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Global Rounds: Advancing Cardiovascular Health in China

Interpretable deep learning of single-cell and epigenetic data reveals novel molecular insights in aging

Cardiac Reprogramming and Gata4 Overexpression Reduce Fibrosis and Improve Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major health concern. Pathological stimuli and interactions between cardiac fibroblasts (CFs) and other cell types may lead to cardiac fibrosis and diastolic dysfunction, which are hallmarks of HFpEF. Interstitial and perivascular cardiac fibrosis correlates with poor prognosis in HFpEF; however, mechanisms of fibrosis remain poorly elucidated, and targeted therapies are lacking. Cardiac reprogramming is a promising therapeutic approach for myocardial infarction that facilitates cardiac regeneration and antifibrosis action through Mef2c/Gata4/Tbx5/Hand2 (MGTH) overexpression in resident CFs. However, the efficacy of this approach on HFpEF is yet to be established. METHODS: Herein, we examined the effects of cardiac reprogramming in HFpEF using Tcf21 iCre /Tomato/MGTH2A transgenic mice, which expressed both MGTH and reporter expression in CFs for cardiac reprogramming and lineage tracing upon tamoxifen administration. To establish HFpEF model mice, we used a combination of a high-fat diet and nitric oxide synthase inhibition. Bulk RNA-sequencing, single-cell RNA-sequencing, and spatial transcriptomics were conducted to determine fibrotic mechanisms and the efficacy of cardiac reprogramming in HFpEF. We generated new tamoxifen-inducible transgenic mice overexpressing each reprogramming factor in CFs to investigate the effect of single factors. Last, we analyzed the effect of reprogramming factors in human CFs. RESULTS: Cardiac reprogramming with MGTH overexpression improved diastolic dysfunction, cardiac hypertrophy, fibrosis, inflammation, and capillary loss in HFpEF. Cardiac reprogramming converted approximately 1% of resident CFs into induced cardiomyocytes. Bulk RNA-seq indicated that MGTH overexpression upregulated genes related to heart contraction and suppressed the fetal gene program ( Nppa and Nppb ) and proinflammatory and fibrotic signatures. Single-cell RNA-sequencing and spatial transcriptomics revealed that multiple CF clusters upregulated fibrotic genes to induce diffuse interstitial fibrosis, whereas distinct CF clusters generated focal perivascular fibrosis in HFpEF. MGTH overexpression reversed these profibrotic changes. Among 4 reprogramming factors, only Gata4 overexpression in CFs reduced fibrosis and improved diastolic dysfunction in HFpEF by suppressing CF activation without generating new induced cardiomyocytes. Gata4 overexpression also suppressed profibrotic signatures in human CFs. CONCLUSIONS: Overexpressing Gata4 in CFs may be a promising therapeutic approach for HFpEF by suppressing fibrosis and improving diastolic dysfunction

Spatial differentiation and coupling between village development intensity and landscape pattern of 100 villages in Anhui, China

Abstract Spatial development and landscape pattern are fundamental elements of the land system of village. Analysing the spatial differentiation and coupling relationship between spatial development intensity and landscape pattern is of great significance for the development and protection of village land resources. In order to address the current research lack on the coupling response between village spatial development intensity and landscape pattern, a technical method for analysing the spatial differentiation and coupling relationship between village spatial development intensity and landscape pattern is constructed based on the methods of village spatial development intensity model, landscape pattern index, bivariate spatial autocorrelation model, coupling degree and coupling coordination degree model. Taking 100 villages in Anhui Province, China as an example, the spatial distribution characteristics and coupling characteristics of village spatial development intensity and landscape pattern are analysed. The results show that there are obvious regional differences in the spatial distribution of village spatial development intensity and landscape pattern in Anhui Province. The village spatial development intensity shows a pattern of the Northern Anhui plain region (NAPR) > along the Yangtze River plain region (YRPR) > Jiang-huai Hilly region (JHHR) > Southern Anhui mountainous region (SAMR) > Western Anhui mountainous region (WAMR). The village landscape pattern in NAPR and YRPR are high fragmentation, while the village in JHHR has the lowest fragmentation, and the villages in SAMR and WAMR show relatively low fragmentation. The spatial coupling relationship between village spatial development intensity and landscape pattern is mainly characterised by high-high clustering and low-high clustering. The coupling coordinated development of villages in NAPR is the best, followed by YRPR, JHHR and SAMR, and WAMR is the worst. There is only a significant multi-linear relationship between village landscape pattern and multiple spatial development intensity indicators in WAMR and NAPR. The spatial differentiation and coupling relationship are influenced by both natural geographical factors and human activity factors. Finally, the study puts forward some targeted countermeasures and suggestions. The research results can provide theoretical method and practical application reference for village land space development and protection and village planning.

Response by Shen et al to Letter Regarding Article, “Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF”

Particle swarm optimization based analysis to unlocking the neutrino mass puzzle using $$SU(2)_L \times U(1)_Y \times A_{4}\times S_2\times Z_{10} \times Z_{3}$$ flavor symmetry

Abstract New research has highlighted a shortfall in the Standard Model (SM) because it predicts neutrinos to have zero mass. However, recent experiments on neutrino oscillation have revealed that the majority of neutrino parameters indeed indicate their significant mass. In response, scientists are increasingly incorporating discrete symmetries alongside continuous ones for the observed patterns of neutrino mixing. In this study, we have examined a model within $$SU(2)_L \times U(1)_Y \times A_{4}\times S_2\times Z_{10} \times Z_{3}$$ symmetry to estimate the neutrino masses using particle swarm optimization technique for both mass hierarchy of neutrino. This model employed a hybrid seesaw mechanism, a combination of seesaw mechanism of type-I and type-II, to establish the effective Majorana neutrino mass matrix. After calculating the mass eigenvalues and lepton mixing matrix upto second order perturbation theory in this framework, this study seeks to investigate the scalar potential for vacuum expectation values (VEVs), optimize the parameters, $$U_{PMNS}$$ matrix, neutrino masses: $${m_{1}^{\prime }}^{(N)}(upper)=4.0000 \times 10^{-2}\ eV,$$ $${m_{2}^{\prime }}^{(N)}(upper)=4.0000 \times 10^{-2}\ eV,$$ $${m_{3}^{\prime }}^{(N)}(upper)=4.0000 \times 10^{-2}\ eV,$$ $${m_{1}^{\prime }}^{(I)}(upper)=3.8628\times 10^{-2}\ eV,$$ $${m_{2}^{\prime }}^{(I)}(upper)=4.0548\times 10^{-2}\ eV,$$ $${m_{3}^{\prime }}^{(I)}(upper)=3.8532\times 10^{-2}\ eV,$$ $${m_{1}^{\prime }}^{(N)}(lower)=2.0000 \times 10^{-2}\ eV,$$ $${m_{2}^{\prime }}^{(N)}(lower)=2.0000 \times 10^{-2}\ eV,$$ $${m_{3}^{\prime }}^{(N)}(lower)=2.0000 \times 10^{-2}\ eV,$$ $${m_{1}^{\prime }}^{(I)}(lower)=1.1049\times 10^{-2}\ eV,$$ $${m_{2}^{\prime }}^{(I)}(lower)=3.9298\times 10^{-2}\ eV$$ and $${m_{3}^{\prime }}^{(I)}(lower)=9.6381\times 10^{-3}\ eV,$$ effective neutrino mass parameters: $$\langle {m_{ee}} \rangle ^{N}(upper)=40.0050 \ meV,$$ $$\langle {m_{\beta }} \rangle ^{N}(upper)=40.0025\ meV,$$ $$\langle {m_{ee}} \rangle ^{I}(upper)=39.2181\ meV,$$ $$\langle {m_{\beta }} \rangle ^{I}(upper)=39.2257\ meV,$$ $$\langle {m_{ee}} \rangle ^{N}(lower)=20.0024\ meV,$$ $$\langle {m_{\beta }} \rangle ^{N}(lower)=20.0012\ meV,$$ $$\langle {m_{ee}} \rangle ^{I}(lower)=19.6608\ meV,$$ $$\langle {m_{\beta }} \rangle ^{I}(lower)=23.5908\ meV,$$ are predicted for both mass hierarchy through particle swarm optimization (PSO), showing strong agreement with recent experimental findings. The Dirac CP-violating phase $$\delta$$ is measured to be $$-\pi /2$$ .

Derivation and Validation of the PRECISE-HBR Score to Predict Bleeding After Percutaneous Coronary Intervention

BACKGROUND: Accurate bleeding risk stratification after percutaneous coronary intervention is important for treatment individualization. However, there is still an unmet need for a more precise and standardized identification of patients at high bleeding risk. We derived and validated a novel bleeding risk score by augmenting the Predicting Bleeding Complications in Patients Undergoing Stent Implantation and Subsequent Dual Antiplatelet Therapy (PRECISE-DAPT) score with the Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria. METHODS: The derivation cohort comprised 29 188 patients undergoing percutaneous coronary intervention, of whom 1136 (3.9%) had Bleeding Academic Research Consortium (BARC) 3 or 5 bleeding at 1 year, from 4 contemporary real-world registries and the XIENCE V USA trial. The PRECISE-DAPT score was refitted with a Fine-Gray model in the derivation cohort and extended with the ARC-HBR criteria. The primary outcome was BARC 3 or 5 bleeding within 1 year. Independent predictors of BARC 3 or 5 bleeding were selected at multivariable analysis ( P <0.01). The discrimination of the score was internally assessed with apparent validation and cross-validation. The score was externally validated in 4578 patients from the MASTER DAPT trial (Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Prolonged DAPT Regimen) and 5970 patients from the STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy-2) total cohort. RESULTS: The PRECISE-HBR score (age, estimated glomerular filtration rate, hemoglobin, white blood cell count, previous bleeding, oral anticoagulation, and ARC-HBR criteria) showed an area under the curve (AUC) for 1-year BARC 3 or 5 bleeding of 0.73 (95% CI, 0.71–0.74) at apparent validation, 0.72 (95% CI, 0.70–0.73) at cross-validation, 0.74 (95% CI, 0.68–0.80) in MASTER DAPT, and 0.73 (95% CI, 0.66–0.79) in STOPDAPT-2, with superior discrimination compared with PRECISE-DAPT (cross-validation: ΔAUC, 0.01; P =0.02; MASTER DAPT: ΔAUC, 0.05; P =0.004; STOPDAPT-2: ΔAUC, 0.02; P =0.20) and other risk scores. In the derivation cohort, a cutoff of 23 points identified 11 414 patients (39.1%) with a 1-year BARC 3 or 5 bleeding risk ≥4%. An alternative version of the score, including acute myocardial infarction on admission instead of white blood cell count, showed similar predictive ability. CONCLUSIONS: The PRECISE-HBR score is a contemporary, simple 7-item risk score to predict bleeding after percutaneous coronary intervention, offering a moderate improvement in discrimination over multiple existing scores. Further evaluation is required to assess its impact on clinical practice.

Response of Red Sea phytoplankton biomass to marine heatwaves and cold-spells

Abstract In tropical oceans, phytoplankton experience significant alterations during marine heatwaves (MHWs), yet the consequences of reduced or absent marine cold-spells (MCSs) on these microscopic algae are currently overlooked. Synergistically combining in situ measurements, Argo-float data, remotely-sensed observations, and hydrodynamic model outputs, we explore such relationships in the Red Sea. Results show a long-term (1982 to 2018) gradual increase in MHW days (5–20 days/decade) and a clear decrease in MCS days (10–30 days/decade). Compound extreme temperature and chlorophyll-a events (Chl-a – an index of phytoplankton biomass) exhibit consistently lower Chl-a concentrations during MHWs and higher ones during MCSs, particularly in the northern and southern Red Sea. In these regions, during the main phytoplankton-growth period, the presence of MHWs/MCSs leads to respective Chl-a anomalies in 94% of the cases. Yet, phytoplankton responses in the central Red Sea are more complex, most likely linked to the region’s highly dynamic circulation (e.g., mesoscale anti-cyclonic eddies), and multiple nutrient sources. In the naturally warm and stratified ecosystem of the Red Sea, where deeper mixed layers enhance the transfer of nutrient-rich waters to the lit zone, the substantial reduction of MCSs could be more impactful for phytoplankton than the gradual rise of MHWs.

Touching the classical scaling in penetrative convection

The Cassini missions have identified the tiger stripes on Enceladus as the source of both thermal emission and plume jets. The hot spots in the tiger stripes are highly localized, and the plumes suggest active hydrothermal processes within the subglacial ocean of Enceladus. However, understanding the mechanism responsible for the heat anomalies in the tiger stripes remains a challenge. About 60 y ago, geoscientist George Veronis proposed a model for cold water oceans, along with the classical notion of a 1/3 scaling relationship between vertical heat transfer and the Rayleigh number ( Ra ), a dimensionless number representing the strength of buoyancy driving the convection within the fluid body. In this study, by delving into the steady coherent rolls arising in Veronis’ model, we first confirm the existence of the classical scaling as proposed. We identify two distinct pathways, characterized by different flow patterns, that converge to the unified classical scaling. In scenarios where stratification resulting from the density’s nonlinear temperature dependence is insignificant, convection rolls with fixed (width-to-height) aspect ratios achieve the classical scaling as Ra approaches infinity. Conversely, under high stratification levels, convection rolls with a heat-transport-maximizing aspect ratio achieve the classical scaling. This investigation also reveals a notable correspondence between optimal coherent rolls and turbulent flow patterns. Based on these coherent rolls, we offer insights into the formation of heat anomalies in the tiger stripes. The predicted heat flux through the ocean and the lateral flow length, are consistent with the measurements obtained by the Cassini spacecraft.

Letter by Tunçez and Gürses Regarding Article, “Effect of Sacubitril/Valsartan on Cognitive Function in Patients With Heart Failure With Preserved Ejection Fraction: A Prespecified Analysis of PARAGON-HF”

Retraction Note: DNA encoding schemes herald a new age in cybersecurity for safeguarding digital assets

Major Adverse Cardiovascular Events 1 Year After Discharge in Out-of-Hospital Cardiac Arrest Survivors

Synergistic combination of ceftazidime and avibactam with Aztreonam against MDR Klebsiella pneumoniae in ICU patients

Abstract The proliferation of multidrug-resistant, metallo-beta-lactamase-producing Klebsiella pneumoniae (MBL-producing K. pneumoniae) poses a major threat to public health resulting in increasing treatment costs, prolonged hospitalization, and mortality rate. Treating such bacteria presents substantial hurdles for clinicians. The combination of Aztreonam (ATM) and ceftazidime/avibactam (CAZ/AVI) is likely the most successful approach. The study evaluated the in vitro activity of CAZ/AVI in combination with ATM against MBL-producing K. pneumoniae clinical isolates collected from Suez Canal University Hospital patients. Carbapenem-resistant K. pneumoniae were isolated and identified from different specimens. The presence of metallo-β-lactamases was detected phenotypically by modified carbapenem inactivation method (mCIM) and EDTA-CIM (eCIM) testing, and genotypically for the three metallo-β-lactamase genes: blaNDM, blaIMP, and blaVIM by conventional PCR method. The synergistic effect of CAZ/AVI with ATM against MBL-producing K. pneumoniae was detected by ceftazidime-avibactam combination disks and E-test for antimicrobial susceptibility testing. Out of the 65 K. pneumoniae isolates recovered, 60% (39/65) were carbapenem-resistant (CRKP). According to the mCIM and eCIM tests, 89.7% (35/39) of CRKP isolates were carbapenemase-positive, and 68.6% (24/35) were metallo-β-lactamase (MBL)-positive. By using the conventional PCR, at least one of the MBL genes was present in each metallo-bata-lactamase-producing isolate: 8.3% carried the blaVIM gene, 66.7% the blaNDM, and 91.7% the blaIMP gene. After doing the disk combination method for ceftazidime-avibactam plus Aztreonam, 62.5% of the isolates shifted from resistance to sensitivity. Also, ceftazidime/avibactam plus Aztreonam resistance was reduced markedly among CRKP using the E-test. The addition of Aztreonam to ceftazidime/avibactam is an effective therapeutic option against MBL-producing K. pneumoniae. Clinical Trials Registry: Pan African Clinical Trials Registry. Trial No.: PACTR202410744344899. Trial URL: https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=32000

Identifying new classes of financial price jumps with wavelets

We introduce an unsupervised classification framework that leverages a multiscale wavelet representation of time-series and apply it to stock price jumps. In line with previous work, we recover the fact that time-asymmetry of volatility is the major feature that separates exogenous, news-induced jumps from endogenously generated jumps. Local mean-reversion and trend are found to be two additional key features, allowing us to identify new classes of jumps. Using our wavelet-based representation, we investigate the endogenous or exogenous nature of cojumps, which occur when multiple stocks experience price jumps within the same minute. Perhaps surprisingly, our analysis suggests that a significant fraction of cojumps result from an endogenous contagion mechanism.

Lipoprotein(a) as a Pharmacological Target: Premises, Promises, and Prospects

Atherosclerotic cardiovascular disease is a major health concern worldwide and requires effective preventive measures. Lp(a) (lipoprotein [a]) has recently garnered attention as an independent risk factor for astherosclerotic cardiovascular disease, with proinflammatory and prothrombotic mechanisms contributing to its atherogenicity. On an equimolar basis, Lp(a) is ~5 to 6 times more atherogenic than particles that have been widely associated with adverse cardiovascular outcomes, such as LDL (low-density lipoprotein). Lp(a) can enter the vessel wall, leading to the accumulation of oxidized phospholipids in the arterial intima, which are crucial for initiating plaque inflammation and triggering vascular disease progression. In addition, Lp(a) may cause atherothrombosis through interactions between apoA (apolipoprotein A) and the platelet PAR-1 (protease-activated receptor 1) receptor, as well as competitive inhibition of plasminogen. Because Lp(a) is mostly determined on genetic bases, a 1-time assessment in a lifetime can suffice to identify patients with elevated levels. Mendelian randomization studies and post hoc analyses of randomized trials of LDL cholesterol–lowering drugs showed a causal link between Lp(a) concentrations and cardiovascular outcomes, with therapeutic reduction of Lp(a) expected to contribute to estimated cardiovascular risk mitigation. Many Lp(a)-lowering drugs, including monoclonal antibodies, small interfering ribonucleic acids, antisense oligonucleotides, small molecules, and gene editing compounds, are at different stages of clinical investigation and show promise for clinical use. In particular, increased Lp(a) testing and treatment are expected to have a substantial impact at the population level, enabling the identification of high-risk individuals and the subsequent prevention of a large number of cardiovascular events. Ongoing phase 3 trials will further elucidate the cardiovascular benefits of Lp(a) reduction over the long term, offering potential avenues for targeted interventions and improved cardiovascular outcomes.

Non-isolated common-grounded high step-up DC-DC converter with continuous source current suitable for low power applications

Temperature-dependent polar lignification of a seed coat suberin layer promoting dormancy in <i>Arabidopsis thaliana</i>

The seed is a landmark plant adaptation where the embryo is sheltered by a protective seed coat to facilitate dispersion. In Arabidopsis , the seed coat, derived from ovular integuments, plays a critical role in maintaining dormancy, ensuring germination occurs during a favorable season. Dormancy is enhanced by cold temperatures during seed development by affecting seed coat permeability through changes in apoplastic barriers. However, their localization and composition are poorly understood. This study identifies and investigates a polar barrier in the seed coat’s outer integument (oi1) cells. We present histological, biochemical, and genetic evidence showing that cold promotes polar seed coat lignification of the outer integument 1 (oi1) cells and suberization throughout the entire oi1 cell boundary. The polar oi1 barrier is regulated by the transcription factors MYB107 and MYB9. MYB107, in particular, is crucial for the lignified polar oi1 barrier formation under cold temperatures. The absence of the oi1 barrier in mutant seeds correlates with increased permeability and reduced dormancy. Our findings elucidate how temperature-induced modifications in seed coat composition regulate dormancy, highlighting the roles of suberin and lignin in this process.

Unipolar Voltage Mapping to Predict Recovery of Left Ventricular Ejection Fraction in Patients With Recent-Onset Nonischemic Cardiomyopathy

BACKGROUND: The ability to predict recovery of left ventricular ejection fraction (LVEF) in response to guideline-directed therapy among patients with nonischemic cardiomyopathy is desired. We sought to determine whether left ventricular endocardial unipolar voltage measured during invasive electroanatomic mapping could be used to predict LVEF recovery among those with recent-onset nonischemic cardiomyopathy. METHODS: We analyzed the left ventricular voltage maps of patients included in the eMAP trial (Electrogram-Guided Myocardial Advanced Phenotyping; NCT03293381), a prospective, nonrandomized, interventional trial conducted at 2 institutions between 2017 and 2020. Patients had recent-onset nonischemic cardiomyopathy defined by LVEF ≤45% and development of symptoms or signs of heart failure within the past 6 months. Detailed voltage maps of the left ventricular endocardium were generated using the Carto electroanatomic mapping system. Abnormal unipolar amplitude was defined as &lt;8.27 mV. The primary end point was recovery of LVEF (Recovery) defined by a 1-year LVEF ≥50% or ≥45% with ≥10% increase from baseline. RESULTS: Of the 29 enrolled patients (median age, 49 years [25th percentile, 39; 75th percentile, 59], 8 females [27.6%]), LVEF recovered in 13 (44.8%) by 1-year follow-up. The percentage of total endocardial surface area with unipolar voltage abnormality (AUA) was significantly lower among Recovery patients than No Recovery patients (18.2% [25th percentile, 6.4; 75th percentile, 22.4] versus 80.0% [25th percentile, 29.5; 75th percentile, 90.9]; P =0.004). Percent AUA was associated with lower likelihood of Recovery (odds ratio, 0.64 per 10% increase in AUA; 95% CI, 0.47–0.88; P =0.006). A 28% cutoff value for percent AUA was 92% sensitive and 75% specific with an area under the receiver operating characteristic curve of 0.81 (95% CI, 0.63–0.99; P =0.001) for predicting recovery versus no recovery. The majority of patients (12 of 13; 92.3%) with a percent AUA &gt;28% did not recover. CONCLUSIONS: Left ventricular unipolar voltage abnormality is a potent predictor of LVEF recovery among patients recently diagnosed with nonischemic cardiomyopathy. Detailed left ventricular unipolar voltage mapping could therefore be used as a valuable prognostic tool in guiding treatment decisions.

Serum biomarkers associated with health impacts of high residential radon exposure: a metabolomic pilot study

Robust inattentive discrete choice

Rational inattention models characterize optimal decision-making in data-rich environments. In such environments, it can be costly to look carefully at all of the information. Some information is much more salient for the decision at hand and merits closer scrutiny. The inattention decision model formalizes this choice and deduces how best to navigate through the potentially vast array of data when making decisions. In the rational formulation, the decision-maker commits fully to a subjective prior distribution over the possible states of the world that could be realized. We relax this assumption and look for a robustly optimal solution to the inattention problem by allowing the decision-maker to be ambiguity averse with respect to this prior. We feature a setup that is deliberately simple by a) assuming a discrete set of choices, b) using Shannon’s mutual information to quantify attention costs, and c) imposing relative entropy with respect to a baseline probability distribution to quantify prior divergence. We provide necessary and sufficient conditions for the robust solution and develop numerical methods to solve it. In comparison to the rational solution with no prior uncertainty, our decision-maker slants priors in more cautious or pessimistic directions when deducing how to allocate attention over the range of available information. This approach implements a form of robustness to prior misspecification, or equivalently, a form of ambiguity aversion. We explore some examples that show how the robust solution differs from the rational solution with a commitment to a subjective prior distribution and how it differs from imposing risk aversion.