Cardiovascular Pathophysiology Research Articles

Evidence for heterodimerization and functional interaction of the urotensin II and the angiotensin II type 1 receptors

Despite the observation of synergistic interactions between the urotensinergic and angiotensinergic systems, the interplay between the urotensin II receptor (hUT) and the angiotensin II type 1 receptor (hAT1R) in regulating cellular signaling remains incompletely understood. Notably, the putative interaction between hUT and hAT1R could engender reciprocal allosteric modulation of their signaling signatures, defining a unique role for these complexes in cardiovascular physiology and pathophysiology. Using a combination of co-immunoprecipitation, bioluminescence resonance energy transfer (BRET) and FlAsH BRET-based conformational biosensors, we first demonstrated the physical interaction between hUT and hAT1R. Next, to analyze how this functional interaction regulated proximal and distal hUT- and hAT1R-associated signaling pathways, we used BRET-based signaling biosensors and western blots to profile pathway-specific signaling in HEK 293 cells expressing hUT, hAT1R or both. We observed that hUT-hAT1R heterodimers triggered distinct signaling outcomes compared to their respective parent receptors alone. Notably, co-transfection of hUT and hAT1R has no impact on hUII-induced Gq activation but significantly reduced the potency and efficacy of Ang II to mediate Gq activation. Interestingly, URP, the second hUT endogenous ligand, produce a distinct signaling signature compared to hUII at hUT-hAT1R. Our results therefore suggest that assembly of hUT with hAT1R might be important for allosteric modulation of outcomes associated with specific hardwired signaling complexes in healthy and disease states. Altogether, our work, which potentially explains the interplay observed in native cells and tissues, validates such complexes as potential targets to promote the design of compounds that can modulate heterodimer function selectively.

Impact of the circadian clock on cardiovascular physiology and pathophysiology

Circadian rhythms are the innate approximately 24-hour oscillations that orchestrate a multitude of physiological processes encompassing sleep-wake cycles, hormone secretion, thermoregulation, metabolism, and behavioral patterns. Also, those rhythms are intrinsically governed by the suprachiasmatic nucleus (SCN) ensconced in the anterior hypothalamic region. The SCN, synchronized during daylight hours receives and transmits diverse bodily signals to calibrate physiological dynamics, and imbue disturbances with potential repercussions reverberating across a plethora of physiological and behavioral domains. Previous studies have proven that the diurnal changes in the circadian rhythm multiple myocardial processes and have a critical impact on the physiology and pathophysiology of the cardiovascular system. This comprehensive review emphasizes the profound influence of circadian rhythms, orchestrated by the suprachiasmatic nucleus, on cardiovascular health. It reveals that disruptions in circadian rhythms impact blood pressure, myocardial function, platelet responsiveness, and the autonomic nervous system, all of which are critical for cardiovascular well-being. The significance of this research lies in its potential to guide interventions for cardiovascular disease prevention and management, particularly in the context of modern challenges like shift work. Understanding this intricate relationship is crucial for safeguarding cardiovascular health in our fast-paced world.

The Role of the Receptor Activator of Nuclear Factor Kappa-B Ligand/Osteoprotegerin Ratio in Vascular Diseases: A Therapeutic Approach.

Cardiovascular and bone diseases contribute independently to mortality and global health. The exact mechanisms involved in the pathophysiology shared between bone and vascular diseases are not well defined. Endothelial cells and osteoblasts communicate during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. One shared mechanism may involve osteoprotegerin (OPG) and its ligand Receptor Activator of NF-κB Ligand (RANKL). The RANKL/OPG ratio is an important modulator for the skeletal, immunological, and vascular systems. OPG levels are elevated due to either osteogenic causes or inflammatory responses in the vasculature. The data obtained from clinical and in vitro studies support the role of the RANKL/OPG ratio as a potential marker for the progression of endothelial damage. Therefore, determining the therapeutic approaches for the targeting RANKL/OPG ratio and evaluating its usage as a biomarker in cardiovascular and bone pathophysiology are needed. By integrating the protective and disease-causing role of OPG with its ligand, this review outlines the role of the RANKL/OPG ratio at the molecular level. We also consider targeted therapeutic approaches.

Unveiling the role of TRPA1 in cardiovascular health and disease: a mini review.

The transient receptor potential ankyrin 1 (TRPA1) ion channel has emerged as significant regulators of cardiovascular physiology and pathology. TRPA1 is a non-selective cation channel permeable to calcium ions. A unique feature of the channel is its function as a sensor of various temperature, chemical and mechanical stimuli, while it can also be activated by endogenous inflammatory mediators and reactive oxygen species. Over the last two decades, much progress has been made in illuminating the role of TRPA1 in the regulation of cardiovascular physiology and pathophysiology in addition to its important function in pain sensation. This review provides a comprehensive analysis of recent studies investigating the involvement of TRPA1 channels in various cardiovascular diseases, including myocardial infarction, ischemia-reperfusion injury, myocardial fibrosis, and response to environmental toxins. We discuss the diverse roles of TRPA1 channels in cardiac pathology and highlight their potential as therapeutic targets for cardiovascular disorders. Moreover, we explore the challenges and opportunities linked with targeting TRPA1 channels for treating cardiovascular diseases, alongside future research directions.

Prognostic implications of thyroid hormones in acute aortic dissection: mediating roles of renal function and coagulation.

Thyroid hormones significantly influence cardiovascular pathophysiology, yet their prognostic role in acute aortic dissection (AAD) remains inadequately explored. This study assesses the prognostic value of thyroid hormone levels in AAD, focusing on the mediating roles of renal function and coagulation. We included 964 AAD patients in this retrospective cohort study. Utilizing logistic regression, restricted cubic splines, and causal mediation analysis, we investigated the association between thyroid hormones and in-hospital mortality and major adverse cardiovascular events (MACEs). In AAD patients overall, an increase of one standard deviation in FT4 levels was associated with a 31.9% increased risk of MACEs (OR 1.319; 95% CI 1.098-1.584) and a 36.1% increase in in-hospital mortality (OR 1.361; 95% CI 1.095-1.690). Conversely, a higher FT3/FT4 ratio was correlated with a 20.2% reduction in risk of MACEs (OR 0.798; 95% CI 0.637-0.999). This correlation was statistically significant predominantly in Type A AAD, while it did not hold statistical significance in Type B AAD. Key renal and coagulation biomarkers, including blood urea nitrogen, creatinine, cystatin C, prothrombin time ratio, prothrombin time, and prothrombin time international normalized ratio, were identified as significant mediators in the interplay between thyroid hormones and MACEs. The FT3/FT4 ratio exerted its prognostic influence primarily through the mediation of renal functions and coagulation, while FT4 levels predominantly impacted outcomes via a partial mediation effect on coagulation. FT4 levels and the FT3/FT4 ratio are crucial prognostic biomarkers in AAD patients. Renal function and coagulation mediate the association between the thyroid hormones and MACEs.

Dynamic cardiac imaging as a preclinical cardiovascular pathophysiology teaching aid: Facta non verba

Dynamic cardiac imaging as a preclinical cardiovascular pathophysiology teaching aid: Facta non verba

Application of Cardiovascular Physiology to the Critically Ill Patient.

To use the ventricular pressure-volume relationship and time-varying elastance model to provide a foundation for understanding cardiovascular physiology and pathophysiology, interpreting advanced hemodynamic monitoring, and for illustrating the physiologic basis and hemodynamic effects of therapeutic interventions. We will build on this foundation by using a cardiovascular simulator to illustrate the application of these principles in the care of patients with severe sepsis, cardiogenic shock, and acute mechanical circulatory support. Publications relevant to the discussion of the time-varying elastance model, cardiogenic shock, and sepsis were retrieved from MEDLINE. Supporting evidence was also retrieved from MEDLINE when indicated. Data from relevant publications were reviewed and applied as indicated. The ventricular pressure-volume relationship and time-varying elastance model provide a foundation for understanding cardiovascular physiology and pathophysiology. We have built on this foundation by using a cardiovascular simulator to illustrate the application of these important principles and have demonstrated how complex pathophysiologic abnormalities alter clinical parameters used by the clinician at the bedside.

Central stress pathways in the development of cardiovascular disease.

Mental stress is of essential consideration when assessing cardiovascular pathophysiology in all patient populations. Substantial evidence indicates associations among stress, cardiovascular disease and aberrant brain-body communication. However, our understanding of the flow of stress information in humans, is limited, despite the crucial insights this area may offer into future therapeutic targets for clinical intervention. Key terms including mental stress, cardiovascular disease and central control, were searched in PubMed, ScienceDirect and Scopus databases. Articles indicative of heart rate and blood pressure regulation, or central control of cardiovascular disease through direct neural innervation of the cardiac, splanchnic and vascular regions were included. Focus on human neuroimaging research and the flow of stress information is described, before brain-body connectivity, via pre-motor brainstem intermediates is discussed. Lastly, we review current understandings of pathophysiological stress and cardiovascular disease aetiology. Structural and functional changes to corticolimbic circuitry encode stress information, integrated by the hypothalamus and amygdala. Pre-autonomic brain-body relays to brainstem and spinal cord nuclei establish dysautonomia and lead to alterations in baroreflex functioning, firing of the sympathetic fibres, cellular reuptake of norepinephrine and withdrawal of the parasympathetic reflex. The combined result is profoundly adrenergic and increases the likelihood of cardiac myopathy, arrhythmogenesis, coronary ischaemia, hypertension and the overall risk of future sudden stress-induced heart failure. There is undeniable support that mental stress contributes to the development of cardiovascular disease. The emerging accumulation of large-scale multimodal neuroimaging data analytics to assess this relationship promises exciting novel therapeutic targets for future cardiovascular disease detection and prevention.

Sex as a biological variable for cardiovascular physiology.

There have been ongoing efforts by federal agencies and scientific communities since the early 1990s to incorporate sex and/or gender in all aspects of cardiovascular research. Scientific journals provide a critical function as change agents to influence transformation by encouraging submissions for topic areas, and by setting standards and expectations for articles submitted to the journal. As part of ongoing efforts to advance sex and gender in cardiovascular physiology research, the American Journal of Physiology-Heart and Circulatory Physiology recently launched a call for papers on Considering Sex as a Biological Variable. This call was an overwhelming success, resulting in 78 articles published in this collection. This review summarizes the major themes of the collection, including Sex as a Biological Variable Within: Endothelial Cell and Vascular Physiology, Cardiovascular Immunity and Inflammation, Metabolism and Mitochondrial Energy, Extracellular Matrix Turnover and Fibrosis, Neurohormonal Signaling, and Cardiovascular Clinical and Epidemiology Assessments. Several articles also focused on establishing rigor and reproducibility of key physiological measurements involved in cardiovascular health and disease, as well as recommendations and considerations for study design. Combined, these articles summarize our current understanding of sex and gender influences on cardiovascular physiology and pathophysiology and provide insight into future directions needed to further expand our knowledge.

Soluble urokinase plasminogen activator receptor, platelet aggregation, and carotid plaque thickness in diabetes: A cross-sectional analysis

BackgroundSoluble urokinase plasminogen activator receptor (suPAR) is an inflammatory biomarker strongly linked with cardiovascular disease in diabetes. By investigating its association with platelet aggregation levels and carotid plaque thickness, we can potentially improve the characterization of cardiovascular pathophysiology in type 1 (T1D) and type 2 diabetes (T2D). MethodsSuPAR was measured post-hoc in plasma collected in two cross-sectional studies including 1) individuals with T1D and 2) individuals with T2D without known cardiovascular disease. Platelet aggregation was analyzed employing impedance aggregometry using the agonists arachidonic acid (ASPI), adenosine diphosphate (ADP), and thrombin receptor activating peptide-6 (TRAP). Carotid plaque thickness was assessed bilaterally, and the thickest plaque (cPTmax) was analyzed. Correlations and associations of suPAR with platelet aggregation and cPTmax were assessed with Pearson's R and linear regressions adjusted for sex, age, C-reactive protein, estimated glomerular filtration rate, and platelet levels (only for aggregation analysis). ASPI analyses were only performed in participant not receiving aspirin treatment. Standardized estimates with 95 % confidence intervals are presented. ResultsTwo-hundred eighty-three with T1D (mean age 55 years, 44 % women) and 493 individuals with T2D (mean age 65 years, 33 % women) were included. SuPAR levels were positively correlated to platelet aggregation in both T1D (ADP: R = 0.18, p = 0.003; ASPI R = 0.13, p = 0.026) and T2D (ADP R = 0.14, p = 0.002; ASPI R = 0.14, p = 0.017). In adjusted linear regressions higher SuPAR levels were associated with higher ADP induced platelet aggregation in both T1D (26 (8, 44) AU/min, p = 0.004) and T2D (22 (3, 42) AU/min, p = 0.025), while associations to the other agonists were not conclusive. Higher suPAR levels were associated with thicker cPTmax in T1D (0.19 (0.07, 0.32) mm, p = 0.003), but not in T2D (p = 0.94). ConclusionHigher levels of suPAR, an inflammatory generalized disease biomarker, were associated with increased platelet aggregation and thicker cPTmax, in type 1 diabetes. Similar associations with platelet aggregation were found in type 2 diabetes, but not for carotid plaque thickness. These results suggest distinct cardiovascular pathomechanisms in T1D and T2D, although prospective studies are needed to confirm these findings.

Vascular aging and cardiovascular disease: pathophysiology and measurement in the coronary arteries

Age is a key risk factor for cardiovascular disease, including atherosclerosis. However, pathophysiological disease processes in the arteries are not an inevitable feature of aging. Large cohort studies with arterial phenotyping along with clinical and demographic data are essential to better understand factors related to the susceptibility or resilience to age-related vascular pathophysiology in humans. This review explores the mechanisms by which vascular structure and function alters with age, and how these changes relate to cardiovascular pathophysiology and disease. Features of vascular aging in the coronary arteries have historically been difficult to quantify pre-mortem due to their size and location. However, non-invasive imaging modalities including CT Coronary Angiogram are now being used to assess coronary vascular age, and further advances in imaging analysis such as the CT Fat Attenuation Index will help provide further measurement of features associated with coronary vascular aging. Currently, markers of vascular aging are not used as therapeutic targets in routine clinical practice, but non-pharmacological interventions including aerobic exercise and low salt diet, as well as anti-hypertensives have been demonstrated to reduce arterial stiffness. Advances in imaging technology, both in acquisition and advanced analysis, as well as harmonisation of measurements for researchers across the globe will be invaluable in understanding what constitutes healthy vascular aging and in identifying features of vascular aging that are associated with coronary artery disease and its adverse outcomes. Assessing such images in large cohorts can facilitate improved definitions of resilient and susceptible phenotypes to vascular aging in the coronary arteries. This is a critical step in identifying further risk factors and biomarkers within these groups and driving forward the development of novel therapies aimed at slowing or stopping age-related vascular changes in the coronary arteries.

A specific molecular signature of extra-vesicles (EVs) was associated with cardiometabolic risk profile and atherosclerotic burden in patients with chronic coronary syndrome: a pilot study

Abstract Background microRNAs (miRs) are pivotal regulators of mRNA and protein expression. They critically contribute to cardiovascular pathophysiology and circulate in the blood using extra-vesicles (EVs) as delivery carrier. The role of EV-associated miRs in atherosclerotic cardiovascular disease, however, is unclear. Purpose The aim of this study was to detect Coronary Artery Disease (CAD)-related miRs carried by EVs in stable patients with Chronic Coronary Syndrome (CCS). In particular we aimed to assess whether a specific miRs signature is associated with the cardiometabolic risk profile and coronary atherosclerotic burden and plaque features, as evaluated by coronary computed tomography angiography (CTA) in these patients. Methods miRs with known effects in the cardiovascular system were analysed by real time-PCR in EVs isolated from CCS patients by density gradient centrifugation (n=21). All patients underwent coronary CTA to assess total, calcified, and noncalcified plaque volume (PV). Obstructive CAD was defined as the presence of stenoses >50% in at least one of the main coronary vessels. Results All CCS patients (n=21) were statin users and had coronary atherosclerosis documented by coronary CTA. Among the 25 miRs tested, 7 were detected within EVs and 4 of them, miR-145-5p, miR-30e5-p, miR-126-5p, miR-375, were significantly related with cardiometabolic profile, showing an alternative association with glucose and insulin, a positive correlation with HDL-Cholesterol and a negative correlation with triglycerides, BMI and waist circumference. No association was observed with Total-Cholesterol and LDL-Cholesterol (Figure1). These miRs were also not associated with the presence of obstructive CAD, but were significantly related with total, calcified, and noncalcified PVs (Figure1). Conclusions In CCS patients, among the 25 miRs studied and out of the 7 EV-associated, only 4 miRs were related with a specific cardiometabolic risk profile, characterized by insulin-resistance, obesity, high triglyceride and low HDL-Cholesterol levels. They were also associated with an increased coronary atherosclerotic burden. These results suggest a potential involvement of specific EV-associated miRs in molecular mechanisms of residual atherosclerotic risk.Figure 1

Abstract 14924: SM22-Cre-Mediated SOCS3 Deficient Mice Exhibit Pericardial Fibrosis, Diastolic Dysfunction, and Increased Mortality Rates Due to Augmented Activation of STAT3 in Fibroblasts

Background: Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible potent negative regulator of STAT3 signaling pathway. Here, we aimed to determine whether SOCS3 in non-cardiomyocytes would play a role in cardiovascular pathophysiology. Methods and Results: To investigate the role of SOCS3 in non-cardiomyocytes, we generated conditional knockout mice by crossing SOCS3-flox mice with SM22-α-Cre mice (SM22-SOCS3-KO mice). Mortality rates in the SM22-SOCS3-KO mice was significantly higher than that in the wild-type mice (WT). Heart weight to body weight ratio was significantly increased in SM22-SOCS3-KO mice compared with WT at 12 months of age. Echocardiographic analyses revealed that SM22-SOCS3-KO mice showed significantly increased left ventricular diastolic dysfunction compared with WT from 12 months of age. Sirius-red staining revealed that thickness of pericardium and cardiac interstitial fibrosis in SM22-SOCS3-KO mice were markedly greater compared with WT mice at 12 months of age. Western blot analyses showed that phosphorylated STAT3 was significantly increased in SM22-SOCS3-KO hearts compared with WT mice at 12 months of age. PCR array analysis revealed that the expression of pro-fibrotic ctgf , pdgf , and TGF-beta family genes including tgf-beta1 , tgf-beta2 , and tgf-beta3 , were significantly higher in SM22-SOCS3-KO hearts than those in WT at 6 months of age. We also found that circulating interleukin-6 concentration was significantly higher in SM22-SOCS3-KO mice compared with WT mice at 12 months of age. After interleukin-6 administration, in the heart tissue from SM22-SOCS3-KO mice, coimmunostaining of phosphorylated STAT3 and ER-TR7 revealed that STAT3 activation occurred in fibroblasts in the coronary arterial adventitia and pericardium. Conclusion: Thus, SM22-Cre-mediated SOCS3 deletion induces higher mortality rates, increased pericardial fibrosis, cardiac interstitial fibrosis, and increased diastolic dysfunction in aging mice, possibly through the increased activation of STAT3 in fibroblasts.

Abstract 15185: Plasma miR-132 Serves as a Blood Biomarker for Monitoring Treatment Efficacy of miR-132 Targeting Drugs Using a Novel CE-Marked Kit System

Introduction: MicroRNAs are critical regulators of cardiovascular pathophysiology and detectable in most body fluids, proposing them as circulating biomarkers. The aim of this study was to investigate if plasma miR-132 can be used as a biomarker for monitoring treatment efficacy of miR-132 targeting drugs and to develop a CE-marked kit for relative quantification of plasma miR-132. Methods and Results: Correlation analysis of a porcine model of post myocardial infarction (MI) induced HF revealed a dose-dependent, highly significant linear correlation between plasma and cardiac miR-132 after treatment with CDR132L. Furthermore, significant correlations between reduced plasma miR-132 and functional improvement based on LVEF change as well as reduced plasma NT-proBNP were identified. Based on this data, we developed a qRT-PCR assay for detection of miR-132. RNA was extracted from cel-miR-39 spiked plasma samples and was transcribed into cDNA with specific primers for both miRs. The miRs were amplified in two singleplex qRT-PCRs based on hydrolysis probes. Delta Cq values were calculated between Cq values of miR-132 and the miR-39 spike-in control. No cross-reaction between both assays and no amplification on human DNA or RNA were observed confirming analytical specificity. Analytical sensitivity was verified by analysis of dilution series of cDNA templates. The clinical evaluation was carried out on a subset of 119 samples from the Phase 1b clinical trial, a safety and tolerability study for CDR132L including patients with chronic ischemic HF (NCT04045405), that also assessed target engagement. CDR132L administration was associated with a dose-dependent, statistically significant reduction in plasma miR-132 at study endpoint (day 112) whereas, the highest dosing groups showed sustained low miR levels. These results were in line with miR-132 levels assessed with commercially available research use only reagents. Conclusion: Plasma miR-132 was validated as a suitable target engagement and therapy monitoring biomarker and the newly developed CE-marked kit “CardiorHealth miR-132 Plasma PCR Kit (IVD)“ fulfilled its intended use to quantify plasma miR-132 and can be used for monitoring treatment with drugs targeting miR-132.

Cardiovascular physiology and pathophysiology at high altitude.

Oxygen is vital for cellular metabolism; therefore, the hypoxic conditions encountered at high altitude affect all physiological functions. Acute hypoxia activates the adrenergic system and induces tachycardia, whereas hypoxic pulmonary vasoconstriction increases pulmonary artery pressure. After a few days of exposure to low oxygen concentrations, the autonomic nervous system adapts and tachycardia decreases, thereby protecting the myocardium against high energy consumption. Permanent exposure to high altitude induces erythropoiesis, which if excessive can be deleterious and lead to chronic mountain sickness, often associated with pulmonary hypertension and heart failure. Genetic factors might account for the variable prevalence of chronic mountain sickness, depending on the population and geographical region. Cardiovascular adaptations to hypoxia provide a remarkable model of the regulation of oxygen availability at the cellular and systemic levels. Rapid exposure to high altitude can have adverse effects in patients with cardiovascular diseases. However, intermittent, moderate hypoxia might be useful in the management of some cardiovascular disorders, such as coronary heart disease and heart failure. The aim of this Review is to help physicians to understand the cardiovascular responses to hypoxia and to outline some recommendations that they can give to patients with cardiovascular disease who wish to travel to high-altitude destinations.

Functional Role of Taurine in Aging and Cardiovascular Health: An Updated Overview.

Taurine, a naturally occurring sulfur-containing amino acid, has attracted significant attention in recent years due to its potential health benefits. Found in various foods and often used in energy drinks and supplements, taurine has been studied extensively to understand its impact on human physiology. Determining its exact functional roles represents a complex and multifaceted topic. We provide an overview of the scientific literature and present an analysis of the effects of taurine on various aspects of human health, focusing on aging and cardiovascular pathophysiology, but also including athletic performance, metabolic regulation, and neurological function. Additionally, our report summarizes the current recommendations for taurine intake and addresses potential safety concerns. Evidence from both human and animal studies indicates that taurine may have beneficial cardiovascular effects, including blood pressure regulation, improved cardiac fitness, and enhanced vascular health. Its mechanisms of action and antioxidant properties make it also an intriguing candidate for potential anti-aging strategies.

Speckle-Tracking Strain Analysis for Mapping Spatiotemporal Contractility of Induced Pluripotent Stem Cell (iPSC)-Derived Cardiomyocytes.

Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs) hold tremendous potential for cardiovascular disease modeling, drug screening, personalized medicine, and pathophysiology studies. The availability of a robust protocol and functional assay for studying phenotypic behavior of hiPSC-CMs is essential for establishing an in vitro disease model. Many heart diseases manifest due to changes in the mechanical strain of cardiac tissue. Therefore, non-invasive evaluation of the contractility properties of hiPSC-CMs remains crucial to gain an insight into the pathogenesis of cardiac diseases. Speckle tracking-based strain analysis is an efficient non-invasive method that uses video microscopy and image analysis of beating hiPSC-CMs for quantitative evaluation of mechanical contractility properties. This article presents step-by-step protocols for extracting quantitative contractility properties of an hiPSC-CM system obtained from five members of a family, of whom three were affected by DiGeorge syndrome, using speckle tracking-based strain analysis. The hiPSCs from the family members were differentiated and purified into hiPSC-CMs using metabolic selection. Time-lapse images of hiPSC-CMs were acquired using high-spatial-resolution and high-time-resolution phase-contrast video microscopy. Speckled images were characterized by evaluating the cross-correlation coefficient, speckle size, speckle contrast, and speckle quality of the images. The optimum parameters of the speckle tracking algorithm were determined by performing sensitivity analysis concerning computation time, effective mapping area, average contraction velocity, and strain. Furthermore, the hiPSC-CM response to adrenaline was evaluated to validate the sensitivity of the strain analysis algorithm. Then, we applied speckle tracking-based strain analysis to characterize the dynamic behavior of patient-specific hiPSC-CMs from the family members affected/unaffected by DiGeorge syndrome. Here, we report an efficient and manipulation-free method to analyze the contraction displacement vector and velocity field, contraction-relaxation strain rate, and contractile cycles. Implementation of this method allows for quantitative analysis of the contractile phenotype characteristics of hiPSC-CMs to distinguish possible cardiac manifestation of DiGeorge syndrome. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Differentiation of iPSCs into iPSC-derived cardiomyocytes (iPSC-CMs) and metabolic selection of differentiated iPSC-CMs Support Protocol 1: Culture, maintenance, and expansion of human iPSCs Support Protocol 2: Immunohistochemistry of iPSC-CMs Basic Protocol 2: Time-lapse speckle imaging of iPSC-CMs and speckle quality characterization Support Protocol 3: Enhancement of local contrast of videos by applying contrast limited adaptive histogram equalization (CLAHE) to all frames Support Protocol 4: Evaluation of average speckle size Support Protocol 5: Evaluation of average speckle contrast Support Protocol 6: Determination of relative peak height, Pc(x), of consecutive images acquired from video microscopy of iPSC-CMs Basic Protocol 3: Speckle tracking-based analysis of beating iPSC-CMs Support Protocol 7: Validation of sensitivity of the speckle tracking analysis for mapping the contractility of iPSC-CMs Basic Protocol 4: Data extraction, visualization, and mapping of contractile cycles of iPSC-CMs.

Torsional and strain dysfunction precede overt heart failure in a mouse model of dilated cardiomyopathy pathogenesis.

Detailed assessments of whole heart mechanics are crucial for understanding the consequences of sarcomere perturbations that lead to cardiomyopathy in mice. Echocardiography offers an accessible and cost-effective method of obtaining metrics of cardiac function, but the most routine imaging and analysis protocols might not identify subtle mechanical deficiencies. This study aims to use advanced echocardiography imaging and analysis techniques to identify previously unappreciated mechanical deficiencies in a mouse model of dilated cardiomyopathy (DCM) before the onset of overt systolic heart failure (HF). Mice lacking muscle LIM protein expression (MLP-/-) were used to model DCM-linked HF pathogenesis. Left ventricular (LV) function of MLP-/- and wild-type (WT) controls were studied at 3, 6, and 10 wk of age using conventional and four-dimensional (4-D) echocardiography, followed by speckle-tracking analysis to assess torsional and strain mechanics. Mice were also studied with RNA-seq. Although 3-wk-old MLP-/- mice showed normal LV ejection fraction (LVEF), these mice displayed abnormal torsional and strain mechanics alongside reduced β-adrenergic reserve. Transcriptome analysis showed that these defects preceded most molecular markers of HF. However, these markers became upregulated as MLP-/- mice aged and developed overt systolic dysfunction. These findings indicate that subtle deficiencies in LV mechanics, undetected by LVEF and conventional molecular markers, may act as pathogenic stimuli in DCM-linked HF. Using these analyses in future studies will further help connect in vitro measurements of the sarcomere function to whole heart function.NEW & NOTEWORTHY A detailed study of how perturbations to sarcomere proteins impact whole heart mechanics in mouse models is a major yet challenging step in furthering our understanding of cardiovascular pathophysiology. This study uses advanced echocardiographic imaging and analysis techniques to reveal previously unappreciated subclinical whole heart mechanical defects in a mouse model of cardiomyopathy. In doing so, it offers an accessible set of measurements for future studies to use when connecting sarcomere and whole heart function.

Is polycystic ovary syndrome associated with elevated muscle sympathetic nerve activity?

Polycystic ovary syndrome (PCOS) is a complex disorder characterized by reproductive abnormalities, cardiometabolic disturbances and a heightened risk of cardiovascular disease. A small but compelling body of research demonstrates that females with PCOS present with elevated muscle sympathetic nerve activity (MSNA) at rest. Heightened MSNA is present in lean, overweight and obese females with PCOS, but limited evidence suggests that androgens may be more strongly linked to elevated MSNA in lean females with PCOS than in obese females with PCOS. Although the specific mechanisms underlying elevated MSNA in PCOS remain elusive, sympathetic activation is implicated in the progression of several cardiovascular diseases and may contribute to the cardiovascular pathophysiology of PCOS. Encouragingly, MSNA appears responsive to non-pharmacological intervention, making the sympathetic nervous system a promising therapeutic target to mitigate cardiovascular risk in PCOS. This brief review summarizes the existing evidence regarding elevated MSNA, cardiovascular risk profile and vascular function, as well as the potential for clinical intervention and future research directions in females with PCOS. NEW FINDINGS: What is the topic of this review? The presence of elevated muscle sympathetic nerve activity in females with polycystic ovary syndrome and the implications for cardiovascular health. What advance does it highlight? The sympathetic nervous system likely contributes to elevated cardiovascular disease risk in females with polycystic ovary syndrome. Moreover, it presents as a promising therapeutic target for mitigating cardiovascular disease and merits further investigation.

Short-term changes in klotho and FGF23 in heart failure with reduced ejection fraction-a substudy of the DAPA-VO2 study.

The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO2 (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%-p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8-72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5-37.8), 67.4 ml/min/1.73 m2 (50.7-82.8), 1,285 pg/ml (898-2,305), 623.4 pg/ml (533.5-736.6), and 72.6 RU/ml (62.6-96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9-37.2); p = 0.009] and a non-significant decrease of FGF-23 [Δ-4.6, (-1.7 to -5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23.