Ventricular-arterial coupling as a potential therapeutic target in diabetes

2021 ◽  
Author(s):  
Sahrai Saeed ◽  
Hannes Holm ◽  
Peter Nilsson
Keyword(s):  
Heart Failure ◽  
Therapeutic Target ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Arterial System ◽  
Protective Effects ◽  
Potential Therapeutic Target ◽  
Lower Plasma Glucose ◽  
Glucagon Like Peptide 1 ◽  
Long Term Prognosis

Patients with type 2 diabetes (T2D) are at high risk of cardiovascular complications. Novel anti-diabetic medications such as sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and Glucagon-like peptide-1 receptor agonists (GLP-1RA) have been shown to possess cardiac and renal protective effects beyond their ability to lower plasma glucose. Use of SGLT-2i and GLP-1RA in patients with T2D and heart failure reduce cardiovascular risk and heart failure related hospitalizations. SGLT-2i treatment has shown to improve the long-term prognosis of patients with heart failure. Both drugs also have the potential to normalize ventricular-arterial coupling (VAC). VAC is the crosstalk between the left ventricular function and the arterial system, and is an indicator of the global cardiovascular performance. In this overview, we will describe the concept of VAC and the features of diabetic cardiomyopathy, as well as VAC as a potential therapeutic target in diabetes by use of novel anti-diabetic drugs, primarily SGLT-2i and GLP-1RA. Continuous...

Erythropoietin-mediated Signaling in the Heart as a Potential Therapeutic Target in Chronic Heart Failure

2007 ◽  
Vol 13 (6) ◽  
pp. S22-S23
Author(s):  
Yutaka Kagaya ◽  
Yasuhide Asaumi ◽  
Tomohiro Tada ◽  
Nobuyuki Shiba ◽  
Kunio Shirato ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Therapeutic Target ◽  
Potential Therapeutic Target

scholarly journals Cardiovascular morbidity and mortality in patients treated with hemodialysis: Epidemiological analysis

2008 ◽  
Vol 65 (12) ◽  
pp. 893-900 ◽  
Author(s):  
Dejan Petrovic ◽  
Biljana Stojimirovic
Keyword(s):  
Risk Factors ◽  
Heart Failure ◽  
Mortality Rate ◽  
Cardiovascular Mortality ◽  
Cardiovascular Complications ◽  
Left Ventricular ◽  
Cardiovascular Morbidity ◽  
Morbidity And Mortality ◽  
Cardiovascular Morbidity And Mortality ◽  
Lv Mass

Background/Aim. Cardiovascular diseases are the leading cause of death in patients treated with hemodialysis (HD). The annual cardiovascular mortality rate in these patients is 9%. Left ventricular (LV) hypertrophy, ischemic heart disease and heart failure are the most prevalent cardiovascular causes of death. The aim of this study was to assess the prevalence of traditional and nontraditional risk factors for cardiovascular complications, to assess the prevalence of cardiovascular complications and overall and cardiovascular mortality rate in patients on HD. Methods. We investigated a total of 115 patients undergoing HD for at least 6 months. First, a cross-sectional study was performed, followed by a two-year follow-up study. Beside standard biochemical parameters, we also determined cardiac troponins and echocardiographic parameters of LV morphology and function (LV mass index, LV fractional shortening, LV ejection fraction). The results were analyzed using the Student's t test and Mann-Whitney U test. Results. The patients with adverse outcome had significantly lower serum albumin (p < 0.01) and higher serum homocystein, troponin I and T, and LV mass index (p < 0.01). Hyperhomocysteinemia, anemia, hypertriglyceridemia and uncontrolled hypertension had the highest prevalence (86.09%, 76.52%, 43.48% and 36.52%, respectively) among all investigated cardiovascular risk factors. Hypertrophy of the LV was presented in 71.31% of the patients and congestive heart failure in 8.70%. Heart valve calcification was found in 48.70% of the patients, pericardial effusion in 25.22% and disrrhythmia in 20.87% of the investigated patients. The average annual overall mortality rate was 13.74%, while average cardiovascular mortality rate was 8.51%. Conclusion. Patients on HD have high risk for cardiovascular morbidity and mortality.

In vivo application and validation of a novel non-invasive method to estimate the end-systolic elastance

2021 ◽  
Author(s):  
Stamatia Pagoulatou ◽  
Karl-Philipp Rommel ◽  
Karl-Patrik Kresoja ◽  
Maximilian von Roeder ◽  
Philipp Lurz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Systolic Function ◽  
Cuff Pressure ◽  
Left Ventricular ◽  
Aortic Flow ◽  
Arterial System ◽  
Patient Specific ◽  
Correct Prediction ◽  
Non Invasive ◽  
Cardiac Model

Accurate assessment of the left ventricular (LV) systolic function is indispensable in the clinic. However, estimation of a precise index of cardiac contractility, i.e., the end-systolic elastance (Ees), is invasive and cannot be established as clinical routine. The aim of this work was to present and validate a methodology that allows for the estimation of Ees from simple and readily available non-invasive measurements. The method is based on a validated model of the cardiovascular system and non-invasive data from arm-cuff pressure and routine echocardiography to render the model patient-specific. Briefly, the algorithm first uses the measured aortic flow as model input and optimizes the properties of the arterial system model in order to achieve correct prediction of the patient's peripheral pressure. In a second step, the personalized arterial system is coupled with the cardiac model (time-varying elastance model) and the LV systolic properties, including Ees, are tuned to predict accurately the aortic flow waveform. The algorithm was validated against invasive measurements of Ees (multiple pressure-volume loop analysis) taken from n=10 heart failure patients with preserved ejection fraction and n=9 patients without heart failure. Invasive measurements of Ees (median 2.4 mmHg/mL, range [1.0, 5.0] mmHg/mL) agreed well with method predictions (nRMSE=9%, ρ=0.89, bias=-0.1 mmHg/mL and limits of agreement [-0.9, 0.6] mmHg/mL). This is a promising first step towards the development of a valuable tool that can be used by clinicians to assess systolic performance of the LV in the critically ill.

Abstract 96: Thioredoxin-1 Is Essential for Hydrogen Sulfide-Mediated Cardioprotection in the Setting of Ischemic-Induced Heart Failure

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Chad K Nicholson ◽  
Bridgette F Moody ◽  
Rebecca L Hood ◽  
Junichi Sadoshima ◽  
John W Calvert
Keyword(s):  
Heart Failure ◽  
Hydrogen Sulfide ◽  
Left Ventricular ◽  
Dominant Negative ◽  
Left Ventricular Ejection ◽  
Protective Effects ◽  
Ventricular Ejection Fraction ◽  
Left Ventricular Dimensions ◽  
Thioredoxin 1 ◽  
And Function

Background: Numerous studies have reported the cytoprotective effects of hydrogen sulfide (H2S) in various models of myocardial injury. Here we examined the role that thioredoxin-1 (Trx1) plays in mediating the protective effects of H2S in a model of heart failure. Methods and Results: Mice were subjected to 60 min of left coronary artery ischemia followed by 4 wks of reperfusion (R) at which time left ventricular dimensions and function were assessed. Mice received saline (Veh) or H2S in the form of sodium sulfide (Na2S, 100 μ g/kg) at the time of R followed by daily i.v. injections for the first 7 days of R. Mice treated with Na2S experienced less left ventricular dilatation and hypertrophy, displayed improved left ventricular ejection fraction, and displayed improved contractility and relaxation when compared to Veh-treated mice. Studies aimed at evaluating the underlying cardioprotective mechanisms found that Na2S treatment increased the expression of Trx1. Further analysis revealed that this was accompanied by an increase in phosphorylation of apoptosis signaling kinase-1 (ASK1) at serine residue 966 (inhibitory site), as well as a decrease in the phosphorylation of JNK and p38 (downstream targets of ASK1). We also found that Na2S treatment did not improve cardiac dilatation, cardiac dysfunction, or cardiac hypertrophy in cardiac specific Trx1 dominant negative transgenic (Trx1 dnTg) mice when compared to Veh-treated mice. Conclusion: These findings provide important information that the upregulation of cardiac Trx1 by H2S in the setting of ischemic-induced heart failure sets into motion events, including ASK1 inhibition, which ultimately leads to cardioprotection.

Abstract 13483: Pathological Decline in Incretin Hormone Glucagon-like Peptide-1 Causes Cardiac Apoptosis and Dysfunction in Pressure-overloaded Heart Failure Through Cyclic AMP-dependent Mechanisms. -Distinct Role of Protein Kinase a and EPAC

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Morihiko Aoyama ◽  
Yasuko K Bando ◽  
Haruya Kawase ◽  
Akio Monji ◽  
Toko Mitsui ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cyclic Amp ◽  
Left Ventricular ◽  
Ample Evidence ◽  
Incretin Hormone ◽  
Myocardial Apoptosis ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Distinct Role

Introduction: Ample evidence demonstrates cardiovascular protection by incretin hormone glucagon-like peptide-1 (GLP-1) through the cyclic AMP axis. GLP-1 is known for its inotropic effect on heart, however, the role of GLP-1 in heart failure remains uncertain. Hypothesis: To explore the pathophysiological role of GLP-1 in heart failure Methods: Pressure overload-induced heart failure model was generated by transverse aortic constriction in mice (TAC). Results: At 4 week after the operation, TAC exhibited systolic left-ventricular dysfunction, myocardial hypertrophy and augmented apoptosis. Unexpectedly, circulating GLP-1 concentration was markedly decreased in TAC (in pM; 0.86±0.10 for TAC versus 2.13±0.54 for sham) with concomitant reduction of myocardial cyclic AMP concentration (in pmole/mg protein; 33.0±1.4 for TAC versus 42.2±1.5). TAC exhibited pathological changes in signaling molecules of myocardial contractility [SERCA, phospho-phospholamban(Serine16; pPL), β-myosin heavy chain (MYH7)], remodeling (Akt/mTOR/S6K), and cell death markers (procaspase-3/Bcl2 for apoptosis and PINK/PARKIN complex for mitophagy detecting damaged mitochondria). All of these changes observed in TAC heart were reversed selectively by treatment with GLP-1 analog exendin-4 (Ex4; 24nmole/kg/day for 4 weeks) and indirect supplement of GLP-1 by a DPP4 inhibitor alogliptin (ALO; 10mg/kg/day for 4 weeks). In vitro TUNEL assay using cultured cardiomyocytes revealed that Ex-4 reduced myocardial apoptosis in a cAMP/EPAC1-dependent but PKA-independent manner (Figure). Conclusions: Pressure-overloaded heart failure exhibits decline in GLP-1, leading to cAMP/EPAC1-dependent impairment in myocardial apoptosis, and cAMP/PKA/pPL/SERCA-dependent myocardial contractile dysfunction. Our data suggest the distinct role of PKA and EPAC in pathophysiology underlying heart failure.

scholarly journals Qiliqiangxin Attenuates Cardiac Remodeling via Inhibition of TGF-β1/Smad3 and NF-κB Signaling Pathways in a Rat Model of Myocardial Infarction

2018 ◽  
Vol 45 (5) ◽  
pp. 1797-1806 ◽  
Author(s):  
Anbang Han ◽  
Yingdong Lu ◽  
Qi Zheng ◽  
Jian Zhang ◽  
YiZhou Zhao ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Cardiac Function ◽  
Signaling Pathways ◽  
Rat Model ◽  
Cardiac Remodeling ◽  
Left Ventricular ◽  
Protective Effects ◽  
Tnf Α ◽  
Tgf Β1

Background/Aims: Qiliqiangxin (QL), a traditional Chinese medicine, has been demonstrated to be effective and safe for the treatment of chronic heart failure. Left ventricular (LV) remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after myocardial infarction (MI). Our previous studies have shown that QL exhibits cardiac protective effects against heart failure after MI. The objective of this study was to explore the effects of QL on myocardial fibrosis in rats with MI and to investigate the underlying mechanism of these effects. Methods: A rat model of acute myocardial infarction was induced by ligating the left anterior descending coronary artery. The rats were treated with QL (1.0 g/kg/day) for 4 weeks after surgery. Echocardiography and histology examination were performed to evaluate heart function and fibrosis, respectively. Protein levels of transforming growth factor-β1 (TGF-β1), phosphorylated Smad3 (p-Smad3), phosphorylated Smad7 (p-Smad7), collagen I (Col- I), alpha smooth muscle actin (a-SMA), tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), nuclear factor κB (NF-κB), and phosphorylated inhibitor of kappa B alpha (p-IκBα) were measured by western blot analysis. Results: QL treatment ameliorated adverse cardiac remodeling 8 weeks after AMI, including better preservation of cardiac function, decreased inflammation, and reduced fibrosis. In addition, QL treatment reduced Col-I, a-SMA, TGF-β1, and p-Smad3 expression levels but increased p-Smad7 levels in postmyocardial infarct rat hearts. QL administration also reduced the elevated levels of cardiac inflammation mediators, such as TNF-α and IL-6, as well as NF-κB and p-IκBα expression. Conclusions: QL therapy exerted protective effects against cardiac remodeling potentially by inhibiting TGF-β1/Smad3 and NF-κB signaling pathways, thereby preserving cardiac function, as well as reducing myocardial inflammation and fibrosis.

P3476High-resolution respirometry reveals enhanced myocardial mitochondrial ketone oxidation after fasting and ventricular unloading

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
E Zweck ◽  
V Burkart ◽  
C Wessel ◽  
D Scheiber ◽  
K H M Leung ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ketone Body ◽  
Ketone Bodies ◽  
Ex Vivo ◽  
Oxidative Capacity ◽  
Left Ventricular ◽  
University Hospital ◽  
Oxygen Flux ◽  
Protective Effects ◽  
Coa Transferase

Abstract Background Impairment of myocardial mitochondrial function is regarded as an established pathomechanism in heart failure. Enhanced oxidation of ketone bodies may potentially exert protective effects on myocardial function. High-resolution respirometry (HRR) resembles a gold-standard methodology to determine myocardial mitochondrial metabolism and oxidative function but has not been validated for ketone substrates yet. Purpose We hypothesized that (1) quantification of ketone body oxidative capacity (OC) in myocardium utilizing ex-vivo HRR is feasible and that (2) ketone-associated OC is elevated after fasting and under conditions of chronic mechanical ventricular unloading. Methods We established new HRR (Oxygraph-2k) protocols, measuring oxygen flux generated by oxidation of the ketone substrates beta-hydroxybutyrate (HBA) and acetoacetate (ACA). Ketone protocols were then applied to twelve C57BL/6 mice' (of which six were fasted for 16h) left ventricular and right liver lobe tissue, as well as to eleven terminal heart failure patients' left ventricular tissue, harvested at heart transplantation. Heart transplant recipients were subdivided into patients with left ventricular assist device prior to transplantation (LVAD group, n=6) or no unloading prior to transplantation (HTX group, n=5). Results In non-fasted rodent hearts, HBA yielded an OC of 25±4 pmol/(s*mg tissue) above basal respiration, when applied as sole substrate (21±11 pmol/(s*mg) in liver). ACA alone did not induce oxygen flux, but ACA+succinate yielded 229% higher oxygen flux than succinate alone in state III (146±32 vs 44±12 pmol/(s*mg); p=0.0003). When titrated after succinate, ACA increased OC by 93±25 pmol/(s*mg) (p=0.0003). In 16h-fasted rodent hearts, HBA-supported OC was 27% higher (41±3 vs 52±9 pmol/(s*mg); p=0.04), while OC with ACA+succinate was unchanged (p=0.60). In rodent liver, no oxygen flux was induced by ACA, reflecting absence of 3-oxoacid CoA-transferase. However, HBA-supported OC was 118% higher in fasted liver (37±13 vs 57±13 pmol/(s*mg); p=0.03). In humans, left ventricular unloading was not associated with altered myocardial OC for fatty acids and glycolytic substrates (standard protocol, p=0.13), but HBA-supported OC was 39% higher in the LVAD group compared to the HTX group (54±12 vs 39±9 pmol/(s*mg), p=0.04). Conclusion Quantification of ketone body OC with HRR is feasible in permeabilized myocardial fibers. Applying this novel method revealed increased HBA-supported myocardial mitochondrial respiration after fasting and chronic left ventricular unloading. These data support a concept of enhanced ketone oxidation following ventricular unloading in myocardial mitochondria. Our findings facilitate new studies on myocardial ketone turnover and the interaction of mitochondrial ketone metabolism with cardiac performance. Acknowledgement/Funding CRC 1116, Research commission of the University Hospital Düsseldorf

Glucagon-like peptide-1 preserves coronary microvascular endothelial function after cardiac arrest and resuscitation: potential antioxidant effects

2013 ◽  
Vol 304 (4) ◽  
pp. H538-H546 ◽  
Author(s):  
Betsy B. Dokken ◽  
Charles V. Piermarini ◽  
Mary K. Teachey ◽  
Michael T. Gura ◽  
Christian J. Dameff ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Spontaneous Circulation ◽  
Left Ventricular ◽  
Placebo Control ◽  
Lv Function ◽  
Protective Effects ◽  
Lv Dysfunction ◽  
Flow Reserve ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Glucagon-like peptide-1 (GLP-1) has protective effects in the heart. We hypothesized that GLP-1 would mitigate coronary microvascular and left ventricular (LV) dysfunction if administered after cardiac arrest and resuscitation (CAR). Eighteen swine were subjected to ventricular fibrillation followed by resuscitation. Swine surviving to return of spontaneous circulation (ROSC) were randomized to receive an intravenous infusion of either human rGLP-1 (10 pmol·kg−1·min−1; n = 8) or 0.9% saline ( n = 8) for 4 h, beginning 1 min after ROSC. CAR caused a decline in coronary flow reserve (CFR) in control animals (pre-arrest, 1.86 ± 0.20; 1 h post-ROSC, 1.3 ± 0.05; 4 h post-ROSC, 1.25 ± 0.06; P < 0.05). GLP-1 preserved CFR for up to 4 h after ROSC (pre-arrest, 1.31 ± 0.17; 1 h post-ROSC, 1.5 ± 0.01; 4 h post-ROSC, 1.55 ± 0.22). Although there was a trend toward improvement in LV relaxation in the GLP-1-treated animals, overall LV function was not consistently different between groups. 8 -iso-PGF2α, a measure of reactive oxygen species load, was decreased in post-ROSC GLP-1-treated animals [placebo, control (NS): 38.1 ± 1.54 pg/ml; GLP-1: 26.59 ± 1.56 pg/ml; P < 0.05]. Infusion of GLP-1 after CAR preserved coronary microvascular and LV diastolic function. These effects may be mediated through a reduction in oxidative stress.

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