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Assessment of Omecamtiv Mecarbil for the Treatment of Patients With Severe Heart Failure: A Post Hoc Analysis of Data From the GALACTIC-HF Randomized Clinical Trial.
Felker, GM, Solomon, SD, Claggett, B, Diaz, R, McMurray, JJV, Metra, M, Anand, I, Crespo-Leiro, MG, Dahlström, U, Goncalvesova, E, et al
JAMA cardiology. 2022;(1):26-34
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Abstract
IMPORTANCE Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients' condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies. OBJECTIVE To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial. DESIGN, SETTING, AND PARTICIPANTS The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months. INTERVENTIONS Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo. MAIN OUTCOMES AND MEASURES The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability. RESULTS Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08; P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25]; P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo. CONCLUSIONS AND RELEVANCE In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02929329.
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Short-Term RCT of Increased Dietary Potassium from Potato or Potassium Gluconate: Effect on Blood Pressure, Microcirculation, and Potassium and Sodium Retention in Pre-Hypertensive-to-Hypertensive Adults.
Stone, MS, Martin, BR, Weaver, CM
Nutrients. 2021;(5)
Abstract
Increased potassium intake has been linked to improvements in cardiovascular and other health outcomes. We assessed increasing potassium intake through food or supplements as part of a controlled diet on blood pressure (BP), microcirculation (endothelial function), and potassium and sodium retention in thirty pre-hypertensive-to-hypertensive men and women. Participants were randomly assigned to a sequence of four 17 day dietary potassium treatments: a basal diet (control) of 60 mmol/d and three phases of 85 mmol/d added as potatoes, French fries, or a potassium gluconate supplement. Blood pressure was measured by manual auscultation, cutaneous microvascular and endothelial function by thermal hyperemia, utilizing laser Doppler flowmetry, and mineral retention by metabolic balance. There were no significant differences among treatments for end-of-treatment BP, change in BP over time, or endothelial function using a mixed-model ANOVA. However, there was a greater change in systolic blood pressure (SBP) over time by feeding baked/boiled potatoes compared with control (-6.0 mmHg vs. -2.6 mmHg; p = 0.011) using contrast analysis. Potassium retention was highest with supplements. Individuals with a higher cardiometabolic risk may benefit by increasing potassium intake. This trial was registered at ClinicalTrials.gov as NCT02697708.
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A Smartphone Intervention to Promote Time Restricted Eating Reduces Body Weight and Blood Pressure in Adults with Overweight and Obesity: A Pilot Study.
Prasad, M, Fine, K, Gee, A, Nair, N, Popp, CJ, Cheng, B, Manoogian, ENC, Panda, S, Laferrère, B
Nutrients. 2021;(7)
Abstract
The goal of this study was to test the feasibility of time restricted eating (TRE) in adults with overweight and obesity. Participants (n = 50) logged all eating occasions (>0 kcal) for a 2-week run-in period using a smartphone application. Participants with eating duration ≥14 h enrolled in an open label, non-randomized, prospective 90-day TRE intervention, with a self-selected reduced eating window of 10 h. No dietary counseling was provided. Changes in anthropometrics, eating patterns and adherence after TRE were analyzed using t-tests or Wilcoxon Rank-Sum Test. The mean duration of the baseline eating window was 14 h 32 m ± 2 h 36 m (n = 50) with 56% of participants with duration ≥14 h. TRE participants (n = 16) successfully decreased their eating window from 16 h 04 m ± 1 h 24 m to 11 h 54 m ± 2 h 06 m (p < 0.001), and reduced the number of daily eating occasions by half (p < 0.001). Adherence to logging and to the reduced eating window was 64% ± 22% and 47% ± 19%, respectively. TRE resulted in decreases in body weight (-2.1 ± 3.0 kg, p = 0.017), waist circumference (-2.2 ± 4.6 cm, p = 0.002) and systolic blood pressure (-12 ± 11 mmHg, p = 0.002). This study demonstrates the feasibility and efficacy of TRE administered via a smartphone, in adults with overweight and obesity.
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Mindfulness and cardiovascular health: Qualitative findings on mechanisms from the mindfulness-based blood pressure reduction (MB-BP) study.
Nardi, WR, Harrison, A, Saadeh, FB, Webb, J, Wentz, AE, Loucks, EB
PloS one. 2020;(9):e0239533
Abstract
BACKGROUND Mindfulness-based programs hold promise for improving cardiovascular health (e.g. physical activity, diet, blood pressure). However, despite theoretical frameworks proposed, no studies have reported qualitative findings on how study participants themselves believe mindfulness-based programs improved their cardiovascular health. With an emphasis on in-depth, open-ended investigation, qualitative methods are well suited to explore the mechanisms underlying health outcomes. The objective of this qualitative study was to explore the mechanisms through which the mindfulness-based program, Mindfulness-Based Blood Pressure Reduction (MB-BP), may influence cardiovascular health. METHODS This qualitative study was conducted as part of a Stage 1 single arm trial with one-year follow-up. The MB-BP curriculum was adapted from Mindfulness-Based Stress Reduction to direct participants' mindfulness skills towards modifiable determinants of blood pressure. Four focus group discussions were conducted (N = 19 participants), and seven additional participants were selected for in-depth interviews. Data analysis was conducted using the standard approach of thematic analysis. Following double-coding of audio-recorded transcripts, four members of the study team engaged in an iterative process of data analysis and interpretation. RESULTS Participants identified self-awareness, attention control, and emotion regulation as key mechanisms that led to improvements in cardiovascular health. Within these broader themes, many participants detailed a process beginning with increased self-awareness to sustain attention and regulate emotions. Many also explained that the specific relationship between self-awareness and emotion regulation enabled them to respond more skillfully to stressors. In a secondary sub-theme, participants suggested that higher self-awareness helped them engage in positive health behaviors (e.g. healthier dietary choices). CONCLUSION Qualitative analyses suggest that MB-BP mindfulness practices allowed participants to engage more effectively in self-regulation skills and behaviors lowering cardiovascular disease risk, which supports recent theory. Results are consistent with quantitative mechanistic findings showing emotion regulation, perceived stress, interoceptive awareness, and attention control are influenced by MB-BP.
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Hemodynamic and perceptual responses to blood flow-restricted exercise among patients undergoing dialysis.
Clarkson, MJ, Brumby, C, Fraser, SF, McMahon, LP, Bennett, PN, Warmington, SA
American journal of physiology. Renal physiology. 2020;(3):F843-F850
Abstract
End-stage kidney disease is associated with reduced exercise capacity, muscle atrophy, and impaired muscle function. While these may be improved with exercise, single modalities of exercise do not traditionally elicit improvements across all required physiological domains. Blood flow-restricted exercise may improve all of these physiological domains with low intensities traditionally considered insufficient for these adaptions. Investigation of this technique appeals, but is yet to be evaluated, in patients undergoing dialysis. With the use of a progressive crossover design, 10 satellite patients undergoing hemodialysis underwent three exercise conditions over 2 wk: two bouts (10 min) of unrestricted cycling during two consecutive hemodialysis sessions (condition 1), two bouts of cycling with blood flow restriction while off hemodialysis on 2 separate days (condition 2), and two bouts of cycling with blood flow restriction during two hemodialysis sessions (condition 3). Outcomes included hemodynamic responses (heart rate and blood pressure) throughout all sessions, participant-perceived exertion and discomfort on a Borg scale, and evaluation of ultrafiltration rates and dialysis adequacy (Kt/V) obtained post hoc. Hemodynamic responses were consistent regardless of condition. Significant increases in heart rate, systolic blood pressure, and mean arterial blood pressure (P < 0.05) were observed postexercise followed by a reduction in blood pressures during the 60-min recovery (12, 5, and 11 mmHg for systolic, diastolic, and mean arterial pressures, respectively). Blood pressures returned to predialysis ranges following the recovery period. Blood flow restriction did not affect ultrafiltration achieved or Kt/V. Hemodynamic safety and tolerability of blood flow restriction during aerobic exercise on hemodialysis is comparable to standard aerobic exercise.
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Randomised, double-blind, placebo-controlled clinical trial investigating the effects of inorganic nitrate in hypertension-induced target organ damage: protocol of the NITRATE-TOD study in the UK.
Lau, CWZ, Hamers, AJP, Rathod, KS, Shabbir, A, Cooper, J, Primus, CP, Davies, C, Mathur, A, Moon, JC, Kapil, V, et al
BMJ open. 2020;(1):e034399
Abstract
INTRODUCTION Arterial stiffness and left ventricular (LV) hypertrophy are the key markers of hypertensive target organ damage (TOD) associated with increased cardiovascular morbidity and mortality. We have previously shown that dietary inorganic nitrate supplementation lowers blood pressure (BP) in hypertension, however, whether this approach might also improve markers of hypertensive TOD is unknown. In this study, we will investigate whether daily dietary inorganic nitrate administration reduces LV mass and improves measures of arterial stiffness. METHODS AND DESIGN NITRATE-TOD is a double-blind, randomised, single-centre, placebo-controlled phase II trial aiming to enrol 160 patients with suboptimal BP control on one or more antihypertensives. Patients will be randomised to receive 4 months once daily dose of either nitrate-rich beetroot juice or nitrate-deplete beetroot juice (placebo). The primary outcomes are reduction in LV mass and reduction in pulse wave velocity (PWV) and central BP.The study has a power of 95% for detecting a 9 g LV mass change by cardiovascular MRI (~6% change for a mildly hypertrophied heart of 150 g). For PWV, we have a power of >95% for detecting a 0.6 m/s absolute change. For central systolic BP, we have a>90% power to detect a 5.8 mm Hg difference in central systolic BP.Secondary end points include change in ultrasound flow-mediated dilation, change in plasma nitrate and nitrite concentration and change in BP. ETHICS AND DISSEMINATION The study was approved by the London-City and East Research Ethics Committee (10/H0703/98). Trial results will be published according to the Consolidated Standards of Reporting Trials statement and will be presented at conferences and reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT03088514.
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Serum levels of miR-199a-5p correlates with blood pressure in premature cardiovascular disease patients homozygous for the MTHFR 677C > T polymorphism.
Lynch, SM, Ward, M, McNulty, H, Angel, CZ, Horigan, G, Strain, JJ, Purvis, J, Tackett, M, McKenna, DJ
Genomics. 2020;(1):669-676
Abstract
This investigation profiled circulating serum concentrations of microRNAs (miRNAs) in premature cardiovascular disease (CVD) patients screened for the 677C > T polymorphism in methylenetetrahydrofolate reductase (MTHFR), a risk factor for hypertension. Serum samples from 75 premature CVD patients of known MTHFR genotype were analysed for CVD-related miRNA expression, to identify those that were associated with blood pressure. Samples were collected at baseline and following intervention with riboflavin as part of a randomized controlled trial. In patients with the MTHFR 677TT genotype, expression of miR-199a-5p in serum was inversely correlated with hypertension at baseline, and with change in blood pressure in TT genotype patients who responded to riboflavin intervention. These correlations were not observed in MTHFR 677CC genotype patients. In vitro experiments and in silico data analysis provided evidence that miR-199a-5p targets SMAD4. This is the first study to link miR-199a-5p expression with hypertension in a genetically at-risk cohort of premature CVD patients.
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Effect of Prenatal Docosahexaenoic Acid Supplementation on Blood Pressure in Children With Overweight Condition or Obesity: A Secondary Analysis of a Randomized Clinical Trial.
Kerling, EH, Hilton, JM, Thodosoff, JM, Wick, J, Colombo, J, Carlson, SE
JAMA network open. 2019;(2):e190088
Abstract
IMPORTANCE The blood pressure-lowering property of docosahexaenoic acid (DHA) in children and adults is known, and an observational study from the Netherlands has linked higher intrauterine DHA exposure to lower childhood blood pressure. However, the association of prenatal intake of DHA supplement with childhood blood pressure has not been evaluated in randomized clinical trials. OBJECTIVE To determine the effect of DHA supplementation during pregnancy on childhood blood pressure. DESIGN, SETTING, AND PARTICIPANTS This prespecified secondary analysis of the Kansas University DHA Outcome Study (KUDOS), a phase 3, double-blind, randomized, placebo-controlled clinical trial was conducted at several local hospitals in the Kansas City, Kansas, metropolitan area. Pregnant women (n = 350) were enrolled in the KUDOS trial between January 10, 2006, and November 17, 2009, and were followed up until their children were 18 months of age. During pregnancy, the women received either 3 capsules per day of placebo or 600 mg per day of DHA from a mean (SD) of 14.5 (3.7) weeks' (all before 20 weeks) gestation until birth. The parents of 190 children consented to additional follow-up of their children until 6 years, which ended April 29, 2016. Study personnel involved in testing were blind to the randomization until all children had completed the trial. Data analysis was performed from May 23, 2017, to July 10, 2018. INTERVENTIONS Pregnant women were assigned to either 600 mg per day of DHA or a placebo that was half soy and half corn oil. Both placebo and DHA were provided in 3 capsules per day. MAIN OUTCOMES AND MEASURES Childhood blood pressure was a planned secondary outcome of a study powered to measure cognitive development. The hypothesis was that DHA would lower blood pressure prior to data analysis. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured at 4, 4.5, 5, 5.5, and 6 years and were analyzed for possible covariates using mixed models to generate a final model. RESULTS In total, 171 children (88 [51.5%] female) were included in this analysis. Of these children, 89 (52.0%) were randomized to the DHA group and 82 (47.9%) to the placebo group. A statistically significant interaction was found between treatment (placebo or DHA) and child weight status (5-year body mass index ≤85th or >85th percentile) for both SBP and DBP. Children who were overweight or obese whose mothers received placebo during pregnancy had higher SBP and DBP compared with children who were overweight or obese whose mothers received DHA (mean [SE] SBP, 104.28 [1.37] mm Hg vs 100.34 [1.02] mm Hg; DBP, 64.7 [1.23] mm Hg vs 59.76 [0.91] mm Hg). No differences in the SBP and DBP were found between children who were overweight or obese whose mothers received DHA and children who were not overweight or obese. In the mixed model analysis, the child's age at blood pressure measurement and the maternal prepregnancy body mass index were the only other statistically significant variables (child age, SBP: F = 7.385; P = .001; DBP: F = 7.39; P = .001; prepregnancy BMI, SBP: r = 0.284; P = .001; DBP: r = 0.216; P = .01). CONCLUSIONS AND RELEVANCE Maternal docosahexaenoic acid intake during pregnancy appeared to mitigate the association between childhood overweight condition or obesity and blood pressure. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02487771.
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Effects of a dietary supplement on inflammatory marker expression in middle-aged and elderly hypertensive patients.
Wang, J, Hong, Z, Wang, N, Wu, L, Ding, B, Ge, Z, Bi, Y, Li, W
Clinics (Sao Paulo, Brazil). 2019;:e890
Abstract
OBJECTIVES We aimed to explore the effects of diet on the inflammatory response in middle-aged and elderly people with hypertension. METHODS Thirty overweight or obese patients with stage one hypertension (age range, 45-75 years) were allocated to either the intervention or control group (n=15 per group; age- and sex-matched). Patients in the intervention group consumed a food powder supplement (100 g) instead of a regular meal. The control group maintained their normal dietary habits. This study lasted for six weeks. Blood pressure, inflammatory marker levels, and energy intake were measured before and after the study. RESULTS After 6 weeks, the diet composition of the intervention group changed significantly (p<0.05). The intake of proteins, dietary fibre, monounsaturated fat, and polyunsaturated fat increased significantly (p<0.05), while the total energy intake trended towards an increase (p>0.05). In the control group, the total energy intake decreased significantly (p<0.05). The levels of nuclear factor-κB (NF-κB), soluble intercellular adhesion molecule-1 (sICAM-1) and high sensitivity C-reactive protein (hs-CRP) decreased, and adiponectin increased significantly in the intervention group (p<0.05); however, no significant changes were observed in the inflammatory marker levels of the control group. In the intervention group, systolic blood pressure decreased significantly (p<0.05), and diastolic blood pressure also exhibited a decreasing trend. No significant change in blood pressure was observed in the control group. CONCLUSION The consumption of a food powder supplement can improve diet composition, decrease blood pressure and reduce inflammation in middle-aged and elderly overweight or obese hypertensive patients. The food powder supplement may also have an anti-atherosclerotic effect in hypertensive patients.
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Efficacy and Safety of Incremental Dosing of a New Single-Pill Formulation of Perindopril and Amlodipine in the Management of Hypertension.
Poulter, NR, Dolan, E, Gupta, AK, O'Brien, E, Whitehouse, A, Sever, PS
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2019;(3):313-323
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Abstract
BACKGROUND Angiotensin-converting enzyme inhibitors and calcium channel blockers in combination are widely recommended in hypertension guidelines. The advantages of single-pill combinations (SPCs) are increasingly recognized, so a dosage-adapted combination of perindopril and amlodipine was developed for the initial management of hypertension. OBJECTIVE This randomized trial evaluated the blood pressure (BP)-lowering efficacy of four incremental doses of perindopril/amlodipine SPC in adults with mild-to-severe hypertension. METHODS Eligible patients (N = 1617) were randomized to SPC perindopril 3.5 mg/amlodipine 2.5 mg (i.e., 3.5/2.5 mg) daily, uptitrating as required on a monthly basis up to 14/10 mg until BP < 140/90 mmHg (< 130/80 mmHg in patients with diabetes). The primary endpoint (proportion with controlled BP at each uptitrated dose) was evaluated at 6 months, and safety was evaluated at 9 months; 24-h ambulatory BP measurement and BP variability were also investigated. Control-arm participants (n = 1653) were randomized to irbesartan 150 mg daily, uptitrating over 3 months to irbesartan/hydrochlorothiazide 300/25 mg. RESULTS Significant increases in BP control were observed with each dosage increment of perindopril/amlodipine, which was well tolerated, rising from 21% (3.5/2.5 mg) to 30% (7/5 mg), 37% (14/5 mg), and 42% (14/10 mg) after 1, 2, 3, and 6 months, respectively. Reductions in mean systolic and diastolic BP occurred with each incremental dose of perindopril/amlodipine. After 6 months, mean BP had fallen by 24.8/10.8 mmHg. Irbesartan-based therapy reduced clinic and 24-h BP similarly to perindopril/amlodipine, but perindopril/amlodipine reduced BP variability more in comparison. CONCLUSIONS Incremental uptitration with dosage-adapted perindopril/amlodipine SPC is a safe and effective strategy for managing hypertension. TRIAL REGISTRATION EudraCT (No. 2006-005799-42).