Free fatty acid availability is closely related to myocardial lipid storage and cardiac function in hypoglycemia counterregulation

2015 ◽  
Vol 308 (8) ◽  
pp. E631-E640 ◽  
Author(s):  
Yvonne Winhofer ◽  
Martin Krššák ◽  
Peter Wolf ◽  
Christian-Heinz Anderwald ◽  
Angelika Geroldinger ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Resonance Spectroscopy ◽  
Insulin Hypoglycemia ◽  
Patients With Diabetes ◽  
Plasma Ffa ◽  
Adipose Tissue Lipolysis ◽  
Acute Hypoglycemia ◽  
The Impact

Hypoglycemia, a major side effect of intensive glucose-lowering therapy, was recently linked to increased cardiovascular risk in patients with diabetes. Whether increased circulating free fatty acids (FFA) owing to catecholamine-induced lipolysis affect myocardial energy metabolism and thus link hypoglycemia to cardiac vulnerability is unclear. Therefore, this study investigated the impact of hypoglycemia counterregulation (± inhibition of lipolysis) on myocardial lipid content (MYCL) and left ventricular function in healthy subjects. Nine healthy men were studied in randomized order: 1) insulin/hypoglycemia test (IHT; ins+/aci−), 2) IHT during inhibition of adipose tissue lipolysis by acipimox (ins+/aci+), 3) normoglycemia with acipimox (ins−/aci+), and 4) normoglycemia with placebo (ins−/aci−). MYCL and cardiac function were assessed by employing magnetic resonance spectroscopy/imaging at baseline and at 2 and 6 h. In response to acute hypoglycemia, plasma FFA ( P < 0.0001) and ejection fraction (EF; from 63.2 ± 5.5 to 69.6 ± 6.3%, P = 0.0001) increased significantly and were tightly correlated with each other ( r = 0.68, P = 0.0002); this response was completely blunted by inhibition of adipose tissue lipolysis. In the presence of normoglycemia, inhibition of lipolysis was associated with a drop in EF (from 59.2 ± 5.5 to 53.9 ± 6.9%, P = 0.005) and a significant decrease in plasma FFA, triglycerides, and MYCL (by 48.5%, P = 0.0001). The present data indicate that an intact interorgan cross-talk between adipose tissue and the heart is a prerequisite for catecholamine-mediated myocardial contractility and preservation of myocardial lipid stores in response to acute hypoglycemia.

scholarly journals P6419Machine learning in critical care: the role of diabetes and age in acute coronary syndromes

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
E Cenko ◽  
M Van Der Schaar ◽  
J Yoon ◽  
Z Vasiljevic ◽  
S Kedev ◽  
...  
Keyword(s):  
Medical Treatment ◽  
Primary Endpoint ◽  
Left Ventricular ◽  
Adverse Outcomes ◽  
Secondary Endpoint ◽  
Coronary Syndrome ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Patients With Diabetes ◽  
The Impact

Abstract Background Patients with diabetes and non-ST elevation acute coronary syndrome (NSTE-ACS) have an increased risk of mortality and adverse outcomes following percutaneous coronary intervention (PCI). Purpose We aimed to investigate the impact of early, within 24 hours PCI compared with only routine medical treatment on clinical outcomes in a large international cohort of patients with NSTE-ACS and diabetes. Methods We identified 1,250 patients with diabetes and NSTE-ACS from a registry-based population between October 2010 and April 2016. The primary endpoint was 30-day all-cause mortality. The secondary endpoint was the composite outcome of 30-day all-cause mortality and left ventricular dysfunction (ejection fraction <40%). We undertook analyses to explore the heterogeneity of treatment effects using meta-classification (MC) algorithms followed by propensity score matching and inverse-probability-of-treatment weighting (IPTW) from a landmark of 24 hours from hospitalization. Results Of 1,250 NSTE-ACS first-day survivors with diabetes (median age 67 years; 59%, men), 470 (37.6%) received early PCI and 780 routine medical treatment. The overall 30-day all-cause mortality rates were higher in the routine medical treatment than the early PCI group (6.3% vs. 2.5%). The prediction results of the MC algorithms accounted for only one interaction term that was statistically significant: age ≥65 years. After propensity-matched analysis as well as IPTW, early PCI was associated with reduced 30-day all-cause mortality in the older age (OR: 0.35; 95% CI: 0.14 to 0.92 and 0.43; 95% CI: 0.21 to 0.86, respectively), whereas younger age had no association with the primary endpoint. Similar results were also obtained for the secondary endpoint. Conclusions Among patients with diabetes hospitalized for NSTE-ACS, an early, within 24 hours, PCI strategy is associated with reduced odds of 30-day mortality only for patients aged 65 years or over. MC algorithms provide accurate identification of treatment effect modifiers.

Increased cholinergic activity under conditions of low estrogen leads to adverse cardiac remodeling

2020 ◽  
Author(s):  
Vanessa P. Teixeira ◽  
Kiany Miranda ◽  
Sergio Scalzo ◽  
Cibele Rocha-Resende ◽  
Mário Morais Silva ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Postmenopausal Women ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
Genetically Engineered ◽  
Cardiac Response ◽  
Cholinesterase Inhibition ◽  
Functional Changes ◽  
Concentric Hypertrophy ◽  
The Impact

Cholinesterase inhibitors are used in postmenopausal women for the treatment of neurodegenerative diseases. Despite their widespread use in the clinical practice, little is known about the impact of augmented cholinergic signaling on cardiac function under reduced estrogen conditions. To address this gap, we subjected a genetically engineered murine model of systemic vesicular acetylcholine transporter overexpression (Chat-ChR2) to ovariectomy and evaluated cardiac parameters. Left-ventricular function was similar between Chat-ChR2 and wild-type (WT) mice. Following ovariectomy, WT mice showed signs of cardiac hypertrophy. Conversely, ovariectomized (OVX) Chat-ChR2 mice evolved to cardiac dilation and failure. Transcript levels for cardiac stress markers ANP and BNP were similarly upregulated in WT/OVX and Chat-ChR2/OVX mice. 17β-Estradiol (E2) treatment normalized cardiac parameters in Chat-ChR2/OVX to the Chat-ChR2/SHAM levels, providing a link between E2 status and the aggravated cardiac response in this model. To investigate the cellular basis underlying the cardiac alterations, ventricular myocytes were isolated and their cellular area and contractility were assessed. Myocytes from WT/OVX mice were wider than WT/SHAM, an indicative of concentric hypertrophy, but their fractional shortening was similar. Conversely, Chat-ChR2/OVX myocytes were elongated, and presented contractile dysfunction. E2 treatment again prevented the structural and functional changes in Chat-ChR2/OVX myocytes. We conclude that hypercholinergic mice under reduced estrogen conditions do not develop concentric hypertrophy, a critical compensatory adaptation, evolving towards cardiac dilation and failure. This study emphasizes the importance of understanding the consequences of cholinesterase inhibition, used clinically to treat dementia, for cardiac function in postmenopausal women.

scholarly journals Breast Cancer Promotes Cardiac Dysfunction Through Deregulation of Cardiomyocyte Ca 2+ ‐Handling Protein Expression That is Not Reversed by Exercise Training

2021 ◽  
Vol 10 (5) ◽  
Author(s):  
Tassia S. R. da Costa ◽  
Ursula Urias ◽  
Marcelo V. Negrao ◽  
Camila P. Jordão ◽  
Clévia S. Passos ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Exercise Training ◽  
Cardiac Function ◽  
Protein Expression ◽  
Exercise Capacity ◽  
Tolerance Test ◽  
Left Ventricular ◽  
T Antigen ◽  
Significant Difference ◽  
The Impact

Background Patients treated for breast cancer have a high incidence of cardiovascular complications. In this study, we evaluated the impact of breast cancer on cardiac function and cardiomyocyte Ca 2+ ‐handling protein expression. We also investigated whether exercise training (ET) would prevent these potential alterations. Methods and Results Transgenic mice with spontaneous breast cancer (mouse mammary tumor virus–polyomavirus middle T antigen [MMTV‐PyMT+], n=15) and littermate mice with no cancer (MMTV‐PyMT−, n=14) were studied. For the ET analysis, MMTV‐PyMT+ were divided into sedentary (n=10) and exercise‐trained (n=12) groups. Cardiac function was evaluated by echocardiography with speckle‐tracking imaging. Exercise tolerance test was conducted on a treadmill. Both studies were performed when the tumor became palpable and when it reached 1 cm 3 . After euthanasia, Ca 2+ ‐handling protein expression (Western blot) was evaluated. Exercise capacity was reduced in MMTV‐PyMT+ compared with MMTV‐PyMT− ( P interaction =0.031). Longitudinal strain ( P group <0.001) and strain rate ( P group =0.030) were impaired. Cardiomyocyte phospholamban was increased ( P =0.011), whereas phospho‐phospholamban and sodium/calcium exchanger were decreased ( P =0.038 and P =0.017, respectively) in MMTV‐PyMT+. No significant difference in sarcoplasmic or endoplasmic reticulum calcium 2 ATPase (SERCA2a) was found. SERCA2a/phospholamban ratio was reduced ( P =0.007). ET was not associated with increased exercise capacity. ET decreased left ventricular end‐systolic diameter ( P group =0.038) and end‐diastolic volume ( P group =0.026). Other morphological and functional cardiac parameters were not improved by ET in MMTV‐PyMT+. ET did not improve cardiomyocyte Ca 2+ ‐handling protein expression. Conclusions Breast cancer is associated with decreased exercise capacity and subclinical left ventricular dysfunction in MMTV‐PyMT+, which is at least partly associated with dysregulation of cardiomyocyte Ca 2+ handling. ET did not prevent or reverse these changes.

Hypoxic pHi and function modulation by Na+/H+ exchange and alpha-adrenoreceptor inhibition in heart in vivo

1997 ◽  
Vol 272 (6) ◽  
pp. H2664-H2670 ◽  
Author(s):  
M. A. Portman ◽  
Y. Xiao ◽  
B. G. Broers ◽  
X. H. Ning
Keyword(s):  
Cardiac Function ◽  
Contractile Function ◽  
High Energy ◽  
Left Ventricular ◽  
Resonance Spectroscopy ◽  
Cardiac Contractile Function ◽  
Significant Drop ◽  
And Function ◽  
Phi Regulation

Regulation of intracellular pH (pHi) may contribute to maintenance of cardiac contractile function during graded hypoxia in vivo. To test this hypothesis, we disturbed pHi regulation in vivo using two approaches: alpha-adrenoreceptor antagonism with phentolamine (1 mg/kg) (Phen; n = 9); and Na+/H+ exchange inhibition with HOE-642 (2 mg/kg; n = 6) before graded hypoxia in open-chest sheep. Hemodynamic parameters including left ventricular maximal pressure development (dP/dtmax) cardiac index (CI), and left ventricular power were monitored continuously and simultaneously with high-energy phosphate levels and pHi, measured with 31P nuclear magnetic resonance spectroscopy in Phen, HOE-642, and control (Con; n = 9). In subgroups (n = 6) in Con and Phen, coronary flow, myocardial oxygen consumption (MVO2), and lactate uptake were also measured. During hypoxia, the functional parameters left ventricular dP/dtmax, CI, and left ventricular power decreased significantly compared with baseline and Con values. These decreases were preceded by a significant drop (P < 0.05) in pHi from 7.10 +/- 0.04 to 6.69 +/- 0.05 in Phen and corresponded temporally to a pHi drop from 7.10 +/- 0.02 to 6.77 +/- 0.03 in HOE-642. Decreases in pHi in Phen were not preceded by decreases in cardiac function or MVO2. In contrast, cardiac function parameters increased significantly in Con, whereas no significant pHi decrease occurred (7.07 +/- 0.03 to 6.98 +/- 0.04). We conclude that these data indicate that pHi regulation can be disrupted through alpha-adrenergic antagonism or Na+/H(+)-exchange inhibition in vivo. These studies demonstrate that pHi regulation performs a role in the modulation of cardiac function during hypoxia in vivo.

Abstract 17332: Endothelial-Specific Deletion of Aryl Hydrocarbon Receptor Nuclear Translocator (ARNT) Leads to Microvascular Barrier Dysfunction and Cardiomyopathy

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Maura Knapp ◽  
Mei Zheng ◽  
Alik Stikov ◽  
Nikola Sladojevic ◽  
Anna Chen ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cardiac Function ◽  
Aryl Hydrocarbon Receptor ◽  
Left Ventricular ◽  
Vascular Leakage ◽  
Cell Permeability ◽  
Barrier Dysfunction ◽  
Aryl Hydrocarbon ◽  
Patients With Diabetes

Introduction: Cardiac microvascular hyperpermeability is a key contributor to heart disease in patients with diabetes. Although the link between diabetes and microvascular barrier dysfunction is largely unknown, expression of the transcription factor aryl hydrocarbon receptor nuclear translocator (ARNT) is significantly downregulated in the cardiac microvascular endothelial cells (CMECs) of both diabetic mouse hearts (n=5, p<0.01) and the explanted hearts of patients with diabetes mellitus (n=3, p<0.05). We hypothesize that cardiac microvascular permeability is limited by the expression of ARNT in the endothelium and, consequently that endothelial-cell ARNT (ecARNT) expression is essential for normal cardiac function. Methods and Results: We have recently generated tamoxifen-inducible, endothelial-cell-specific, VE-cadherin-Cre ETR2 ARNT-knockout mice (ecARNT -/- mice). ecARNT deletion is achieved by tamoxifen oral administration for two weeks. Littermates controls are either mice without tamoxifen chow or ARNT flox/flox treated with tamoxifen diet. Induction of the ecARNT -/- mutation led to vascular leakage (as determined via in-vivo endothelial permeability assay) (n=5, p<0.05), which occurred predominantly in the heart, and to increases in matrix metalloproteinase (MMP) expression (microarray analysis), including a 3.8-fold increase in the expression of MMP3 (n=3, p<0.01). Furthermore, MMP3 inhibition attenuated the increase in cell permeability observed in CMECs from ecARNT -/- mouse hearts (as measured via electrical cell-substrate impedance sensing), as well as cardiac vascular leakage in ecARNT -/- mice, while long-term studies indicated that ejection fractions were significantly lower (ecARNT -/- : 22.3±2.6%, Control: 33.2±1.8%;), and Left ventricular end-diastolic diameters were significantly greater (ecARNT -/- : 4.8±0.8 mm, Control: 3.6±0.6 mm; n=8,p<0.01) six months after ecARNT deletion (echocardiography). Conclusion: ARNT-mediated MMP3 downregulation is required for maintaining cardiac microvascular barrier integrity and preserving cardiac function; thus, modulation of the ARNT/MMP3 axis could be a novel approach for the treatment of cardiovascular diseases such as diabetic cardiomyopathy.

scholarly journals Left ventricular volume analysis as a basic tool to describe cardiac function

2018 ◽  
Vol 42 (1) ◽  
pp. 130-139 ◽  
Author(s):  
Peter L. M. Kerkhof ◽  
Tatiana Kuznetsova ◽  
Rania Ali ◽  
Neal Handly
Keyword(s):  
Cardiac Function ◽  
Volume Regulation ◽  
Function Analysis ◽  
Group Analysis ◽  
Ventricular Volume ◽  
Left Ventricular ◽  
Ventricular Performance ◽  
Healthy Humans ◽  
End Diastolic Volume ◽  
The Impact

The heart is often regarded as a compression pump. Therefore, determination of pressure and volume is essential for cardiac function analysis. Traditionally, ventricular performance was described in terms of the Starling curve, i.e., output related to input. This view is based on two variables (namely, stroke volume and end-diastolic volume), often studied in the isolated (i.e., denervated) heart, and has dominated the interpretation of cardiac mechanics over the last century. The ratio of the prevailing coordinates within that paradigm is termed ejection fraction (EF), which is the popular metric routinely used in the clinic. Here we present an insightful alternative approach while describing volume regulation by relating end-systolic volume (ESV) to end-diastolic volume. This route obviates the undesired use of metrics derived from differences or ratios, as employed in previous models. We illustrate basic principles concerning ventricular volume regulation by data obtained from intact animal experiments and collected in healthy humans. Special attention is given to sex-specific differences. The method can be applied to the dynamics of a single heart and to an ensemble of individuals. Group analysis allows for stratification regarding sex, age, medication, and additional clinically relevant covariates. A straightforward procedure derives the relationship between EF and ESV and describes myocardial oxygen consumption in terms of ESV. This representation enhances insight and reduces the impact of the metric EF, in favor of the end-systolic elastance concept advanced 4 decades ago.

A Sodium Glucose Cotransporter 2 Inhibitor Fails to Improve Perivascular Adipose Tissue-Mediated Modulation of Vasodilation and Cardiac Function in Rats With Metabolic Syndrome

2021 ◽  
pp. 107424842110018
Author(s):  
Satomi Kagota ◽  
Kana Maruyama-Fumoto ◽  
John J. McGuire ◽  
Kazumasa Shinozuka
Keyword(s):  
Metabolic Syndrome ◽  
Adipose Tissue ◽  
Cardiac Function ◽  
Coronary Flow ◽  
Left Ventricular ◽  
Organ Bath ◽  
Perivascular Adipose Tissue ◽  
Treatment Groups ◽  
Glucose Levels ◽  
Serum And Urine

Arterial perivascular adipose tissue (PVAT) can elicit vasodilator signals complementary to those elicited by the endothelium in SHRSP.Z- Leprfa/IzmDmcr (SHRSP.ZF) rats, an animal model of metabolic syndrome (MetS). Here, we tested whether a glucose cotransporter 2 inhibitor (SGLT2-i; tofogliflozin) increased this PVAT effect to prevent the deterioration of cardiac function in aging SHRSP.ZF rats. Tofogliflozin treatments (1 or 10 mg/kg/day) or vehicle (control) were administered for 10 weeks by oral gavage to SHRSP.ZF rats, starting at 13 weeks of age. At 23 weeks of age, glucose levels in the serum and urine (24 h after the last administration) were determined using commercial kits. Vasodilator responsiveness of PVAT-surrounded or PVAT-free superior mesenteric arteries was determined using acetylcholine with organ-bath methods. Cardiac ventricular function and coronary flow were determined using Langendorff heart preparations. Serum and urine glucose levels in SGLT2-i treatment groups did not differ from those in the controls, but the ratios of glycated to non-glycated albumin were lower than those in the controls. Tofogliflozin treatments did not alter relaxations in the presence of PVAT or affect relaxations of PVAT-free arteries. Left ventricular systolic pressures, maximum rate of pressure decline, and coronary flow in ex vivo hearts did not differ among the treatment groups. PVAT effects and cardiac dysfunction were not altered by tofogliflozin treatment in SHRSP.ZF rats with MetS. These results do not provide strong evidence to support the use of SGLT2-i as a cardiovascular protective therapy in MetS, which occurs prior to the onset of type 2 diabetes.

Abstract P021: Adipose-Derived Stromal Cell Therapy Stabilizes Cardiac Function and Improves Border Zone Remodeling After Coronary Occlusion in Rats

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Antonio C Campos de Carvalho ◽  
Luiza Bagno ◽  
João Pedro Werneck de Castro ◽  
Patricia Oliveira ◽  
Marcia Abreu ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Coronary Artery ◽  
Cardiac Function ◽  
Left Coronary Artery ◽  
Enzymatic Digestion ◽  
Left Ventricular ◽  
Female Rats ◽  
Border Zone ◽  
Functional Improvement ◽  
Vehicle Group

Recent studies have identified adipose tissue as a new source of mesenchymal stem cells for therapy. The purpose of this study was to investigate the therapy with rat adipose derived stromal cells (ASC) in a rat model of healed myocardial infarction (MI). ASC from inguinal subcutaneous adipose tissue of male Wistar rats were isolated by enzymatic digestion and filtration. Cells were then cultured until passage 3. Four weeks after ligation of the left coronary artery of female rats, a suspension of either 100µl with PBS + Matrigel + 2 x 106 ASC labeled with Hoechst (n=11) or 100µ;l of PBS + Matrigel (n=10) was injected along the borders of the ventricular wall scar tissue. A sham operated group (n=5) was submitted to the same surgical procedure except permanent ligation of left coronary artery. Cardiac performance was assessed by electro and echocardiogram. Echo was performed prior to injections (baseline-BL) and six weeks after injections (follow-up - FU), and values after treatment were normalized by values obtained before treatment. Hemodynamic measurements were performed 6 weeks after injections. All data are expressed as mean ± SEM. Student's paired or unpaired T test was used to compare the same group in two different times or two distinct groups, while two way ANOVA was used to compare more than two groups along different times and p was set at <0.05. All infarcted animals exhibited cardiac function impairment. Ejection fraction (EF), shortening fractional area (SFA) and left ventricular akynesia (LVA) were similar between infarcted groups before treatment. Six weeks after therapy, ASC group showed significant improvement in all three Echo indexes in comparison to vehicle group. In non-anesthetized animals dp/dt+ was also significantly higher in ASC when compared to vehicle. In agreement with functional improvement scar area was diminished in the ASC group. We conclude that ASC stabilize cardiac function in infarcted rats when administered directly to the myocardium.

Abstract MP202: The Effects Of Maternal Hypothyroidism On Fetal And Adult Cardiac Function

2021 ◽  
Vol 129 (Suppl_1) ◽  
Author(s):  
Yijia Li ◽  
Guihong Chen ◽  
Xiaoying Zhang ◽  
Ran Zhao ◽  
Steven R Houser ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Heart Function ◽  
Weight Ratio ◽  
Left Ventricular ◽  
Abdominal Circumference ◽  
Left Ventricular Ejection ◽  
Heart Weight ◽  
Systematic Research ◽  
Ventricular Ejection Fraction ◽  
The Impact

Objectives: Maternal hypothyroidism (MH), a common clinical condition with a reported prevalence from 2.5% to 13%. MH could have an adverse effect on fetal cardiac development and adult heart function. However, there is a lack of systematic research for its effect on fetal and offspring’s development and cardiac function. This study aimed to determine the impact of MH on fetal and offspring’s organ structural and functional development at different gestation stages and during postnatal and puberty. Methods: MH model had been built through thyroidectomy (TX) with total thyroxine (TT4) under 1ng/dl after surgery. Pups from mice that underwent TX and Sham surgery were named THD (Deficient) and THN (Normal). Times of parturition and miscarriage from TX and Sham groups were recorded. Ultrasound was performed for fetuses and/or offspring to check the gestation, miscarriage, embryo arrest, development, malformation, and cardiac function. At different postnatal days, mice were euthanized for organ development evaluation. Result: TX mice had reduced parturition frequencies and smaller litter size but increased miscarriage frequency and malformed fetuses than the sham group. In addition, THD fetuses had smaller biparietal diameter (BPD) and abdominal circumference (AC) and significantly lower left ventricular ejection fraction (LVEF) on E14.5, but not at E18.5. Tei index, a parameter representing both systolic and diastolic cardiac function, was lower in THD fetuses than in THN fetuses at both E14.5 and E18.5. The cardiac systolic and diastolic function of female TX mice after a 9-month breeding period was also abnormal. The Postnatal T4 level was not significantly different between the two groups. On and after d21 after birth, THD mice had a higher heart weight/body weight ratio and lower LVEF still d21. Conclusion: MH impaired the development and cardiac function of the fetus and young adult. In addition, MH impaired the mother's fertility and depressed cardiac function.

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