Cardiovascular Alterations Research Articles

Susceptibility of Mice Lacking Renin‐b to Chronic Angiotensin II Infusion

Previous experience to various hypertensive conditions enhances the response to subsequent hypertensive challenges. Importantly, the activation of the brain renin angiotensin system (RAS) is required for the sensitization to these hypertensive challenges. We previously reported that the brain‐specific renin isoform (Ren‐b) tonically inhibits the activation of the brain RAS and that ablation of Ren‐b (Ren‐b KO) results in brain RAS disinhibition leading to mild hypertension. Retrospective analysis of five cohorts of mice indicated that Ren‐b KO model exhibits a high degree of variability in blood pressure (BP) and heart rate, which may be attributed to the susceptibility to stress. Therefore, we hypothesized that Ren‐b KO mice are sensitized to a hypertensive challenge such as angiotensin II (Ang II). Wildtype (WT) or Ren‐b KO mice were infused with either vehicle or Ang II (400 ng/kg/min; sc) via osmotic minipumps for 4 weeks. All data was expressed as mean ± SE and unpaired t‐test was used for statistical analysis. P <0.05 was considered significant. Ang II significantly increased BP in both WT and Ren‐b KO to the same degree (WT+veh: 103±4 vs WT+Ang: 120±4 mmHg; p = 0.0143 (n=10–12) and KO+veh: 104±3 vs KO+Ang: 118±5 mmHg; p = 0.0291 (n=10–14)). Although the BP between Ren‐b KO and WT mice was elevated equally, Ang II induced an exaggerated suppression of plasma renin in Ren‐b KO compared to WT (WT+Ang: 14.8±2.1 vs KO±Ang: 7.2±2.6 ng/ml; p = 0. 0251; n=7–9). Ren‐b KO exhibited enhanced Ang II‐induced dipsogenic response (WT+Ang: 3.7±0.3 vs KO+Ang: 4.6±0.4 ml/day; p = 0. 0495; n=10–12) and exhibited elevated heart weight (WT+Ang: 4.8±0.2 vs KO±Ang: 5.2±0.1 mg/g of body weight; p = 0.026; n=10–12) concomitant with a 87% increase in cardiac collagen type I alpha‐2 mRNA expression (p = 0.0275; n=7–9). Altogether, this data indicates that in the presence of Ang II, Ren‐b KO exhibits susceptibility to cardiovascular disease including cardiac hypertrophy and fibrosis. After successive breeding and backcrossing Ren‐b KO mice at baseline developed a milder and more variable BP elevation compared to our initial cohorts. This suggests that epigenetic silencing or other physiological mechanisms, such as downregulation of peripheral RAS, might compensate for some, but not all, of the cardiovascular alterations driven by the genetic deletion of renin‐b. Studies of a conditional Ren‐b KO model will be used to elucidate the physiological and/or pathophysiological consequences of an acute downregulation of renin‐b in adulthood.Support or Funding InformationNHLBI PPG P01 HL084207This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Generation and characterization of a novel knockin minipig model of Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease is characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo LMNA c.1824C > T mutation, which provokes the expression of a dominant-negative mutant protein called progerin. Therapies proven effective in HGPS-like mouse models have yielded only modest benefit in HGPS clinical trials. To overcome the gap between HGPS mouse models and patients, we have generated by CRISPR-Cas9 gene editing the first large animal model for HGPS, a knockin heterozygous LMNA c.1824C > T Yucatan minipig. Like HGPS patients, HGPS minipigs endogenously co-express progerin and normal lamin A/C, and exhibit severe growth retardation, lipodystrophy, skin and bone alterations, cardiovascular disease, and die around puberty. Remarkably, the HGPS minipigs recapitulate critical cardiovascular alterations seen in patients, such as left ventricular diastolic dysfunction, altered cardiac electrical activity, and loss of vascular smooth muscle cells. Our analysis also revealed reduced myocardial perfusion due to microvascular damage and myocardial interstitial fibrosis, previously undescribed readouts potentially useful for monitoring disease progression in patients. The HGPS minipigs provide an appropriate preclinical model in which to test human-size interventional devices and optimize candidate therapies before advancing to clinical trials, thus accelerating the development of effective applications for HGPS patients.

Preeclampsia-Associated Alteration of DNA Methylation in Fetal Endothelial Progenitor Cells

ObjectiveThe pregnancy complication preeclampsia represents an independent risk factor for cardiovascular disease. Our previous research shows a diminished function of fetal endothelial colony-forming cells (ECFC), a proliferative subgroup of endothelial progenitor cells (EPC) in preeclampsia. The aim of this study was to further investigate whether DNA methylation of fetal EPC is affected in preeclampsia.MethodsThe genomic methylation pattern of fetal ECFC from uncomplicated and preeclamptic pregnancies was compared for 865918 CpG sites, and genes were classified into gene networks. Low and advanced cell culture passages were compared to explore whether expansion of fetal ECFC in cell culture leads to changes in global methylation status and if methylation characteristics in preeclampsia are maintained with increasing passage.ResultsA differential methylation pattern of fetal ECFC from preeclampsia compared to uncomplicated pregnancy was detected for a total of 1266 CpG sites in passage 3, and for 2362 sites in passage 5. Key features of primary networks implicated by methylation differences included cell metabolism, cell cycle and transcription and, more specifically, genes involved in cell-cell interaction and Wnt signaling. We identified an overlap between differentially regulated pathways in preeclampsia and cardiovascular system development and function. Cell culture passages 3 and 5 showed similar gene network profiles, and 1260 out of 1266 preeclampsia-associated methylation changes detected in passage 3 were confirmed in passage 5.ConclusionMethylation modification caused by preeclampsia is stable and detectable even in higher cell culture passages. An epigenetically modified endothelial precursor may influence both normal morphogenesis and postnatal vascular repair capacity. Further studies on epigenetic modifications in complicated pregnancies are needed to facilitate development of EPC based therapies for cardiovascular alterations.

Vascular smooth muscle cell-specific progerin expression in a mouse model of Hutchinson-Gilford progeria syndrome promotes arterial stiffness: Therapeutic effect of dietary nitrite.

Vascular stiffness is a major cause of cardiovascular disease during normal aging and in Hutchinson–Gilford progeria syndrome (HGPS), a rare genetic disorder caused by ubiquitous progerin expression. This mutant form of lamin A causes premature aging associated with cardiovascular alterations that lead to death at an average age of 14.6 years. We investigated the mechanisms underlying vessel stiffness in LmnaG609G/G609G mice with ubiquitous progerin expression, and tested the effect of treatment with nitrites. We also bred LmnaLCS/LCSTie2Cre+/tgand LmnaLCS/LCSSM22αCre+/tg mice, which express progerin specifically in endothelial cells (ECs) and in vascular smooth muscle cells (VSMCs), respectively, to determine the specific contribution of each cell type to vascular pathology. We found vessel stiffness and inward remodeling in arteries of LmnaG609G/G609G and LmnaLCS/LCSSM22αCre+/tg, but not in those from LmnaLCS/LCSTie2Cre+/tgmice. Structural alterations in aortas of progeroid mice were associated with decreased smooth muscle tissue content, increased collagen deposition, and decreased transverse waving of elastin layers in the media. Functional studies identified collagen (unlike elastin and the cytoskeleton) as an underlying cause of aortic stiffness in progeroid mice. Consistent with this, we found increased deposition of collagens III, IV, V, and XII in the media of progeroid aortas. Vessel stiffness and inward remodeling in progeroid mice were prevented by adding sodium nitrite in drinking water. In conclusion, LmnaG609G/G609G arteries exhibit stiffness and inward remodeling, mainly due to progerin‐induced damage to VSMCs, which causes increased deposition of medial collagen and a secondary alteration in elastin structure. Treatment with nitrites prevents vascular stiffness in progeria.

Endocrine Adjuvant Therapy might Impair Cardiac Autonomic Regulation in Breast Cancer Survivors

Introduction: Cardiovascular diseases and mortality represent a major issue in breast cancer survivors (BCS). Unhealthy lifestyle and some side effects of long term adjuvant therapy may contribute to increase cardiovascular risk. Autonomic Nervous System (ANS) impairment may contribute to initial cardiovascular alteration and early detection of its malfunction in clinical settings could help foster cardiovascular health in these patients.Methods: This observational study involved 229 outpatient subjects subdivided into three groups: 1) BCS under long term Adjuvant Endocrine Therapy (AET), 2) BCS not on AET, 3) matched healthy controls. Autoregressive spectral analysis of cardiovascular variabilities furnished markers of ANS control, considering simple time and frequency domain classifiers (such as RR variance), and meta-classifiers (such as the index alpha, combining RR and arterial pressure oscillatory information, or ANSI, a percent ranked multivariate unitary index of Autonomic control). Patients’ history, medical examination, blood tests and a lifestyle questionnaire, focusing on exercise, nutrition, and stress, were also employed. Results: Amplitude indices of ANS regulation (in particular RR variance) appeared progressively (p<0.001) reduced from Controls to Patients not receiving (AET-) and to those receiving (AET+) endocrine therapy; similar changes were observed for meta-classifiers (particularly ANSI: 65.2 ± 21.7; 56.9 ± 27.7; 43.1 ± 26.2, p<0.001)). Conclusion: Endocrine therapy is associated with impaired autonomic regulation. Autoregressive spectral analysis of heart rate variability may be an affordable and convenient tool to furnish, in a clinical setting, early markers of cardiovascular dysregulation, which may possibly contribute to an overall increased cardiovascular risk.

Rapid changes in the microvascular circulation of skeletal muscle impair insulin delivery during sepsis.

Sepsis costs the healthcare system $23 billion annually and has a mortality rate between 10 and 40%. An early indication of sepsis is the onset of hyperglycemia, which is the result of sepsis-induced insulin resistance in skeletal muscle. Previous investigations have focused on events in the myocyte (e.g., insulin signaling and glucose transport and subsequent metabolism) as the causes for this insulin-resistant state. However, the delivery of insulin to the skeletal muscle is also an important determinant of insulin action. Skeletal muscle microvascular blood flow, which delivers the insulin to the muscle, is known to be decreased during sepsis. Here we test whether the reduced capillary blood flow to skeletal muscle belies the sepsis-induced insulin resistance by reducing insulin delivery to the myocyte. We hypothesize that decreased capillary flow and consequent decrease in insulin delivery is an early event that precedes gross cardiovascular alterations seen with sepsis. This hypothesis was examined in mice treated with either lipopolysaccharide (LPS) or polymicrobial sepsis followed by intravital microscopy of the skeletal muscle microcirculation. We calculated insulin delivery to the myocyte using two independent methods and found that LPS and sepsis rapidly reduce insulin delivery to the skeletal muscle by ~50%; this was driven by decreases in capillary flow velocity and the number of perfused capillaries. Furthermore, the changes in skeletal muscle microcirculation occur before changes in both cardiac output and arterial blood pressure. These data suggest that a rapid reduction in skeletal muscle insulin delivery contributes to the induction of insulin resistance during sepsis.

TRP Channels: Current Perspectives in the Adverse Cardiac Remodeling.

Calcium is an important second messenger required not only for the excitation-contraction coupling of the heart but also critical for the activation of cell signaling pathways involved in the adverse cardiac remodeling and consequently for the heart failure. Sustained neurohumoral activation, pressure-overload, or myocardial injury can cause pathologic hypertrophic growth of the heart followed by interstitial fibrosis. The consequent heart’s structural and molecular adaptation might elevate the risk of developing heart failure and malignant arrhythmia. Compelling evidences have demonstrated that Ca2+ entry through TRP channels might play pivotal roles in cardiac function and pathology. TRP proteins are classified into six subfamilies: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPA (ankyrin), TRPML (mucolipin), and TRPP (polycystin), which are activated by numerous physical and/or chemical stimuli. TRP channels participate to the handling of the intracellular Ca2+ concentration in cardiac myocytes and are mediators of different cardiovascular alterations. This review provides an overview of the current knowledge of TRP proteins implication in the pathologic process of some frequent cardiac diseases associated with the adverse cardiac remodeling such as cardiac hypertrophy, fibrosis, and conduction alteration.

Biopsychosocial Needs of the Patients Post Renal Transplant

Renal transplantation is the surgical implantation of a human functioning kidney from either living donor or a cadaver into a patient with end-stage renal failure. Aim of the study: to assess biopsychosocial needs of patients post renal transplant. Design: A descriptive exploratory design was utilized. Setting: this study was conducted at out-patient clinics of the National Institute of Nephrology and Urology in Matariya Hospital. Study subjects: A Purposive sample including all patients admitted to outpatient clinics in the previous mentioned setting. Data collection tools: 1)Patient`s interviewing questionnaire, it includes the following parts, 1) concerned with demographic characteristics of the study subjects (age, gender and marital status),2) Past medical history of patients under study,) Biopsychosocial needs assessment sheet including the following sections: A) Physical needs assessment, B) Psychological needs assessment, C)Social needs assessment, D) Educational needs assessment. Results: the study showed that, the common systemic needs among studied patients were cardiovascular system alterations followed by rest and sleep alterations. Regarding daily living activity function, it was found that more than one third of patients under study had severe function impairment. Conclusion: this study concluded that, regarding psychological needs, it was found more than one third of study subjects had moderate depression and extremely severe anxiety level. Recommendation: the study recommended supportive care services in any hospital care setting should be directed towards meeting biopsychosocial needs of patients post renal transplant.

Glutamate and GABA neurotransmission are increased in paraventricular nucleus of hypothalamus in rats induced to 6‐OHDA parkinsonism: Involvement of nNOS

Parkinson's disease (PD) is a progressive neurodegenerative disease that manifests itself clinically after reaching an advanced pathological stage. Besides motor signals, PD patients present cardiovascular and autonomic alterations. Recent data showed that rats induced to Parkinsonism by 6-hydroxydopamine (6-OHDA) administration in the substantia nigra pars compacta (SNpc) showed lower mean arterial pressure (MAP) and heart rate (HR), as reduction in sympathetic modulation. The paraventricular nucleus of the hypothalamus (PVN) is an important site for autonomic and cardiovascular control, and amino acid neurotransmission has a central role. We evaluate PVN amino acid neurotransmission in cardiovascular and autonomic effects of 6-OHDA Parkinsonism. Male Wistar rats were submitted to guide cannulas implantation into the PVN. 6-OHDA or sterile saline (sham) was administered bilaterally in the SNpc. After 7days, cardiovascular recordings in conscious state was performed. Bicuculline promoted an increase in MAP and HR in sham group and exacerbated those effects in 6-OHDA group. NBQX (non-NMDA inhibitor) did not promote changes in sham as in 6-OHDA group. On the other hand, PVN microinjection of LY235959 (NMDA inhibitor) in sham group did not induced cardiovascular alterations, but decreased MAP and HR in 6-OHDA group. Compared to Sham group, 6-OHDA lesion increased the number of neuronal nitric oxide synthase (nNOS)-immunoreactive neurons in the PVN and, nNOS inhibition promoted higher increases in MAP and HR. Our data suggest that the decreased baseline blood pressure and heart rate in animals with Parkinsonism may be due to an increased GABAergic tone via nNOS in the PVN.

Nondipping Pattern and Cardiovascular and Renal Damage in a Population-Based Study (The STANISLAS Cohort Study).

The attenuation of physiological nocturnal decline of blood pressure (BP)-called nondipper pattern-has previously been reported to be associated with target organ damage in hypertensive subjects. However, this association remains debated and poorly studied in normotensive patients. This study aimed to investigate the association between nondipper pattern and subclinical cardiovascular and renal damage in an initially healthy population-based cohort study. The STANISLAS Cohort is a single-center, familial longitudinal cohort composed of 1,006 families (4,295 subjects) recruited in 1993-1995 for a 5-year periodic health examination. A total of 1,334 subjects from the 4th visit (2011-2016) of the STANISLAS cohort were included. This 4th examination included estimated glomerular filtration rate, albumin/creatinine ratio, pulse wave velocity, central systolic BP, carotid intima-media thickness and distensibility, left ventricular mass index, left ventricular hypertrophy, diastolic dysfunction, and ambulatory blood pressure monitoring (ABPM). Nondipping status was defined as a mean reduction in systolic BP (SBP) or diastolic BP (DBP) lower than 10% during nighttime. Data were obtained from 798 normotensive subjects (45 ± 14 years, 395 [49%] nondippers, SBP/DBP mmHg 24 hours: 116/71 ± 7/5) and 536 hypertensive patients (56 ± 11 years, 257 [48%] nondippers, SBP/DBP mmHg 24 hours: 127/78 ± 10/7). Mean 24-hour and daytime ABPM measurements were within the normal range, even in hypertensive participants (19% treated). The nondipping pattern was not associated with cardiovascular or renal alterations in this population. In this middle-aged population with an overall 24-hour optimal BP control, the nondipper pattern was not associated with increased cardiovascular or renal damage.

¿Cuál es la seguridad de un programa de ejercicio, como intervención, durante la hemodiálisis para el paciente con enfermedad renal crónica?

La enfermedad renal crónica es una patología de alto costo, disminuye la calidad de vida, especialmente, la de los pacientes en hemodiálisis, es importante implementar estrategias para reducir su impacto clínico y económico. El ejercicio intradiálisis ha mostrado la reducción en la mortalidad por cualquier causa y mejoría en la calidad de vida.

Risk of cardiovascular involvement in pediatric patients with X-linked hypophosphatemia.

To find out if cardiovascular alterations are present in pediatric patients with X-linked hypophosphatemia (XLH). Multicentre prospective clinical study on pediatric patients included in the RenalTube database ( www.renaltube.com ) with genetically confirmed diagnosis of XLH by mutations in the PHEX gene. The study's protocol consisted of biochemical work-up, 24-h ambulatory blood pressure monitoring (ABPM), carotid ultrasonography, and echocardiogram. All patients were on chronic treatment with phosphate supplements and 1-hydroxy vitamin D metabolites. Twenty-four patients (17 females, from 1 to 17years of age) were studied. Serum concentrations (X ± SD) of phosphate and intact parathyroid hormone were 2.66 ± 0.60mg/dl and 58.3 ± 26.8pg/ml, respectively. Serum fibroblast growth factor 23 (FGF23) concentration was 278.18 ± 294.45pg/ml (normal < 60pg/ml). Abnormally high carotid intima media thickness was found in one patient, who was obese and hypertensive as revealed by ABPM, which disclosed arterial hypertension in two other patients. Z scores for echocardiographic interventricular septum end diastole and left ventricular posterior wall end diastole were + 0.77 ± 0.77 and + 0.94 ± 0.86, respectively. Left ventricular mass index (LVMI) was 44.93 ± 19.18g/m2.7, and four patients, in addition to the obese one, had values greater than 51g/m2.7, indicative of left ventricular hypertrophy. There was no correlation between these echocardiographic parameters and serum FGF23 concentrations. XLH pediatric patients receiving conventional treatment have echocardiographic measurements of ventricular mass within normal reference values, but above the mean, and 18% have LVMI suggestive of left ventricular hypertrophy without correlation with serum FGF23 concentrations. This might indicate an increased risk of cardiovascular involvement in XLH.

Non Electrocardiographic alterations in exercise testing in asymptomatic women. Associations with cardiovascular risk factors

OBJECTIVES:To estimate the prevalence of exercise testing alterations in middle-aged women without symptoms of heart disease and to verify the associations of functional capacity and heart rate behavior during and after exercise with cardiovascular risk factors.METHODS:A cross-sectional study was conducted with 509 asymptomatic women aged between 46 and 65 years who underwent clinical evaluations and exercise testing (Bruce protocol). The heart rate behavior was evaluated by the maximal predicted heart rate achieved, chronotropic index and recovery heart rate.RESULTS:The mean age was 56.4±4.8 years, and 13.4% of the patients had a Framingham risk score above 10%. In the exercise treadmill testing, 58.0% presented one or more of the following alterations (listed in order of ascending prevalence): symptoms (angina, dyspnea, and dizziness), ST-segment depression, arrhythmia, reduction in recovery heart rate of ≤12 bpm at 1 minute, altered maximal predicted heart rate achieved, abnormal blood pressure, functional capacity deficiency, and altered chronotropic index. In the multivariate analysis, the following associations (odds ratio) were observed for these alterations: chronotropic index was associated with obesity (2.08) and smoking (4.47); maximal predicted heart rate achieved was associated with smoking (6.45); reduction in the recovery heart rate at 1 minute was associated with age (1.09) and obesity (2.78); functional capacity was associated with age (0.92), an overweight status (2.29) and obesity (6.51).CONCLUSIONS:More than half of middle-aged women without cardiovascular symptoms present alterations in one or more exercise testing parameters. Alterations in the functional capacity or heart rate behavior, as verified by exercise testing, are associated with age, smoking, an overweight status and obesity.

Non-obstetric complications in preeclampsia.

Preeclampsia is a multisystem disorder of pregnancy that remains a leading cause of maternal and foetal morbidity and mortality. It is still an underestimated risk factor for future cardiovascular, cerebrovascular, and kidney disease, developing often in the perimenopausal period of a woman’s life. It remains unclear whether preeclampsia is an individual risk factor for future cardiovascular, cerebrovascular, and renal events or an early marker of women with high-risk profiles for these diseases. Risk factors for cardiovascular disorders and preeclampsia are very similar and include the following: obesity, dyslipidaemia, insulin resistance, pro-inflammatory and hypercoagulable state, and endothelial dysfunction. Thus, the pregnancy can only be a trigger for cardiovascular alterations that manifest in development of preeclampsia. On the other hand, there is strong evidence that changes in cardiovascular, endothelial, and metabolic systems occurring in the course of preeclampsia may not fully recover after delivery and can be a cause of future disease, especially in the presence of other metabolic risk factors regarding, for example, perimenopause. In this review the authors present current knowledge about short- and long-term maternal consequences of preeclampsia, such as: cardiovascular disease, cerebrovascular incidents (posterior reversible encephalopathy and stroke), kidney injury (including the risk of end-stage renal disease), liver failure, and coagulopathy (thrombocytopenia and disseminated intravascular coagulation).

Diseases and symptoms associated with changes in postural balance in diabetics: an integrating literature review

ABSTRACT Purpose: to verify the diseases and symptoms associated with changes in postural balance in middle-aged and elderly individuals with type 2 diabetes mellitus. Methods: an integrative review was performed using the following descriptors: "Dizziness," "Vertigo," "Vestibular Diseases," "Labyrinth Diseases," and "Type 2, Diabetes Mellitus" in English and in Portuguese in databases such as PubMed, SciELO, LILACS, Web of Science, and Scopus. Observational articles involving individuals aged 40 years or more with type 2 diabetes mellitus and with alteration in postural balance having presented at least one disease or symptom associated with that alteration were selected. Results: the search yielded 1,209 articles, but only five met the eligibility criteria. Individuals in the selected studies had systemic arterial hypertension, high body mass index, peripheral neuropathy, and postural instability when walking on irregular surfaces and in the dark, when looking at moving objects, moving the head quickly and changing posture, resulting in stumbling when walking, and falls. The articles were classified as IIb and III, according to the levels of evidence of the American Speech-Language Hearing Association. Conclusion: the subjects in the studied articles presented cardiovascular alterations, peripheral neuropathy, vestibular symptoms, difficulties in tasks/movements in challenging contexts, and falls.

105: Regulatory dendritic cell treatment prevents the development of vasopressin-induced preeclampsia in mice

The concept that poor fetal tolerance is important in the pathogenesis of preeclampsia (PE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion throughout pregnancy phenocopies human PE in mice mirroring the tonically elevated AVP secretion throughout human PE pregnancy. These findings identify AVP as a potential contributor to poor fetal tolerance and the development of PE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCreg) promote tolerance via regulatory T cell induction, cell-to-cell interactions, and anti-inflammatory cytokine production. The objective of this study is to determine if DCreg treatment will prevent PE in an AVP-induced mouse model of PE. C57BL/6 dams were infused with AVP (24 ng/hour) or saline throughout gestation via osmotic minipump. To generate DCreg, bone marrow derived cells from C57BL/6 mice were cultured with human TGFβ1 and murine GM- CSF and IL-10. At the time of pump implantation (gestational day, GD -3) or early post-placentation on GD 7, AVP dams received a single intravenous injection of DCreg. Blood pressure was taken throughout pregnancy and total urine protein was measured on GD 18. Maternal tissues were collected on GD 18. Cytokine concentrations were determined via ELISA and normalized to total protein. Treatment of AVP-infused dams with DCreg before mating (GD -3) or on GD 7 prevented PE development. DCreg prevented hypertension (AVP: 120 ±1.8, n=27 vs GD -3: 108 ±3.3, n=7 vs GD 7: 110 ±4.4, n=5 p<0.05) and elevations in proteinuria (AVP: 37.4 ±2.3, n=24 vs GD -3: 25.6 ±2.9, n=7 vs GD 7: 24.1 ±3.1, n=5 p<0.05) (Figure 1). Elevations in pro- inflammatory plasma IFNγ were reversed with treatment (AVP: 27.7 ±12.0, n=6 vs GD -3: 0.0±0.0, n=4 vs GD 7: 0.0±0.0, n=6 pg/g, p<0.05) (Figure 2A). DCreg also reversed suppression of anti-inflammatory TGFβ in the plasma (AVP: 1.3 ± 0.91, n=9 vs GD -3: 3.2 ±0.50, n=4 vs GD 7: 2.9 ±0.25, n=6 ug/g, p<0.05) (Figure 2B). These data support the hypothesis that DCreg treatment prevents AVP-induced PE. It further provides evidence for the potential use of personalized, cellular therapy in the prevention of cardiovascular, renal, and immune alterations induced by preeclampsia.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Effects of vagotomy on cardiovascular and heart rate variability alterations following chronic normobaric hypoxia in adult rabbits

Backgroundchronic hypoxia increases basal ventilation and pulmonary vascular resistance, with variable changes in arterial blood pressure and heart rate, but it’s impact on heart rate variability and autonomic regulation have been less well examined. We studied changes in arterial blood pressure, heart rate and heart rate variability (HRV) in rabbits subjected to chronic normobaric hypoxia (CNH; PB ~ 719 mmHg; FIO2 ~ 9.2%) for 14 days and assess the effect of autonomic control by acute bilateral vagal denervation.Resultsexposure to CNH stalled animal weight gain and increased the hematocrit, without affecting heart rate or arterial blood pressure. Nevertheless, Poincaré plots of the electrocardiographic R–R intervals showed a reduced distribution parallel to the line of identity, which interpreted as reduced long-term HRV. In the frequency domain, CNH reduced the very-low- (< 0.2 Hz) and high-frequency components (> 0.8 Hz) of the R–R spectrograms and produced a prominent component in the low-frequency component (0.2–0.5 Hz) of the power spectrum. In control and CNH exposed rabbits, bilateral vagotomy had no apparent effect on the short- and long-term HRV in the Poincaré plots. However, bilateral vagotomy differentially affected higher-frequency components (> 0.8 Hz); reducing it in control animals without modifying it in CNH-exposed rabbits.ConclusionsThese results suggest that CNH exposure shifts the autonomic balance of heart rate towards a sympathetic predominance without modifying resting heart rate or arterial blood pressure.

Betamethasone: a novel therapeutic intervention for preeclampsia

The early pathogenesis of preeclampsia (PE) involves a systemic inflammatory immune response. Recent data demonstrate that increased circulating arginine vasopressin (AVP) in humans is predictive of PE and that infusion of AVP in mouse dams phenocopies the pregnancy-specific cardiovascular and immune alterations observed in human PE. Specifically, AVP suppresses anti-inflammatory cytokines and cells. Betamethasone (BMTZ), commonly given to women at risk for preterm birth, is both an AVP and immune response modulator. We hypothesize that early treatment with BMTZ will prevent the development of AVP-induced PE.

Regulatory dendritic cell treatment prevents the development of vasopressin-induced preeclampsia

The concept that persistent feto-placental intolerance is important in the pathogenesis of preeclampsia (PE) has been demonstrated by our lab and others. Arginine vasopressin (AVP) infusion during pregnancy induces cardiovascular, renal, and immune alterations in mice consistent with human PE. These findings identify AVP as a potential contributor to poor fetal tolerance and the development of PE. In addition to their conventional immuno-stimulatory role, dendritic cells (DCs) also play a vital role in immune tolerance. In contrast to conventional DCs, regulatory DCs (DCregs) express low levels of co-stimulatory markers, produce anti-inflammatory cytokines, induce T regulatory cells, and promote tolerance. In mice, DCregs are able to prevent pro-inflammatory responses and induce antigen-specific tolerance. Given these known functions of DCregs, we hypothesize that DCregs will prevent the development of AVP-induced PE.

Polychlorinated biphenyls reduce the kinematics contractile properties of embryonic stem cells-derived cardiomyocytes by disrupting their intracellular Ca2+ dynamics

Persistent organic pollutants are a group of chemicals that include polychlorinated biphenyls (PCBs). PCBs exposure during adult life increases incidence and severity of cardiomyopathies, whereas in utero exposure determines congenital heart defects. Being fat-soluble, PCBs are passed to newborns through maternal milk, impairing heart functionality in the adult. It is still unknown how PCBs impair cardiac contraction at cellular/molecular levels. Here, we study the molecular mechanisms by which PCBs cause the observed heart contraction defects, analysing the alterations of Ca2+ toolkit components that regulate contraction. We investigated the effect that Aroclor 1254 (Aroclor), a mixture of PCBs, has on perinatal-like cardiomyocytes derived from mouse embryonic stem cells. Cardiomyocytes, exposed to 1 or 2 µg/ml Aroclor for 24 h, were analyzed for their kinematics contractile properties and intracellular Ca2+ dynamics. We observed that Aroclor impairs cardiomyocytes contractile properties by inhibiting spontaneous Ca2+ oscillations. It disrupts intracellular Ca2+ homeostasis by reducing the sarcoplasmic reticulum Ca2+ content and by inhibiting voltage-gated Ca2+ entry. These findings contribute to the understanding of the molecular underpinnings of PCBs-induced cardiovascular alterations, which are emerging as an additional life-threatening hurdle associated to PCBs pollution. Therefore, PCBs-dependent alteration of intracellular Ca2+ dynamics is the most likely trigger of developmental cardiac functional alteration.