study period. CONCLUSION: This new role in cardiology was broadly welcomed as a model of care by the participating GPs and by patients, because of the potential to improve the quality of care for patients in primary care and reduce costs. As this was a pilot study further development and continuing evaluation of the model is recommended.

Developing a rapid access chest pain clinic: qualitative studies of patients' needs and experiences.

OBJECTIVE: The aims of this study are to understand the needs and experiences of rapid access chest pain clinic attenders and to determine the acceptability and effectiveness of simple procedural changes. METHODS: Two qualitative studies of clinic attenders before and after procedural changes which were guided by the first study. RESULTS: Study 1: Patients wanted to be reassured, by knowing what was causing their pain, understanding the cause, and feeling able to help themselves. Often, these needs were not met, and uncertainties left some patients feeling ill-equipped to help themselves. Communication problems were identified. Study 2: The changes were acceptable to patients, and almost all were reassured. Most valued receiving extra verbal and written advice and information. Many felt more aware of cardiac risk factors and intended to change their lifestyle. CONCLUSION: There were clear opportunities for improvements in care. Changes in procedures helped patients to understand their pain, to practice self-management, and to consider altering their lifestyle.

Revascularization for acute coronary syndromes in older people.

BACKGROUND: randomised controlled trials have demonstrated that early revascularisation improves outcome in patients with acute coronary syndromes. However, since older people were excluded from these trials, it is not known whether the findings are applicable to them. OBJECTIVES: to evaluate the outcome of revascularisation by percutaneous coronary intervention or coronary artery bypass surgery in older people with acute coronary syndromes. To determine the factors which predict outcome of revascularisation in these patients. DESIGN: systematic review of studies obtained from the Medline and Embase electronic databases and through bibliographic searches. Analysis by descriptive overview and statistical meta-analysis using pooled proportions. INCLUDED STUDIES: studies published from 1990 onwards describing the outcome of percutaneous coronary intervention or coronary artery bypass surgery in patients 75 or 80 years, of whom 75% or more were classified as unstable angina. Studies published from 1990 onwards describing the factors predicting outcome of percutaneous coronary intervention or coronary artery bypass surgery in all patients 75 or 80 years. RESULTS: 26 studies were included. In-hospital mortality from percutaneous coronary intervention was 5.4% (95% confidence interval 3.9% to 7.0%) and after coronary artery bypass surgery was 12.1% (9.5% to 14.7%). Large observational studies indicate expected 30-day mortality of 6-12% with medical treatment. Serious complications following percutaneous coronary intervention were rare, but there was a high rate of major adverse cardiac events over the following year. Major complications, including stroke, were common after coronary artery bypass. However, long-term survival and functional outcome in those who survived the peri-operative period were excellent. Clinical variables predicted those at highest risk from both percutaneous coronary intervention and coronary artery bypass. CONCLUSIONS: percutaneous coronary intervention offers an attractive option for the management of older people with acute coronary syndromes and may improve outcome over conservative treatment. In contrast, coronary artery bypass carries a substantial mortality and morbidity, and is likely to be reserved for patients with refractory symptoms unsuitable for percutaneous intervention. Further data from randomised controlled trials are required.