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The maternal cardiovascular system undergoes functional and structural adaptations during pregnancy and postpartum to support increased metabolic demands of offspring and placental growth, labor, and delivery, as well as recovery from childbirth. Thus, pregnancy imposes physiological stress upon the maternal cardiovascular system, and in the absence of an appropriate response it imparts potential risks for cardiovascular complications and adverse outcomes. The proportion of pregnancy-related maternal deaths from cardiovascular events has been steadily increasing, contributing to high rates of maternal mortality. Despite advances in cardiovascular physiology research, there is still no comprehensive understanding of maternal cardiovascular adaptations in healthy pregnancies. Furthermore, current approaches for the prognosis of cardiovascular complications during pregnancy are limited. Machine learning (ML) offers new and effective tools for investigating mechanisms involved in pregnancy-related cardiovascular complications as well as the development of potential therapies. The main goal of this review is to summarize existing research that uses ML to understand mechanisms of cardiovascular physiology during pregnancy and develop prediction models for clinical application in pregnant patients. We also provide an overview of ML platforms that can be used to comprehensively understand cardiovascular adaptations to pregnancy and discuss the interpretability of ML outcomes, the consequences of model bias, and the importance of ethical consideration in ML use.
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Aprendizado de Máquina , Humanos , Gravidez , Feminino , Fenômenos Fisiológicos Cardiovasculares , Complicações Cardiovasculares na Gravidez/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Obstetrícia/métodos , Adaptação Fisiológica , Animais , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/diagnósticoRESUMO
Coronary microvascular disease (CMD) and impaired coronary blood flow control are defects that occur early in the pathogenesis of heart failure in cardiometabolic conditions, prior to the onset of atherosclerosis. In fact, recent studies have shown that CMD is an independent predictor of cardiac morbidity and mortality in patients with obesity and metabolic disease. CMD is comprised of functional, structural, and mechanical impairments that synergize and ultimately reduce coronary blood flow in metabolic disease and in other co-morbid conditions, including transplant, autoimmune disorders, chemotherapy-induced cardiotoxicity, and remote injury-induced CMD. This review summarizes the contemporary state-of-the-field related to CMD in metabolic and these other co-morbid conditions based on mechanistic data derived mostly from preclinical small- and large-animal models in light of available clinical evidence and given the limitations of studying these mechanisms in humans. In addition, we also discuss gaps in current understanding, emerging areas of interest, and opportunities for future investigations in this field.
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Comorbidade , Doenças Metabólicas , Humanos , Animais , Doenças Metabólicas/complicações , Doenças Metabólicas/epidemiologia , Circulação Coronária , Microvasos/patologia , Microvasos/metabolismoRESUMO
Introduction: Vascular stiffness is a predictor of cardiovascular disease and pulse wave velocity (PWV) is the current standard for measuring in vivo vascular stiffness. Mean arterial pressure is the largest confounding variable to PWV; therefore, in this study we aimed to test the hypothesis that increased aortic PWV in type 2 diabetic mice is driven by increased blood pressure rather than vascular biomechanics. Methods and Results: Using a combination of in vivo PWV and ex vivo pressure myography, our data demonstrate no difference in ex vivo passive mechanics, including outer diameter, inner diameter, compliance (Db/db: 0.0094 ± 0.0018 mm2/mmHg vs. db/db: 0.0080 ± 0.0008 mm2/mmHg, p > 0.05 at 100 mmHg), and incremental modulus (Db/db: 801.52 ± 135.87 kPa vs. db/db: 838.12 ± 44.90 kPa, p > 0.05 at 100 mmHg), in normal versus diabetic 16 week old mice. We further report no difference in basal or active aorta biomechanics in normal versus diabetic 16 week old mice. Finally, we show here that the increase in diabetic in vivo aortic pulse wave velocity at baseline was completely abolished when measured at equivalent pharmacologically-modulated blood pressures, indicating that the elevated PWV was attributed to the concomitant increase in blood pressure at baseline, and therefore "stiffness." Conclusions: Together, these animal model data suggest an intimate regulation of blood pressure during collection of pulse wave velocity when determining in vivo vascular stiffness. These data further indicate caution should be exerted when interpreting elevated PWV as the pure marker of vascular stiffness.
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Early stopping is an extremely common tool to minimize overfitting, which would otherwise be a cause of poor generalization of the model to novel data. However, early stopping is a heuristic that, while effective, primarily relies on ad hoc parameters and metrics. Optimizing when to stop remains a challenge. In this paper, we suggest that for some biomedical applications, a natural dichotomy of invasive/non-invasive measurements, or more generally proximal vs distal measurements of a biological system can be exploited to provide objective advice on early stopping. We discuss the conditions where invasive measurements of a biological process should provide better predictions than non-invasive measurements, or at best offer parity. Hence, if data from an invasive measurement are available locally, or from the literature, that information can be leveraged to know with high certainty whether a model of non-invasive data is overfitted. We present paired invasive/non-invasive cardiac and coronary artery measurements from two mouse strains, one of which spontaneously develops type 2 diabetes, posed as a classification problem. Examination of the various stopping rules shows that generalization is reduced with more training epochs and commonly applied stopping rules give widely different generalization error estimates. The use of an empirically derived training ceiling is demonstrated to be helpful as added information to leverage early stopping in order to reduce overfitting.
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The lack of pre-clinical large animal models of heart failure with preserved ejection fraction (HFpEF) remains a growing, yet unmet obstacle to improving understanding of this complex condition. We examined whether chronic cardiometabolic stress in Ossabaw swine, which possess a genetic propensity for obesity and cardiovascular complications, produces an HFpEF-like phenotype. Swine were fed standard chow (lean; n = 13) or an excess calorie, high-fat, high-fructose diet (obese; n = 16) for ~ 18 weeks with lean (n = 5) and obese (n = 8) swine subjected to right ventricular pacing (180 beats/min for ~ 4 weeks) to induce heart failure (HF). Baseline blood pressure, heart rate, LV end-diastolic volume, and ejection fraction were similar between groups. High-rate pacing increased LV end-diastolic pressure from ~ 11 ± 1 mmHg in lean and obese swine to ~ 26 ± 2 mmHg in lean HF and obese HF swine. Regression analyses revealed an upward shift in LV diastolic pressure vs. diastolic volume in paced swine that was associated with an ~ twofold increase in myocardial fibrosis and an ~ 50% reduction in myocardial capillary density. Hemodynamic responses to graded hemorrhage revealed an ~ 40% decrease in the chronotropic response to reductions in blood pressure in lean HF and obese HF swine without appreciable changes in myocardial oxygen delivery or transmural perfusion. These findings support that high-rate ventricular pacing of lean and obese Ossabaw swine initiates underlying cardiac remodeling accompanied by elevated LV filling pressures with normal ejection fraction. This distinct pre-clinical tool provides a unique platform for further mechanistic and therapeutic studies of this highly complex syndrome.
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Insuficiência Cardíaca , Animais , Frutose , Obesidade/complicações , Oxigênio , Fenótipo , Volume Sistólico/fisiologia , Suínos , Função Ventricular EsquerdaRESUMO
BACKGROUND: Notch signaling is an evolutionarily conserved pathway that functions via direct cell-cell contact. The Notch ligand Jagged1 (Jag1) has been extensively studied in vascular development, particularly for its role in smooth muscle cell maturation. Endothelial cell-expressed Jag1 is essential for blood vessel formation by signaling to nascent vascular smooth muscle cells and promoting their differentiation. Given the established importance of Jag1 in endothelial cell/smooth muscle crosstalk during development, we sought to determine the extent of this communication in the adult vasculature for blood vessel function and homeostasis. METHODS: We conditionally deleted Jag1 in endothelial cells of adult mice and examined the phenotypic consequences on smooth muscle cells of the vasculature. RESULTS: Our results show that genetic loss of Jag1 in endothelial cells has a significant impact on Notch signaling and vascular smooth muscle function in mature blood vessels. Endothelial cell-specific deletion of Jag1 causes a concomitant loss of JAG1 and NOTCH3 expression in vascular smooth muscle cells, resulting in a transition to a less differentiated state. Aortic vascular smooth muscle cells isolated from the endothelial cell-specific Jag1 deficient mice retain an altered phenotype in culture with fixed changes in gene expression and reduced Notch signaling. Utilizing comparative RNA-sequence analysis, we found that Jag1 deficiency preferentially affects extracellular matrix and adhesion protein gene expression. Vasoreactivity studies revealed a reduced contractile response and impaired agonist-induced relaxation in endothelial cell Jag1-deficient aortas compared to controls. CONCLUSIONS: These data are the first to demonstrate that Jag1 in adult endothelial cells is required for the regulation and homeostasis of smooth muscle cell function in arterial vessels partially through the autoregulation of Notch signaling and cell matrix/adhesion components in smooth muscle cells.
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Células Endoteliais , Receptores Notch , Animais , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Células Endoteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ligantes , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Músculo Liso Vascular/metabolismo , Fenótipo , RNA/metabolismo , Receptores Notch/genética , Receptores Notch/metabolismo , Proteínas Serrate-Jagged/genética , Proteínas Serrate-Jagged/metabolismoRESUMO
Aging is a nonmodifiable risk factor for cardiovascular disease associated with arterial stiffening and endothelial dysfunction. We hypothesized that sex differences exist in vascular aging processes and would be attenuated by global deletion of the G protein-coupled estrogen receptor. Blood pressure was measured by tail-cuff plethysmography, pulse wave velocity (PWV) and echocardiography were assessed with high-resolution ultrasound, and small vessel reactivity was measured using wire myography in adult (25 wk) and middle-aged (57 wk) male and female mice. Adult female mice displayed lower blood pressure and PWV, but this sex difference was absent in middle-aged mice. Aging significantly increased PWV but not blood pressure in both sexes. Adult female carotids were more distensible than males, but this sex difference was lost during aging. Acetylcholine-induced relaxation was greater in female than male mice at both ages, and only males showed aging-induced changes in cardiac hypertrophy and function. GPER deletion removed the sex difference in PWV and ex vivo stiffness in adult mice. The sex difference in blood pressure was absent in KO mice and was associated with endothelial dysfunction in females. These findings indicate that the impact of aging on arterial stiffening and endothelial function is not the same in male and female mice. Moreover, nongenomic estrogen signaling through GPER impacted vascular phenotype differently in male and female mice. Delineating sex differences in vascular changes during healthy aging is an important first step in improving early detection and sex-specific treatments in our aging population.NEW & NOTEWORTHY Indices of vascular aging were different in male and female mice. Sex differences in pulse wave velocity, blood pressure, and large artery stiffness were abrogated in middle-aged mice, but the female advantage in resistance artery vasodilator function was maintained. GPER deletion abrogated these sex differences and significantly reduced endothelial function in adult female mice. Additional studies are needed to characterize sex differences in vascular aging to personalize early detection and treatment for vascular diseases.
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Análise de Onda de Pulso , Rigidez Vascular , Animais , Pressão Sanguínea/fisiologia , Artérias Carótidas/diagnóstico por imagem , Feminino , Masculino , Camundongos , Receptores Acoplados a Proteínas G/genética , Caracteres Sexuais , Rigidez Vascular/fisiologiaRESUMO
Background: Tissue-engineered vascular grafts (TEVGs) have the potential to advance the surgical management of infants and children requiring congenital heart surgery by creating functional vascular conduits with growth capacity. Methods: Herein, we used an integrative computational-experimental approach to elucidate the natural history of neovessel formation in a large animal preclinical model; combining an in vitro accelerated degradation study with mechanical testing, large animal implantation studies with in vivo imaging and histology, and data-informed computational growth and remodeling models. Results: Our findings demonstrate that the structural integrity of the polymeric scaffold is lost over the first 26 weeks in vivo, while polymeric fragments persist for up to 52 weeks. Our models predict that early neotissue accumulation is driven primarily by inflammatory processes in response to the implanted polymeric scaffold, but that turnover becomes progressively mechano-mediated as the scaffold degrades. Using a lamb model, we confirm that early neotissue formation results primarily from the foreign body reaction induced by the scaffold, resulting in an early period of dynamic remodeling characterized by transient TEVG narrowing. As the scaffold degrades, mechano-mediated neotissue remodeling becomes dominant around 26 weeks. After the scaffold degrades completely, the resulting neovessel undergoes growth and remodeling that mimicks native vessel behavior, including biological growth capacity, further supported by fluid-structure interaction simulations providing detailed hemodynamic and wall stress information. Conclusions: These findings provide insights into TEVG remodeling, and have important implications for clinical use and future development of TEVGs for children with congenital heart disease.
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Coronary artery disease is the leading cause of heart disease, and while it can be assessed through transthoracic Doppler echocardiography (TTDE) by observing changes in coronary flow, manual analysis of TTDE is time consuming and subject to bias. In a previous study, a program was created to automatically analyze coronary flow patterns by parsing Doppler videos into a single continuous image, binarizing and separating the image into cardiac cycles, and extracting data values from each of these cycles. The program significantly reduced variability and time to complete TTDE analysis, but some obstacles such as interfering noise and varying video sizes left room to increase the program's accuracy. The goal of this current study was to refine the existing automation algorithm and heuristics by (1) moving the program to a Python environment, (2) increasing the program's ability to handle challenging cases and video variations, and (3) removing unrepresentative cardiac cycles from the final data set. With this improved analysis, examiners can use the automatic program to easily and accurately identify the early signs of serious heart diseases.
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Doença da Artéria Coronariana , Cardiopatias , Velocidade do Fluxo Sanguíneo , Doença da Artéria Coronariana/diagnóstico por imagem , Circulação Coronária , Vasos Coronários/diagnóstico por imagem , Ecocardiografia/métodos , Ecocardiografia Doppler/métodos , Coração , Humanos , Ultrassonografia DopplerRESUMO
OBJECTIVE: Aortic valve disease is a common worldwide health burden with limited treatment options. Studies have shown that the valve endothelium is critical for structure-function relationships, and disease is associated with its dysfunction, damage, or injury. Therefore, therapeutic targets to maintain a healthy endothelium or repair damaged endothelial cells could hold promise. In this current study, we utilize a surgical mouse model of heart valve endothelial cell injury to study the short-term response at molecular and cellular levels. The goal is to determine if the native heart valve exhibits a reparative response to injury and identify the mechanisms underlying this process. Approach and Results: Mild aortic valve endothelial injury and abrogated function was evoked by inserting a guidewire down the carotid artery of young (3 months) and aging (16-18 months) wild-type mice. Short-term cellular responses were examined at 6 hours, 48 hours, and 4 weeks following injury, whereas molecular profiles were determined after 48 hours by RNA-sequencing. Within 48 hours following endothelial injury, young wild-type mice restore endothelial barrier function in association with increased cell proliferation, and upregulation of transforming growth factor beta 1 (Tgfß1) and the glycoprotein, collagen triple helix repeat containing 1 (Cthrc1). Interestingly, this beneficial response to injury was not observed in aging mice with known underlying endothelial dysfunction. CONCLUSIONS: Data from this study suggests that the healthy valve has the capacity to respond to mild endothelial injury, which in short term has beneficial effects on restoring endothelial barrier function through acute activation of the Tgfß1-Cthrc1 signaling axis and cell proliferation.
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Doenças da Aorta/metabolismo , Endotélio Vascular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Envelhecimento/metabolismo , Animais , Proliferação de Células , Células Cultivadas , Modelos Animais de Doenças , Matriz Extracelular/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Análise de Sequência de RNA , Suínos , Regulação para CimaRESUMO
The virus responsible for coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has infected over 190 million people to date, causing a global pandemic. SARS-CoV-2 relies on binding of its spike glycoprotein to angiotensin-converting enzyme 2 (ACE2) for infection. In addition to fever, cough, and shortness of breath, severe cases of SARS-CoV-2 infection may result in the rapid overproduction of pro-inflammatory cytokines. This overactive immune response is known as a cytokine storm, which leads to several serious clinical manifestations such as acute respiratory distress syndrome and myocardial injury. Cardiovascular disorders such as acute coronary syndrome (ACS) and heart failure not only enhance disease progression at the onset of infection, but also arise in hospitalized patients with COVID-19. Tissue-specific differentiated cells and organoids derived from human pluripotent stem cells (hPSCs) serve as an excellent model to address how SARS-CoV-2 damages the lungs and the heart. In this review, we summarize the molecular basis of SARS-CoV-2 infection and the current clinical perspectives of the bidirectional relationship between the cardiovascular system and viral progression. Furthermore, we also address the utility of hPSCs as a dynamic model for SARS-CoV-2 research and clinical translation.
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COVID-19/virologia , Sistema Cardiovascular/virologia , Células-Tronco Pluripotentes/virologia , COVID-19/imunologia , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/virologia , Sistema Cardiovascular/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Humanos , Pulmão/imunologia , Pulmão/virologia , Pandemias/prevenção & controle , Células-Tronco Pluripotentes/imunologia , SARS-CoV-2/patogenicidadeRESUMO
Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Whether MR blockade improves in vivo regulation of coronary flow, a process involving voltage-dependent K+ (Kv) channel activation, or reduces coronary structural remodeling in obesity is unclear. Thus, the goals of this investigation were to determine the effects of obesity on coronary responsiveness to reductions in arterial PO2 and potential involvement of Kv channels and whether the benefit of MR blockade involves improved coronary Kv function or altered passive structural properties of the coronary microcirculation. Hypoxemia increased coronary blood flow similarly in lean and obese swine; however, baseline coronary vascular resistance was significantly higher in obese swine. Inhibition of Kv channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. Chronic MR inhibition in obese swine normalized baseline coronary resistance, did not influence hypoxemic coronary vasodilation, and did not restore coronary Kv function (assessed in vivo, ex vivo, and via patch clamping). Lastly, MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of Kv channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening.
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Aldosterona/farmacologia , Doença da Artéria Coronariana/prevenção & controle , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Obesidade/tratamento farmacológico , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Resistência Vascular/efeitos dos fármacos , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Feminino , Masculino , Microcirculação/efeitos dos fármacos , Obesidade/complicações , Obesidade/metabolismo , Obesidade/fisiopatologia , Sus scrofa , Rigidez Vascular/efeitos dos fármacosRESUMO
ΔR4-R23/ΔCT micro-dystrophin (µDys) is a miniaturized version of dystrophin currently evaluated in a Duchenne muscular dystrophy (DMD) gene therapy trial to treat skeletal and cardiac muscle disease. In pre-clinical studies, µDys efficiently rescues cardiac histopathology, but only partially normalizes cardiac function. To gain insights into factors that may impact the cardiac therapeutic efficacy of µDys, we compared by mass spectrometry the composition of purified dystrophin and µDys protein complexes in the mouse heart. We report that compared to dystrophin, µDys has altered associations with α1- and ß2-syntrophins, as well as cavins, a group of caveolae-associated signaling proteins. In particular, we found that membrane localization of cavin-1 and cavin-4 in cardiomyocytes requires dystrophin and is profoundly disrupted in the heart of mdx5cv mice, a model of DMD. Following cardiac stress/damage, membrane-associated cavin-4 recruits the signaling molecule ERK to caveolae, which activates key cardio-protective responses. Evaluation of ERK signaling revealed a profound inhibition, below physiological baseline, in the mdx5cv mouse heart. Expression of µDys in mdx5cv mice prevented the development of cardiac histopathology but did not rescue membrane localization of cavins nor did it normalize ERK signaling. Our study provides the first comparative analysis of purified protein complexes assembled in vivo by full-length dystrophin and a therapeutic micro-dystrophin construct. This has revealed disruptions in cavins and ERK signaling that may contribute to DMD cardiomyopathy. This new knowledge is important for ongoing efforts to prevent and treat heart disease in DMD patients.
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Cardiomiopatias , Distrofia Muscular de Duchenne , Animais , Cardiomiopatias/genética , Distrofina/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos mdx , Distrofia Muscular de Duchenne/metabolismo , Miócitos Cardíacos/metabolismo , ProteômicaRESUMO
The measurement of vascular function in isolated vessels has revealed important insights into the structural, functional, and biomechanical features of the normal and diseased cardiovascular system and has provided a molecular understanding of the cells that constitutes arteries and veins and their interaction. Further, this approach has allowed the discovery of vital pharmacological treatments for cardiovascular diseases. However, the expansion of the vascular physiology field has also brought new concerns over scientific rigor and reproducibility. Therefore, it is appropriate to set guidelines for the best practices of evaluating vascular function in isolated vessels. These guidelines are a comprehensive document detailing the best practices and pitfalls for the assessment of function in large and small arteries and veins. Herein, we bring together experts in the field of vascular physiology with the purpose of developing guidelines for evaluating ex vivo vascular function. By using this document, vascular physiologists will have consistency among methodological approaches, producing more reliable and reproducible results.
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Artérias/fisiologia , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Veias/fisiologia , Animais , Endotélio Vascular/fisiologia , Microscopia/métodos , Miografia/métodos , Reprodutibilidade dos TestesRESUMO
Pressure overload (PO) and volume overload (VO) of the heart result in distinctive changes to geometry, due to compensatory structural remodeling. This remodeling potentially leads to changes in tissue mechanical properties. Understanding such changes is important, as tissue modulus has an impact on cardiac performance, disease progression, and influences on cell phenotype. Pressure-volume (PV) loop analysis, a clinically relevant method for measuring left ventricular (LV) chamber stiffness, was performed in vivo on control rat hearts and rats subjected to either chronic PO through Angiotensin-II infusion (4-weeks) or VO (8-weeks). Immediately following PV loops, biaxial testing was performed on LV free wall tissue to directly measure tissue mechanical properties. The ß coefficient, an index of chamber stiffness calculated from the PV loop analysis, increased 98% in PO (n = 4) and decreased 38% in VO (n = 5) compared to control (n = 6). Material constants of LV walls obtained from ex vivo biaxial testing (n = 9-10) were not changed in Angiotensin-II induced PO and decreased by about half in VO compared to control (47% in the circumferential and 57% the longitudinal direction). PV loop analysis showed the expected increase in chamber stiffness of PO and expected decrease in chamber stiffness of VO. Biaxial testing showed a decreased modulus of the myocardium of the VO model, but no changes in the PO model, this suggests the increased chamber stiffness in PO, as shown in the PV loop analysis, may be secondary to changes in tissue mass and/or geometry but not an increase in passive tissue mechanical properties.