Topic: Journal Club Selection

Abstract

Contributions of Systolic and Diastolic Blood Pressures to Cardiovascular Outcomes in the ALLHAT Study.

Itoga NK, Tawfik DS, Montez-Rath ME, Chang TI
Background
SBP and DBP have important associations with cardiovascular events, but are seldom considered simultaneously.
Objectives
This study sought to simultaneously analyze systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements on the associated risk of a primary composite outcome of all-cause mortality, myocardial infarction (MI), congestive heart failure (CHF), or stroke.
Methods
This study analyzed ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) data, which randomized adults to chlorthalidone, amlodipine, or lisinopril. The authors evaluated the simultaneous association of repeated SBP and DBP measurements on the primary composite outcome, and each outcome using proportional hazards regression. The authors report hazard ratios using a \"heat map\" to represent high and low risk according to SBP and DBP combinations.
Results
During a median follow-up of 4.4 years (interquartile range: 3.6-5.4 years), 33,357 participants experienced 2,636 MIs, 866 CHF events, 936 strokes, and 3,700 deaths; 8,138 patients (24.4%) had at least 1 event. For the composite outcome, all-cause mortality, MI, and CHF, a U-shaped association was observed with SBP and DBP, but the SBP and DBP associated with the lowest hazards differed for each outcome. For example, SBP/DBP of 140-155/70-80 mm Hg was associated with the lowest HR for all-cause mortality, compared with 110-120/85-90 mm Hg for MI and 125-135/70-75 mm Hg for CHF. In contrast, the association of SBP and stroke was linear.
Conclusions
The risk pattern of SBP and DBP differs by clinical outcomes, and the SBP and DBP associated with the lowest risk. Our results suggest individualization of blood pressure targets may depend in part on the cardiovascular event for which the patient is most at risk.

Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 25 Oct 2021; 78:1671-1678
Itoga NK, Tawfik DS, Montez-Rath ME, Chang TI
J Am Coll Cardiol: 25 Oct 2021; 78:1671-1678 | PMID: 34674811
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Abstract

CARMN is an Evolutionarily Conserved Smooth Muscle Cell-specific LncRNA that Maintains Contractile Phenotype by Binding Myocardin.

Dong K, Shen J, He X, Hu G, ... Fulton DJR, Zhou J
Background: Vascular homeostasis is maintained by the differentiated phenotype of vascular smooth muscle cells (VSMCs). The landscape of protein coding genes comprising the transcriptome of differentiated VSMCs has been intensively investigated but many gaps remain including the emerging roles of non-coding genes.
Methods:
We re-analyzed large-scale, publicly available bulk and scRNA-seq datasets from multiple tissues and cell types to identify VSMC-enriched lncRNAs. The in vivo expression pattern of a novel SMC expressed lncRNA, Carmn (CARdiac Mesoderm Enhancer-associated Non-coding RNA) was investigated using a novel Carmn GFP knock-in reporter mouse model. Bioinformatics and qRT-PCR analysis were employed to assess CARMN expression changes during VSMC phenotypic modulation in human and murine vascular disease models. In vitro, functional assays were performed by knocking down CARMN with antisense oligonucleotides and over-expressing Carmn by adenovirus in human coronary artery SMCs. Carotid artery injury was performed in SMC-specific Carmn knockout mice to assess neointima formation and the therapeutic potential of reversing CARMN loss was tested in a rat carotid artery balloon injury model. The molecular mechanisms underlying CARMN function were investigated using RNA pull-down, RNA immunoprecipitation and luciferase reporter assays.
Results:
We identified CARMN, which was initially annotated as the host gene of the MIR143/145 cluster and recently reported to play a role in cardiac differentiation, as a highly abundant and conserved, SMC-specific lncRNA. Analysis of the Carmn GFP knock-in mouse model confirmed that Carmn is transiently expressed in embryonic cardiomyocytes and thereafter becomes restricted to SMCs. We also found that Carmn is transcribed independently of Mir143/145. CARMN expression is dramatically decreased by vascular disease in humans and murine models and regulates the contractile phenotype of VSMCs in vitro. In vivo, SMC-specific deletion of Carmn significantly exacerbated, while overexpression of Carmn markedly attenuated, injury-induced neointima formation in mouse and rat, respectively. Mechanistically, we found that Carmn physically binds to the key transcriptional cofactor myocardin, facilitating its activity and thereby maintaining the contractile phenotype of VSMCs Conclusions: CARMN is an evolutionarily conserved SMC-specific lncRNA with a previously unappreciated role in maintaining the contractile phenotype of VSMCs and is the first non-coding RNA discovered to interact with myocardin.




Circulation: 24 Oct 2021; epub ahead of print
Dong K, Shen J, He X, Hu G, ... Fulton DJR, Zhou J
Circulation: 24 Oct 2021; epub ahead of print | PMID: 34694145
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Abstract

Endothelial GTPCH (GTP Cyclohydrolase 1) and Tetrahydrobiopterin Regulate Gestational Blood Pressure, Uteroplacental Remodeling, and Fetal Growth.

Chuaiphichai S, Yu GZ, Tan CMJ, Whiteman C, ... Leeson P, Channon KM
Abnormal uteroplacental remodeling leads to placental hypoperfusion, causing fetal growth restriction and pregnancy-related hypertension, which are associated with endothelial dysfunction and markers of reduced vascular NO bioavailability and oxidative stress. Tetrahydrobiopterin (BH4) is a redox cofactor for eNOS (endothelial NO synthase) with a required role in NO generation. Using mice models and human samples, we investigated the physiological requirement for endothelial cell BH4 in uteroplacental vascular adaptation and blood pressure regulation to pregnancy. In pregnant mice, selective maternal endothelial BH4 deficiency resulting from targeted deletion of Gch1 caused progressive hypertension during pregnancy and fetal growth restriction. Maternal endothelial cell Gch1 deletion caused defective functional and structural remodeling in uterine arteries and in spiral arteries, leading to placental insufficiency. Using primary endothelial cells isolated from either normal or hypertensive pregnancies, we found that hypertensive pregnancies are associated with reduced endothelial cell BH4 levels, impaired eNOS activity, and reduced endothelial cell proliferation, mediated by reduced GTPCH (GTP cyclohydrolase 1) protein. In rescue experiments, high blood pressure and fetal growth restriction in pregnant endothelial cell Gch1 deficient mice was not rescued by oral BH4 supplementation, due to systemic oxidation of BH4 to dihydrobiopterin. However, the fully reduced folate, 5-methyltetrahydrofolate prevented BH4 oxidation, reduced blood pressure to normal levels, and normalized fetal growth. We identify a critical requirement for maternal endothelial cell BH4 biosynthesis in uteroplacental vascular remodeling in pregnancy. Restoration of endothelial cell BH4 with reduced folates identifies a novel therapeutic target for the prevention and treatment of pregnancy-related hypertension such as preeclampsia.



Hypertension: 24 Oct 2021:HYPERTENSIONAHA12017646; epub ahead of print
Chuaiphichai S, Yu GZ, Tan CMJ, Whiteman C, ... Leeson P, Channon KM
Hypertension: 24 Oct 2021:HYPERTENSIONAHA12017646; epub ahead of print | PMID: 34689592
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Abstract

Aspirin versus P2Y inhibitors with anticoagulation therapy for atrial fibrillation.

Fukaya H, Ako J, Yasuda S, Kaikita K, ... Matsui K, Ogawa H
Objective
Patients with coronary artery disease (CAD) and atrial fibrillation (AF) can be treated with multiple antithrombotic therapies including antiplatelet and anticoagulant therapies; however, this has the potential to increase bleeding risk. Here, we aimed to evaluate the efficacy and safety of P2Y12 inhibitors and aspirin in patients also receiving anticoagulant therapy.
Methods
We evaluated patients from the Atrial Fibrillation and Ischaemic Events with Rivaroxaban in Patients with Stable Coronary Artery Disease (AFIRE) trial who received rivaroxaban plus an antiplatelet agent; the choice of antiplatelet agent was left to the physician\'s discretion. The primary efficacy and safety end points, consistent with those of the AFIRE trial, were compared between P2Y12 inhibitors and aspirin groups. The primary efficacy end point was a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularisation or death from any cause. The primary safety end point was major bleeding according to the International Society on Thrombosis and Haemostasis criteria.
Results
A total of 1075 patients were included (P2Y12 inhibitor group, n=297; aspirin group, n=778). Approximately 60% of patients were administered proton pump inhibitors (PPIs) and there was no significant difference in PPI use in the groups. There were no significant differences in the primary end points between the groups (efficacy: HR 1.31; 95% CI 0.88 to 1.94; p=0.178; safety: HR 0.79; 95% CI 0.43 to 1.47; p=0.456).
Conclusions
There were no significant differences in cardiovascular and bleeding events in patients with AF and stable CAD taking rivaroxaban with P2Y12 inhibitors or aspirin in the chronic phase.
Trial registration number
UMIN000016612; NCT02642419.

© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2021; 107:1731-1738
Fukaya H, Ako J, Yasuda S, Kaikita K, ... Matsui K, Ogawa H
Heart: 30 Oct 2021; 107:1731-1738 | PMID: 34261738
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Abstract

Sacubitril/valsartan in the treatment of systemic right ventricular failure.

Zandstra TE, Nederend M, Jongbloed MRM, Kiès P, ... Schalij MJ, Egorova AD
Objective
Pharmacological options for patients with a failing systemic right ventricle (RV) in the context of transposition of the great arteries (TGA) after atrial switch or congenitally corrected TGA (ccTGA) are not well defined. This study aims to investigate the feasibility and effects of sacubitril/valsartan treatment in a single-centre cohort of patients.
Methods
Data on all consecutive adult patients (n=20, mean age 46 years, 50% women) with a failing systemic RV in a biventricular circulation treated with sacubitril/valsartan in our centre are reported. Patients with a systemic RV ejection fraction of ≤35% who were symptomatic despite treatment with β-blocker and ACE-inhibitor/angiotensin II receptor-blockers were started on sacubitril/valsartan. This cohort underwent structural follow-up including echocardiography, exercise testing, laboratory investigations and quality of life (QOL) assessment.
Results
Six-month follow-up data were available in 18 out of 20 patients, including 12 (67%) patients with TGA after atrial switch and 6 (33%) patients with ccTGA. N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) decreased significantly (950-358 ng/L, p<0.001). Echocardiographic systemic RV fractional area change and global longitudinal strain showed small improvements (19%-22%, p<0.001 and -11% to -13%, p=0.014, respectively). The 6 min walking distance improved significantly from an average of 564 to 600 m (p=0.011). The QOL domains of cognitive function, sleep and vitality improved (p=0.015, p=0.007 and p=0.037, respectively).
Conclusions
We describe the first patient cohort with systemic RV failure treated with sacubitril/valsartan. Treatment appears feasible with improvements in NT-pro-BNP and echocardiographic function. Our positive results show the potential of sacubitril/valsartan for this patient population.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.

Heart: 30 Oct 2021; 107:1725-1730
Zandstra TE, Nederend M, Jongbloed MRM, Kiès P, ... Schalij MJ, Egorova AD
Heart: 30 Oct 2021; 107:1725-1730 | PMID: 33452121
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Abstract

Heart failure medication dosage and survival in women and men seen at outpatient clinics.

Bots SH, Onland-Moret NC, Tulevski II, van der Harst P, ... Somsen GA, den Ruijter HM
Objective
Women with heart failure with reduced ejection fraction (HFrEF) may reach optimal treatment effect at half of the guideline-recommended medication dose. This study investigates prescription practice and its relation with survival of patients with HF in daily care.
Methods
Electronic health record data from 13 Dutch outpatient cardiology clinics were extracted for HF receiving at least one guideline-recommended HF medication. Dose changes over consecutive prescriptions were modelled using natural cubic splines. Inverse probability-weighted Cox regression was used to assess the relationship between dose (reference≥50% target dose) and all-cause mortality.
Results
The study population comprised 561 women (29% HFrEF (ejection fraction (EF)<40%), 49% heart failure with preserved ejection fraction (EF≥50%); HFpEF and 615 men (47% and 25%, respectively). During a median follow-up of 3.7 years, 252 patients died (48% women; 167 HFrEF, 84 HFpEF). Nine hundred thirty-four patients (46% women) received ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), 795 (48% women) beta blockers and 178 (42% women) mineralocorticoid receptor antagonists (MRAs). In both sexes, the mean target dose across prescriptions was 50% for ACEI/ARBs and beta blockers, and 100% for MRAs. ACEI/ARB dose of <50% was associated with lower mortality in women but not in men with HFrEF. This was not seen in patients with HFpEF. Beta-blocker dose was not associated with all-cause mortality.
Conclusion
Patients with HF seen in outpatient cardiology clinics receive half of the guideline-recommended medication dose. Lower ACEI/ARB dose was associated with improved survival in women with HFrEF. These results underscore the importance of (re)defining optimal medical therapy for women with HFrEF.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2021; 107:1748-1755
Bots SH, Onland-Moret NC, Tulevski II, van der Harst P, ... Somsen GA, den Ruijter HM
Heart: 30 Oct 2021; 107:1748-1755 | PMID: 34261736
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Abstract

Prognostic value of coronary computed tomography angiographic derived fractional flow reserve: a systematic review and meta-analysis.

Nørgaard BL, Gaur S, Fairbairn TA, Douglas PS, ... Leipsic J, Abdulla J
Objectives
To obtain more powerful assessment of the prognostic value of fractional flow reserveCT testing we performed a systematic literature review and collaborative meta-analysis of studies that assessed clinical outcomes of CT-derived calculation of FFR (FFRCT) (HeartFlow) analysis in patients with stable coronary artery disease (CAD).
Methods
We searched PubMed and Web of Science electronic databases for published studies that evaluated clinical outcomes following fractional flow reserveCT testing between 1 January 2010 and 31 December 2020. The primary endpoint was defined as \'all-cause mortality (ACM) or myocardial infarction (MI)\' at 12-month follow-up. Exploratory analyses were performed using major adverse cardiovascular events (MACEs, ACM+MI+unplanned revascularisation), ACM, MI, spontaneous MI or unplanned (>3 months) revascularisation as the endpoint.
Results
Five studies were identified including a total of 5460 patients eligible for meta-analyses. The primary endpoint occurred in 60 (1.1%) patients, 0.6% (13/2126) with FFRCT>0.80% and 1.4% (47/3334) with FFRCT ≤0.80 (relative risk (RR) 2.31 (95% CI 1.29 to 4.13), p=0.005). Likewise, MACE, MI, spontaneous MI or unplanned revascularisation occurred more frequently in patients with FFRCT ≤0.80 versus patients with FFRCT >0.80. Each 0.10-unit FFRCT reduction was associated with a greater risk of the primary endpoint (RR 1.67 (95% CI 1.47 to 1.87), p<0.001).
Conclusions
The 12-month outcomes in patients with stable CAD show low rates of events in those with a negative FFRCT result, and lower risk of an unfavourable outcome in patients with a negative test result compared with patients with a positive test result. Moreover, the FFRCT numerical value was inversely associated with outcomes.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 21 Oct 2021; epub ahead of print
Nørgaard BL, Gaur S, Fairbairn TA, Douglas PS, ... Leipsic J, Abdulla J
Heart: 21 Oct 2021; epub ahead of print | PMID: 34686567
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Abstract

Effects of blood pressure and heart rate circadian rhythms on left atrial function.

Zhao Y, Liu Y, Sun Q, Han J, ... Cong T, Jiang Y
Objective
We examined the associations among the circadian rhythms of blood pressure (BP), heart rate (HR) and left atrial function in essential hypertensive patients.
Methods
The study included 237 essential hypertensive patients who completed 24-h ambulatory BP, HR monitoring and two-dimensional speckle tracking echocardiography (2DSTE). The strain and strain rate images were studied, and the following parameters were measured: left atrial reservoir strain and strain rate (LAS-S and LASR-S), left atrial conduit strain and strain rate (LAS-E and LASR-E), and left atrial booster strain and strain rate (LAS-A and LASR-A). The left atrial stiffness index (LASI) was identified as the ratio of E/e\' to LAS-S. All participants were divided into three groups according to the percentage of nocturnal BP dipping (dippers, nondippers and reverse dippers).
Results
The LASI was significantly higher in BP reverse dippers than in dippers and nondippers. LAS-S, LAS-E and LASR-E were significantly lower in BP reverse dippers than dippers and nondippers. Multivariate logistic regression analysis demonstrated that age, night-time mean SBP and the percentage of nocturnal HR decline were independently related to an increased LASI.
Conclusion
Impairment of the left atrial reservoir and conduit functions was correlated with abnormal BP and HR circadian rhythms in hypertension. Increased left atrial stiffness was associated with night-time SBP and the percentage of nocturnal HR decline.

Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

J Hypertens: 31 Oct 2021; 39:2318-2324
Zhao Y, Liu Y, Sun Q, Han J, ... Cong T, Jiang Y
J Hypertens: 31 Oct 2021; 39:2318-2324 | PMID: 34620813
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Abstract

Coarctation of aorta is associated with left ventricular stiffness, left atrial dysfunction and pulmonary hypertension.

Egbe AC, Miranda WR, Connolly HM, Borlaug BA
Background
Brachial systolic blood pressure (BP) is the most commonly used metric for monitoring hypertension. However, recent studies suggest that brachial systolic BP underestimates left ventricle (LV) systolic load in patients with coarctation of aorta (COA). Since brachial systolic BP is used as a surrogate of arterial afterload in clinical practice, it is important to determine how well it correlates with LV remodeling and stiffness in patients with COA as compared to patients with idiopathic hypertension.
Methods
This is cross-sectional study of COA patients with hypertension (COA group) and adults with idiopathic hypertension (control group). Both groups were matched 1:1 based on age, sex, BMI and systolic BP. We hypothesized that the COA group will have higher LV systolic and diastolic stiffness, and more advanced left atrial remodeling and pulmonary hypertension. We assessed LV systolic stiffness using end-systolic elastance, and diastolic stiffness using LV stiffness constant and chamber capacitance (LV-end-diastolic volume at an end-diastolic pressure of 20mm Hg)
Results:
There were 112 patients in each group. Although both groups had similar systolic BP, the COA group had a higher end-systolic elastance (2.37 ± 0.74 vs 2.11 ± 0.54 mm Hg/mL, P= .008), higher LV stiffness constant (6.91 ± 0.81 vs 5.93 ± 0.79, P= .006) and lower LV-end-diastolic volume at an end-diastolic pressure of 20mm Hg (58 ± 9 vs 67 ± 11 mL/m2, P< .001). Additionally, the COA group had more advanced left atrial remodeling and higher pulmonary artery pressures which is corroborating evidence of high LV filling pressure.
Conclusions
COA patients have more LV stiffness and abnormal hemodynamics compared to non-COA patients with similar systolic BP, suggesting that systolic BP may underestimate LV systolic load in this population. Further studies are required to determine whether the observed LV stiffness and dysfunction translates to more cardiovascular events during follow-up, and whether adopting a stricter systolic BP target in clinical practice or changing threshold for COA intervention will lead to less LV stiffness and better clinical outcomes.

Copyright © 2021. Published by Elsevier Inc.

Am Heart J: 30 Oct 2021; 241:50-58
Egbe AC, Miranda WR, Connolly HM, Borlaug BA
Am Heart J: 30 Oct 2021; 241:50-58 | PMID: 34289342
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Abstract

Independent Association of Fatty Liver Index With Left Ventricular Diastolic Dysfunction in Subjects Without Medication.

Furuhashi M, Muranaka A, Yuda S, Tanaka M, ... Shimamoto K, Miura T
Nonalcoholic fatty liver disease has been reported to be potentially linked to cardiovascular disease. Fatty liver index (FLI) is a noninvasive and simple predictor of nonalcoholic fatty liver disease. However, little is known about the relationship between FLI and cardiac function, especially in a general population. We investigated the relationships of FLI with echocardiographic parameters in 185 subjects (men/women: 79/106) of the Tanno-Sobetsu Study, a population-based cohort, who were not being treated with any medication and who underwent echocardiography. FLI was negatively correlated with high-density lipoprotein cholesterol and peak myocardial velocity during early diastole (e\'; r = -0.342, p <0.001), an index of left ventricular (LV) diastolic function, and ratio of peak mitral velocities during early and late diastole (E/A) and was positively correlated with age, systolic and diastolic blood pressures, creatinine, uric acid, homeostasis model assessment of insulin resistance, high-sensitivity C-reactive protein, ratio of mitral to myocardial early diastolic peak velocity (E/e\'), left atrial volume index and LV mass index. No significant correlation was found between FLI and LV ejection fraction. Stepwise multivariable regression analysis showed that FLI was independently and negatively associated with e\' after adjustment of age, gender, high-density lipoprotein cholesterol, homeostasis model assessment of insulin resistance, and high-sensitivity C-reactive protein. Conversely, e\' was independently and negatively associated with FLI after adjustment of age, gender, systolic blood pressure, and LV ejection fraction. In conclusion, elevated FLI is independently associated with LV diastolic dysfunction in a general population without medication. FLI would be a novel marker of LV diastolic dysfunction as an early sign of myocardial injury.

Copyright © 2021 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Oct 2021; 158:139-146
Furuhashi M, Muranaka A, Yuda S, Tanaka M, ... Shimamoto K, Miura T
Am J Cardiol: 31 Oct 2021; 158:139-146 | PMID: 34474907
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This program is still in alpha version.