Physical Activity, Inactivity and Sleep in Individuals with Hypertrophic Cardiomyopathy.

Physical activity presents an important cornerstone in the management and care of individuals with hypertrophic cardiomyopathy (HCM). Twenty-one individuals with HCM (age: 52±15 years old, body mass index (BMI): 30±7 kg/m2) completed 7-day monitoring using wrist-worn triaxial accelerometers (GENEActiv, ActivInsights Ltd, UK) and were compared to age and sex-matched healthy controls (age: 51±14 years old, BMI: 25±4 kg/m2). For individuals with HCM, clinical parameters (left atrial diameter and volume, peak oxygen consumption, NTproBNP and Minnesota Living with Heart Failure (MLHF)) were correlated with accelerometry. After adjusting for BMI, individuals with HCM spent less time in moderate-vigorous physical activity (MVPA) (86 (55-138) vs. 140 (121-149) minutes/day, p<0.05) compared to healthy controls. Individuals with HCM engaged in fewer MVPA-5 min (6 (2-15) vs. 27 (23-37) minutes/day, p<0.01) and MVPA-10 min bouts (9 (0-19) vs. 35 (17-54) minutes/day, p<0.01) versus healthy controls. For HCM only, peak oxygen consumption was correlated with MVPA (r=0.60, p<0.01) and MVPA-5 min bouts (r=0.47, p<0.05). MLHF score was correlated with sleep duration (r=0.45, p<0.05). Individuals with HCM should be encouraged to engage in moderate-intensity physical activity bouts and reduce prolonged periods of inactivity in order to potentially improve exercise tolerance and reduce disease burden.

Haemodynamic determinants of quality of life in chronic heart failure.

BACKGROUND: Heart failure patients demonstrate reduced functional capacity, hemodynamic function, and quality of life (QOL) which are associated with high mortality and morbidity rate. The aim of the present study was to assess the relationship between functional capacity, hemodynamic response to exercise and QOL in chronic heart failure. METHODS: A single-centre prospective study recruited 42 chronic heart failure patients (11 females, mean age 60 ± 10 years) with reduced left ventricular ejection fraction (LVEF = 23 ± 7%). All participants completed a maximal graded cardiopulmonary exercise test with non-invasive hemodynamic (bioreactance) monitoring. QOL was assessed using Minnesota Living with Heart Failure Questionnaire. RESULTS: The average value of QOL score was 40 ± 23. There was a significant negative relationship between the QOL and peak O2 consumption (r = - 0.50, p ≤ 0.01). No significant relationship between the QOL and selected exercise hemodynamic measures was found, including peak exercise cardiac power output (r = 0.15, p = 0.34), cardiac output (r = 0.22, p = 0.15), and mean arterial blood pressure (r = - 0.08, p = 0.60). CONCLUSION: Peak O2 consumption, but not hemodynamic response to exercise, is a significant determinant of QOL in chronic heart failure patients.

Feasibility of the cardiac output response to stress test in suspected heart failure patients.

BACKGROUND: Diagnostic tools available to support general practitioners diagnose heart failure (HF) are limited. OBJECTIVES: (i) Determine the feasibility of the novel cardiac output response to stress (CORS) test in suspected HF patients, and (ii) Identify differences in the CORS results between (a) confirmed HF patients from non-HF patients, and (b) HF reduced (HFrEF) vs HF preserved (HFpEF) ejection fraction. METHODS: Single centre, prospective, observational, feasibility study. Consecutive patients with suspected HF (N = 105; mean age: 72 ± 10 years) were recruited from specialized HF diagnostic clinics in secondary care. The consultant cardiologist confirmed or refuted a HF diagnosis. The patient completed the CORS but the researcher administering the test was blinded from the diagnosis. The CORS assessed cardiac function (stroke volume index, SVI) noninvasively using the bioreactance technology at rest-supine, challenge-standing, and stress-step exercise phases. RESULTS: A total of 38 patients were newly diagnosed with HF (HFrEF, n = 21) with 79% being able to complete all phases of the CORS (91% of non-HF patients). A 17% lower SVI was found in HF compared with non-HF patients at rest-supine (43 ± 15 vs 51 ± 16 mL/beat/m2, P = 0.02) and stress-step exercise phase (49 ± 16 vs 58 ± 17 mL/beat/m2, P = 0.02). HFrEF patients demonstrated a lower SVI at rest (39 ± 15 vs 48 ± 13 mL/beat/m2, P = 0.02) and challenge-standing phase (34 ± 9 vs 42 ± 12 mL/beat/m2, P = 0.03) than HFpEF patients. CONCLUSION: The CORS is feasible and patients with HF responded differently to non-HF, and HFrEF from HFpEF. These findings provide further evidence for the potential use of the CORS to improve HF diagnostic and referral accuracy in primary care.

Heart failure (HF) is a global pandemic affecting 26 million people worldwide with an estimated 1 million people in the United Kingdom. Accurate early diagnosis of HF and the initiation of evidence-based treatment is essential to reduce morbidity and mortality and the associated burden on healthcare. As there are no state-of-the-art approaches, early diagnosis is challenging and often inaccurate, as initial signs and symptoms are nonspecific. We have developed an innovative test, named CORS (cardiac output response to stress test), to help general practitioners identify HF, which uses a method similar to an electrocardiogram and measures heart function at rest and during short step exercise. We recruited suspected HF patients from specialist HF diagnostic clinics in secondary care to complete the CORS test. We successfully demonstrated that 79% of patients with newly diagnosed HF (n = 38) and 91% of non-HF patients (n = 67) were able to complete all phases of the CORS test. Our findings demonstrate that newly diagnosed HF patients are able to complete this test, which provides further evidence for the potential use of the CORS test to improve HF diagnostic and referral accuracy in primary care.

Association between heart rate variability and haemodynamic response to exercise in chronic heart failure.

OBJECTIVES: Heart rate variability (HRV) and haemodynamic response to exercise (i.e. peak cardiac power output) are strong predictors of mortality in heart failure. The present study assessed the relationship between measures of HRV and peak cardiac power output. DESIGN: In a prospective observational study of 33 patients (age 54 ± 16 years) with chronic heart failure with reduced left ventricular ejection fraction (29 ± 11%), measures of the HRV (i.e. R-R interval and standard deviation of normal R-R intervals, SDNN) were recorded in a supine position. All patients underwent maximal graded cardiopulmonary exercise testing with non-invasive (inert gas rebreathing) cardiac output assessment. Cardiac power output, expressed in watts, was calculated as the product of cardiac output and mean arterial blood pressure. RESULTS: The mean RR and SDNN were 837 ± 166 and 96 ± 29 ms, peak exercise cardiac power output 2.28 ± 0.85 watts, cardiac output 10.34 ± 3.14 L/min, mean arterial blood pressure 98 ± 14 mmHg, stroke volume 91.43 ± 40.77 mL/beat, and oxygen consumption 19.0 ± 5.6 mL/kg/min. There was a significant but only moderate relationship between the RR interval and peak exercise cardiac power output (r = 0.43, p = .013), cardiac output (r = 0.35, p = .047), and mean arterial blood pressure (r = 0.45, p = .009). The SDNN correlated with peak cardiac power output (r = 0.42, p = .016), mean arterial blood arterial (r = 0.41, p = .019), and stroke volume (r = 0.35, p = .043). CONCLUSIONS: Moderate strength of the relationship between measures of HRV and cardiac response to exercise suggests that cardiac autonomic function is not good indicator of overall function and pumping capability of the heart in chronic heart failure.

Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.

Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.

Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.

Heart rate variability and haemodynamic function in individuals with hypertrophic cardiomyopathy.

OBJECTIVES: Heart rate variability (HRV) is a measure of cardiac autonomic function. This study: (1) evaluated the differences in HRV and haemodynamic function between individuals with hypertrophic cardiomyopathy (HCM) and healthy controls, and (2) determined the relationship between HRV and haemodynamic variables in individuals with HCM. METHODS: Twenty-eight individuals with HCM (n = 7, females; age 54 ± 15 years; body mass index: 29 ± 5 kg/m2 ) and 28 matched healthy individuals (n = 7 females; age 54 ± 16 years; body mass index: 29 ± 5 kg/m2 ) completed 5-min HRV and haemodynamic measurements under resting (supine) conditions using bioimpedance technology. Frequency domain HRV measures (absolute and normalized low-frequency power (LF), high-frequency power (HF) and LF/HF ratio) and RR interval were recorded. RESULTS: Individuals with HCM demonstrated higher vagal activity (i.e., absolute unit of HF power (7.40 ± 2.50 vs. 6.03 ± 1.35 ms2 , p = 0.01) but lower RR interval (914 ± 178 vs. 1014 ± 168 ms, p = 0.03) compared to controls. Stroke volume (SV) index and cardiac index were lower in HCM compared with healthy individuals (SV, 33 ± 9 vs. 43 ± 7 ml /beat /m², p < 0.01; cardiac index,2.33 ± 0.42 vs. 3.57 ± 0.82 L/min/m2 , p < 0.01), but total peripheral resistance (TPR) was higher in HCM (3468 ± 1027 vs. 2953 ± 1050 dyn·s·m2 cm-5 , p = 0.03). HF power was significantly related to SV (r = -0.46, p < 0.01) and TPR (r = 0.28, p < 0.05) in HCM. CONCLUSIONS: Short-term frequency domain indices of HRV provide a feasible approach to assess autonomic function in individuals with HCM. Vagal activity, represented by HF power, is increased, and associated with peripheral resistance in individuals with HCM.

Change in serum lipids after acute coronary syndromes: secondary analysis of SPACE ROCKET study data and a comparative literature review.

BACKGROUND: It has long been an accepted belief that serum cholesterol significantly falls after myocardial infarction and that a return to pre-event levels takes approximately 3 months. The magnitude and clinical significance of this fall has recently been challenged. METHODS: In the Secondary Prevention of Acute Coronary Events-Reduction Of Cholesterol to Key European Targets (SPACE ROCKET) trial, we measured serum lipids of individuals on day 1 and between days 2 and 4 after acute myocardial infarction (AMI). Second, we performed a thorough literature review and compared all studies reporting data on absolute changes in lipids immediately after AMI, using weighted means. RESULTS: Of 1263 SPACE ROCKET participants, 128 had paired lipid measurements where both samples had been measured using identical methods at baseline and on days 2-4 after AMI. The mean lowering in total cholesterol between day 1 and day 2-4 was 0.71 mmol/L (95% CI 0.58-0.84; P < 0.0001) and in triglycerides was 0.10 mmol/L (-0.14-0.33; P = 0.405). A total of 25 papers showing absolute lipid changes post-AMI were identified. The combined data demonstrated a mean fall in total cholesterol of 9% to 11% from baseline over days 3-14 post-AMI, whereas for triglycerides, there was a rise of 18% from baseline to between day 9 and 12 weeks. CONCLUSIONS: After a secondary analysis of SPACE ROCKET data and a comparison of previously published data, we report a 10% fall in total cholesterol after AMI-a difference that is of high clinical significance. Consequently, measurement of serum lipids in patients with AMI should be performed within the first hours after presentation.

Overcoming barriers to engagement and adherence to a home-based physical activity intervention for patients with heart failure: a qualitative focus group study.

OBJECTIVES: Clinical guidelines recommend regular physical activity for patients with heart failure to improve functional capacity and symptoms and to reduce hospitalisation. Cardiac rehabilitation programmes have demonstrated success in this regard; however, uptake and adherence are suboptimal. Home-based physical activity programmes have gained popularity to address these issues, although it is acknowledged that their ability to provide personalised support will impact on their effectiveness. This study aimed to identify barriers and facilitators to engagement and adherence to a home-based physical activity programme, and to identify ways in which it could be integrated into the care pathway for patients with heart failure. DESIGN: A qualitative focus group study was conducted. Data were analysed using thematic analysis. PARTICIPANTS: A purposive sample of 16 patients, 82% male, aged 68±7 years, with heart failure duration of 10±9 years were recruited. INTERVENTION: A 12-week behavioural intervention targeting physical activity was delivered once per week by telephone. RESULTS: Ten main themes were generated that provided a comprehensive overview of the active ingredients of the intervention in terms of engagement and adherence. Fear of undertaking physical activity was reported to be a significant barrier to engagement. Influences of family members were both barriers and facilitators to engagement and adherence. Facilitators included endorsement of the intervention by clinicians knowledgeable about physical activity in the context of heart failure; ongoing support and personalised feedback from team members, including tailoring to meet individual needs, overcome barriers and increase confidence. CONCLUSIONS: Endorsement of interventions by clinicians to reduce patients' fear of undertaking physical activity and individual tailoring to overcome barriers are necessary for long-term adherence. Encouraging family members to attend consultations to address misconceptions and fear about the contraindications of physical activity in the context of heart failure should be considered for adherence, and peer-support for long-term maintenance. TRIAL REGISTRATION NUMBER: NCT03677271.

A randomized, controlled trial of simvastatin versus rosuvastatin in patients with acute myocardial infarction: the Secondary Prevention of Acute Coronary Events--Reduction of Cholesterol to Key European Targets Trial.

AIMS: We sought to evaluate reports that rosuvastatin 10 mg is a more efficacious treatment of hyperlipidaemia than is simvastatin 40 mg, hoping to assess this issue in the previously unstudied context of acute myocardial infarction. METHODS AND RESULTS: The Secondary Prevention of Acute Coronary Events - Reduction of Cholesterol to Key European Targets (SPACE ROCKET) Trial was an investigator-led, open-label, blinded-endpoint, multicentre, randomized, controlled trial assessing the proportion of patients, at 3 months, achieving European Society of Cardiology 2003 (ESC-03) lipid targets of total cholesterol (TC) less than 4.5 mmol/l (174 mg/dl) or low-density lipoprotein cholesterol (LDLc) less than 2.5 mmol/l (97 mg/dl). Of 1263 patients randomized, 77.6% simvastatin versus 79.9% rosuvastatin achieved ESC-03 targets [odds ratio (OR): 1.16; 95% confidence interval (CI): 0.88-1.53; P = 0.29]. There were statistically significant differences for simvastatin versus rosuvastatin, respectively, for mean LDLc 2.03 mmol/l (78 mg/dl) versus 1.94 mmol/l (75 mg/dl; P = 0.009) and also mean TC 3.88 mmol/l (150 mg/dl) versus 3.75 mmol/l (145 mg/dl; P = 0.005). A post-hoc analysis showed higher achievement of the new ESC, American Heart Association and American College of Cardiology optimal lipid target of LDLc less than 1.81 mmol/l (70 mg/dl) with rosuvastatin (45.0%) compared with simvastatin (37.8%; OR: 1.37; 95% CI: 1.09-1.72; P = 0.007). The proportion of patients achieving the Fourth Joint Task Force European Guidelines (2007) of TC less than 4.0 mmol/l (155 mg/dl) and LDLc less than 2.0 mmol/l (77 mg/dl) was 38.7% for simvastatin 40 mg and 47.7% for rosuvastatin 10 mg (OR: 1.48; 95% CI: 1.18-1.86; P = 0.001). CONCLUSION: We observed no superiority of either treatment for the ESC-03 lipid targets. Rosuvastatin 10 mg lowered mean cholesterol more effectively than simvastatin and achieved better results for the latest, more stringent, ESC target.

NT-proBNP is a weak indicator of cardiac function and haemodynamic response to exercise in chronic heart failure.

AIMS: N-terminal prohormone of brain natriuretic peptide (NT-proBNP) plays an important role in diagnosis and management of heart failure. The aim of the present study was to assess haemodynamic response to exercise and to evaluate the relationship between NT-proBNP, cardiac function, and exercise tolerance in chronic heart failure. METHODS AND RESULTS: A single-centre, cross-sectional pilot study recruited 17 patients with chronic heart failure with reduced left ventricular ejection fraction (age 67 ± 7 years) and 20 healthy volunteers (age 65 ± 12 years). The NT-proBNP was measured in the heart failure group. All participants completed maximal graded cardiopulmonary exercise stress testing coupled with gas exchange (using metabolic analyser for determination of exercise tolerance, i.e. peak O2 consumption) and continuous haemodynamic measurements (i.e. cardiac output and cardiac power output) using non-invasive bioreactance technology. Heart failure patients demonstrated significantly lower peak exercise cardiac function and exercise tolerance than healthy controls, i.e. cardiac power output (5.0 ± 2.0 vs. 3.2 ± 1.2 W, P < 0.01), cardiac output (18.2 ± 6.3 vs. 13.5 ± 4.0 L/min, P < 0.01), heart rate (148 ± 23.7 vs. 111 ± 20.9 beats/min, P < 0.01), and oxygen consumption (24.3 ± 9.5 vs. 16.8 ± 3.8 mL/kg/min, P < 0.01). There was no significant relationship between NT-proBNP and cardiac function at rest, i.e. cardiac power output (r = -0.28, P = 0.28), cardiac output (r = -0.18, P = 0.50), and oxygen consumption (r = -0.18, P = 0.50), or peak exercise, i.e. cardiac power output (r = 0.18, P = 0.49), cardiac output (r = 0.13, P = 0.63), and oxygen consumption (r = -0.05, P = 0.84). CONCLUSIONS: Lack of a significant and strong relationship between the NT-proBNP and measures of cardiac function and exercise tolerance may suggest that natriuretic peptides should be considered with caution in interpretation of the severity of cardiac dysfunction and functional capacity in chronic heart failure.

Acceptability, Feasibility and Preliminary Evaluation of a Novel, Personalised, Home-Based Physical Activity Intervention for Chronic Heart Failure (Active-at-Home-HF): a Pilot Study.

PURPOSE: Less than 10% of heart failure patients in the UK participate in cardiac rehabilitation programmes. The present pilot study evaluated feasibility, acceptability and physiological effects of a novel, personalised, home-based physical activity intervention in chronic heart failure. METHODS: Twenty patients (68 ± 7 years old, 20% females) with stable chronic heart failure due to reduced left ventricular ejection fraction (31 ± 8 %) participated in a single-group, pilot study assessing the feasibility and acceptability of a 12-week personalised home-based physical activity intervention aiming to increase daily number of steps by 2000 from baseline (Active-at-Home-HF). Patients completed cardiopulmonary exercise testing with non-invasive gas exchange and haemodynamic measurements and quality of life questionnaire pre- and post-intervention. Patients were supported weekly via telephone and average weekly step count data collected using pedometers. RESULTS: Forty-three patients were screened and 20 recruited into the study. Seventeen patients (85%) completed the intervention, and 15 (75%) achieved the target step count. Average step count per day increased significantly from baseline to 3 weeks by 2546 (5108 ± 3064 to 7654 ± 3849, P = 0.03, n = 17) and was maintained until week 12 (9022 ± 3942). Following completion of the intervention, no adverse events were recorded and quality of life improved by 4 points (26 ± 18 vs. 22 ± 19). Peak exercise stroke volume increased by 19% (127 ± 34 vs. 151 ± 34 m/beat, P = 0.05), while cardiac index increased by 12% (6.8 ± 1.5 vs. 7.6 ± 2.0 L/min/m2, P = 0.19). Workload and oxygen consumption at anaerobic threshold also increased by 16% (49 ± 16 vs. 59 ± 14 watts, P = 0.01) and 10% (11.5 ± 2.9 vs. 12.8 ± 2.2 ml/kg/min, P = 0.39). CONCLUSION: The Active-at-Home-HF intervention is feasible, acceptable and effective for increasing physical activity in CHF. It may lead to improvements in quality of life, exercise tolerance and haemodynamic function. TRIAL REGISTRATION: www.clinicaltrials.gov NCT0367727. Retrospectively registered on 17 September 2018.

Prospective evaluation and long-term follow-up of patients referred to secondary care based upon natriuretic peptide levels in primary care.

AIMS: The UK National Institute for Health and Care Excellence (UK-NICE) and European Society of Cardiology (ESC) guidelines advise natriuretic peptide (NP) assessment in patients presenting to primary care with symptoms possibly due to chronic heart failure (HF), to determine need for specialist involvement. This prospective service evaluation aimed to describe the diagnostic and prognostic utility of these guidelines. METHODS AND RESULTS: We prospectively collected clinical, echocardiography and outcomes data (minimum 5 years) from all patients referred to the Leeds HF Service for 12 months of following the initiation of the NP-guideline-directed pathway. Between 1 May 2012 and 1 August 2013, 1020 people with symptoms possibly due to HF attended either with a raised NT-pro-BNP or a previous myocardial infarction (MI) with an overall rate of left ventricular systolic dysfunction (LVSD) of 33%. Of these, 991 satisfied the ESC criteria (NT-pro-BNP ≥125 pg/mL) in whom the rate of LVSD was 32%, and 821 the UK-NICE criteria in whom the rate of LVSD was 49% in those with a previous MI, 25% in those with NT-pro-BNP concentration 400-2000 pg/mL, and 54% in those with NT-pro-BNP concentration of >2000 pg/mL. An NT-pro-BNP concentration 125-400 pg/mL had a 12% risk of LVSD. Specificity was poor in women >70 years, who made up the largest proportion of attendees. Elevated NT-pro-BNP levels were associated with lower survival even in the absence of LVSD. CONCLUSION: In people referred through the ESC and UK-NICE guidelines, elevated NT-pro-BNP is a marker of increased mortality risk, but there is wide variation in specificity for LVSD. Age- and sex-adjusted criteria might improve performance.

A novel cardiac output response to stress test developed to improve diagnosis and monitoring of heart failure in primary care.

AIMS: Primary care physicians lack access to an objective cardiac function test. This study for the first time describes a novel cardiac output response to stress (CORS) test developed to improve diagnosis and monitoring of heart failure in primary care and investigates its reproducibility. METHODS AND RESULTS: Prospective observational study recruited 32 consecutive primary care patients (age, 63 ± 9 years; female, n = 18). Cardiac output was measured continuously using the bioreactance method in supine and standing positions and during two 3 min stages of a step-exercise protocol (10 and 15 steps per minute) using a 15 cm height bench. The CORS test was performed on two occasions, i.e. Test 1 and Test 2. There was no significant difference between repeated measures of cardiac output and stroke volume at supine standing and Stage 1 and Stage 2 step exercises (all P > 0.3). There was a significant positive relationship between Test 1 and Test 2 cardiac outputs (r = 0.92, P = 0.01 with coefficient of variation of 7.1%). The mean difference in cardiac output (with upper and lower limits of agreement) between Test 1 and Test 2 was 0.1 (-1.9 to 2.1) L/min, combining supine, standing, and step-exercise data. CONCLUSIONS: The CORS, as a novel test for objective evaluation of cardiac function, demonstrates acceptable reproducibility and can potentially be implemented in primary care.

Hepatic metabolism and transporter gene variants enhance response to rosuvastatin in patients with acute myocardial infarction: the GEOSTAT-1 Study.

BACKGROUND: Pharmacogenetics aims to maximize benefits and minimize risks of drug treatment. Our objectives were to examine the influence of common variants of hepatic metabolism and transporter genes on the lipid-lowering response to statin therapy. METHODS AND RESULTS: The Genetic Effects On STATins (GEOSTAT-1) Study was a genetic substudy of Secondary Prevention of Acute Coronary Events-Reduction of Cholesterol to Key European Targets (SPACE ROCKET) (a randomized, controlled trial comparing 40 mg of simvastatin and 10 mg of rosuvastatin) that recruited 601 patients after myocardial infarction. We genotyped the following functional single nucleotide polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes, CYP2C9*2 (430C>T), CYP2C9*3 (1075A>C), CYP2C19*2 (681G>A), CYP3A5*1 (6986A>G), and hepatic influx and efflux transporters SLCO1B1 (521T>C) and breast cancer resistance protein (BCRP; 421C>A). We assessed 3-month LDL cholesterol levels and the proportion of patients reaching the current LDL cholesterol target of <70 mg/dL (<1.81 mmol/L). An enhanced response to rosuvastatin was seen for patients with variant genotypes of either CYP3A5 (P=0.006) or BCRP (P=0.010). Furthermore, multivariate logistic-regression analysis revealed that patients with at least 1 variant CYP3A5 and/or BCRP allele (n=186) were more likely to achieve the LDL cholesterol target (odds ratio: 2.289; 95% CI: 1.157, 4.527; P=0.017; rosuvastatin 54.0% to target vs simvastatin 33.7%). There were no differences for patients with variants of CYP2C9, CYP2C19, or SLCO1B1 in comparison with their respective wild types, nor were differential effects on statin response seen for patients with the most common genotypes for CYP3A5 and BCRP (n=415; odds ratio: 1.207; 95% CI: 0.768, 1.899; P=0.415). CONCLUSION: The LDL cholesterol target was achieved more frequently for the 1 in 3 patients with CYP3A5 and/or BCRP variant genotypes when prescribed rosuvastatin 10 mg, compared with simvastatin 40 mg. Clinical Trial Registration- URL: http://isrctn.org. Unique identifier: ISRCTN 89508434.