scholarly journals Chronic intermittent hypoxia exposure improves left ventricular contractility in transgenic mice with heart failure

2012 ◽  
Vol 113 (5) ◽  
pp. 791-798 ◽  
Author(s):  
Jahan Naghshin ◽  
Rosa H. Rodriguez ◽  
Eric M. Davis ◽  
Lia C. Romano ◽  
Kenneth R. McGaffin ◽  
...  
Keyword(s):  
Heart Failure ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Natriuretic Peptide ◽  
Intermittent Hypoxia ◽  
Left Ventricular ◽  
Unexpected Finding ◽  
Wild Type ◽  
Obstructive Sleep ◽  
The Impact

We previously reported the unexpected finding that 4 wk of exposure to intermittent hypoxia (IH), which simulates the hypoxic stress of obstructive sleep apnea, improved LV cardiac function in healthy, lean C57BL/6J mice. The purpose of the present study was to assess the impact of 4 wk of IH on cardiac function in a transgenic murine model that exhibits a natural history of heart failure. We hypothesized that IH exposure would exacerbate cardiac decompensation in heart failure. Adult male FVB (wild type) and transgenic mice with cardiac overexpression of tumor necrosis factor α (TNF-αTG) at 10–12 wk of age were exposed to 4 wk of IH (nadir inspired oxygen 5–6% at 60 cycles/h for 12 h during light period) or intermittent air (IA) as control. Cardiac function was assessed by echocardiography and pressure-volume loop analyses, and mRNA and protein expression were performed on ventricular homogenates. TNF-αTG mice exposed to IA exhibited impaired LV contractility and increased LV dilation associated with markedly elevated cardiac expression of atrial natriuretic peptide and brain natriuretic peptide compared with wild-type mice. When wild-type FVB mice were exposed to IH, they exhibited increases in arterial pressure and dP/d tmax, consistent with our previous report in C57BL/6J mice. Surprisingly, we found that TNF-αTG mice exposed to IH showed a reduction in end-diastolic volume (38.7 ± 3.8 to 22.2 ± 2.1 ul; P < 0.01) and an increase in ejection fraction (29.4 ± 2.5 to 41.9 ± 3.1%; P < 0.05). In contrast to our previous study in C56Bl/6J mice, neither FVB nor TNF-αTG mice exhibited an upregulation in β-adrenergic expression or cAMP in response to IH exposure. We conclude that 4 wk of exposure to IH in mice induces adaptive responses that improve cardiac function in not only healthy animals but also in animals with underlying heart failure.

Abstract 1213: Cardiac Overexpression of Epac1 in Transgenic Mice Protects Heart from Lipopolysaccharide-induced Cardiac Dysfunction and Inhibits JAK-STAT Pathway

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Satoshi Okumura ◽  
Yunzhe Bai ◽  
Meihua Jin ◽  
Sayaka Suzuki ◽  
Akiko Kuwae ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cyclic Amp ◽  
Transgenic Mice ◽  
Cardiac Function ◽  
Proinflammatory Cytokines ◽  
Cardiac Dysfunction ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
Stat Pathway

The sympathetic nervous system and proinflammatory cytokines are believed to play independent roles in the pathophysiology of heart failure. However, the recent identification of Epac (exchange protein activated by cyclic AMP), a new cyclic AMP-binding protein that directly activates Rap1, have implicated that there may be a potential cross talk between the sympathetic and cytokine signals. In order to examine the role of Epac in cytokine signal to regulate cardiac function, we have generated transgenic mice expressing the human Epac1 gene under the control of alpha-cardiac myosin heavy chain promoter (Epac1-TG), and examined their response in lipopolysaccharide (LPS)-induced cardiac dysfunction, a well established model for sepsis-induced cardiac dysfunction. Sepsis-induced cardiac dysfunction results from the production of proinflammatory cytokines. At baseline, left ventricular ejection fraction (LVEF) was similar (TG vs. NTG, 67±1.7 vs. 69±2.1%, n =7–9). The degree of cardiac hypertrophy (LV(mg)/tibia(mm)) was also similar at 3 months old (TG vs. NTG 4.0±0.1 vs. 4.2±0.1, n =5–6), but it became slightly but significantly greater in Epac1-TG at 5 month old (TG vs. NTG 4.9±0.1 vs. 4.4±0.1, p< 0.05, n =5–7). LPS (5mg/kg) elicited a significant and robust reduction of LVEF in both Epac1-TG and NTG, but the magnitude of this decrease was much less in Epac1-TG at 6 hr after injection (TG vs. NTG 48±2.4 vs. 57±1.8%, p< 0.01, n =6–9). At 24 hr after injection, cardiac function was restored to the baseline in both Epac1-TG and NTG. We also examined the activation of JAK-STAT pathway at 24 hr after injection. The tyrosine phosphorylation of STAT1 (Tyr701) and STAT3 (Tyr705) in LV, which is an indicator of STAT activation, was reduced to a greater degree in Epac1-TG by 31±8.8% ( p< 0.05, n =4) and 29±5.9% ( p< 0.05, n =7), respectively, relative to that in NTG. Taken together, Epac1 protects the heart from the cytokine-induced cardiac dysfunction, at least in part, through the inhibition of the JAK-STAT pathway, suggesting the beneficial role played by sympathetic signal to antagonize proinflammatory cytokine signal in heart failure.

scholarly journals Therapeutic Strategies for Sleep Apnea in Hypertension and Heart Failure

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Akiko Noda ◽  
Seiko Miyata ◽  
Yoshinari Yasuda
Keyword(s):  
Heart Failure ◽  
Cardiovascular Disease ◽  
Sleep Apnea ◽  
Cardiac Function ◽  
Blood Pressure Reduction ◽  
Intrathoracic Pressure ◽  
Left Ventricular ◽  
Cpap Treatment ◽  
Negative Intrathoracic Pressure ◽  
Obstructive Sleep

Sleep-disordered breathing (SDB) causes hypoxemia, negative intrathoracic pressure, and frequent arousal, contributing to increased cardiovascular disease mortality and morbidity. Obstructive sleep apnea syndrome (OSAS) is linked to hypertension, ischemic heart disease, and cardiac arrhythmias. Successful continuous positive airway pressure (CPAP) treatment has a beneficial effect on hypertension and improves the survival rate of patients with cardiovascular disease. Thus, long-term compliance with CPAP treatment may result in substantial blood pressure reduction in patients with resistant hypertension suffering from OSAS. Central sleep apnea and Cheyne-Stokes respiration occur in 30–50% of patients with heart failure (HF). Intermittent hypoxemia, nocturnal surges in sympathetic activity, and increased left ventricular preload and afterload due to negative intrathoracic pressure all lead to impaired cardiac function and poor life prognosis. SDB-related HF has been considered the potential therapeutic target. CPAP, nocturnal O2therapy, and adaptive servoventilation minimize the effects of sleep apnea, thereby improving cardiac function, prognosis, and quality of life. Early diagnosis and treatment of SDB will yield better therapeutic outcomes for hypertension and HF.

P3554CMR Fast-SENC intramyocardial LV & RV segmental strain helps manage cardioprotective therapy in patients exhibiting cardiotoxicity during cancer treatment

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
H Steen ◽  
M Montenbruck ◽  
P Wuelfing ◽  
S Esch ◽  
A K Schwarz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Heart Failure ◽  
Cardiac Function ◽  
Cancer Treatment ◽  
Cancer Patients ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Ventricular Ejection Fraction ◽  
The Impact

Abstract Background Cardiotoxicity during cancer treatment has become an acknowledged problem of chemotherapy medications and radiation therapy. Limitations of biomarkers and imaging tests such as echocardiography left ventricular ejection fraction (LVEF) hinder early detection of cardiotoxicity and proactive cardioprotective therapy. Once the heart is unable to compensate for subclinical dysfunction, systemic damage and remodeling occurs increasing the potential for heart failure. Fast-SENC segmental intramyocardial strain (fSENC) is a unique cardiac magnetic resonance imaging (CMR) test that regionally detects subclinical intramyocardial dysfunction in 1 heartbeat. This study evaluates the ability of fSENC to detect subclinical cardiotoxicity and manage cardioprotective therapy in cancer patients. Methods This single center, prospective Prefect Study was used to evaluate cardiotoxicity and the impact of cardioprotective therapy in Breast Cancer and Lymphoma patients (NCT03543228). fSENC was acquired with a 1.5T MRI and processed with the MyoStrain software to quantify intramyocardial strain. Segmental strain was measured in three short axis scans (basal, midventricular & apical) with 16LV/6RV longitudinal segments & three long axis scans (2-, 3-, 4-chamber) with 21LV/5RV circumferential segments. fSENC CMR was performed before chemotherapy, during and after anthracycline/taxan therapy, at 1 year follow-up, and as needed in between designated follow-up periods. Cardioprotective therapy was offered to patients meeting the definition of cardiotoxicity by the ESC Guidelines on Cardiotoxicity and/or ESMO Clinical Practice Guidelines or those observing a substantial decline in cardiac function. Comparisons were made with paired t-Test with a 95% confidence interval. Results Two hundred eight (208) CMRs were performed in fifty-two (52) patients (44 female). Patients had an average (± stdev) age of 53 (15) yrs, BMI of 26 (5) kg/m2; 77% had breast cancer, 23% had Lymphoma. fSENC CMRs required 11 (2) min total exam time. Figure 1 shows bar graphs of the % of normal LV myocardium (e.g. % LV MyoStrain Segments <−17%) at baseline and sequential follow-ups for patients without cardiotoxicity and with cardiotoxicity requiring cardioprotective therapy. Patients observing cardiotoxicity had a statistically significant decline in cardiac function measured by segmental fSENC (p=0.0002) which resolved after cardioprotective therapy. Figure 1 Conclusion Segmental fSENC intramyocardial strain detects subclinical cardiotoxicity during chemotherapy and impact of cardioprotective therapy. The ability to serve as a surrogate safety endpoint for chemotherapy or other pharmacological agents, and aid management of cardiotoxicity by serving as a surrogate efficacy endpoint for cardioprotection agents, dosage, and patient compliance may help physicians detect subclinical cardiac dysfunction, and proactively manage cancer patients to avoid early or late heart failure.

scholarly journals Auto positive airway pressure therapy reduces pulmonary pressures in adults admitted for acute heart failure with pulmonary hypertension and obstructive sleep apnea. The ASAP-HF Pilot Trial

SLEEP ◽  
2019 ◽  
Vol 42 (7) ◽  
Author(s):  
Sunil Sharma ◽  
Henrik Fox ◽  
Francisco Aguilar ◽  
Umer Mukhtar ◽  
Leslee Willes ◽  
...  
Keyword(s):  
Heart Failure ◽  
Obstructive Sleep Apnea ◽  
Pulmonary Hypertension ◽  
Sleep Apnea ◽  
Airway Pressure ◽  
Positive Airway Pressure ◽  
Left Ventricular ◽  
Obstructive Sleep ◽  
The Mean ◽  
The Impact

AbstractObjectivesPulmonary hypertension (PH) is extremely common in acute decompensated heart failure (ADHF) patients and predicts increased mortality. Obstructive sleep apnea (OSA), highly prevalent in congestive heart failure patients, may contribute to further elevated pulmonary pressures. This study evaluates the impact of positive airway pressure (PAP) therapy on PH in patients admitted for ADHF with OSA.MethodsA two-center randomized control trial comparing standard of care (SOC) therapy for ADHF versus addition of PAP therapy in patients with concomitant OSA.ResultsTwenty-one consecutive patients were enrolled with 1:1 randomization to SOC versus SOC plus 48-hour PAP therapy protocol. In the intervention arm, the mean pulmonary artery systolic pressure (PASP) difference before therapy and after 48 hours of PAP therapy was −15.8 ± 3.2 (58.6 ± 2.5 mm Hg to 42.8 ± 2.7) versus the SOC arm where the mean PASP difference was −5.2 ± 2.6 (62.7 ± 3.3 mm Hg reduced to 57.5 ± 3.9) (p = 0.025). In addition, ejection fraction in the intervention arm improved (3.4 ± 1.5% versus −0.5 ± 0.5 %) (p = 0.01). Significant improvement was also noted in tricuspid annular plane systolic excursion (TAPSE) and right ventricular systolic area in the intervention arm but not in NT-pro-BNP or 6-minute walk distance.ConclusionsIn patients with ADHF and OSA, addition of 48 hours of PAP therapy to SOC treatment significantly reduced PH. In addition, PAP therapy was able to improve right and left ventricular function.ClinicalTrials.gov identifier: NCT02963597.

scholarly journals Protective Effects of Thyroid Hormone Deprivation on Progression of Maladaptive Cardiac Hypertrophy and Heart Failure

2021 ◽  
Vol 8 ◽  
Author(s):  
Helena Kerp ◽  
Georg Sebastian Hönes ◽  
Elen Tolstik ◽  
Judith Hönes-Wendland ◽  
Janina Gassen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Function ◽  
Heart Function ◽  
Pressure Overload ◽  
Left Ventricular Pressure ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Cardiovascular Morbidity And Mortality ◽  
The Impact

Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification.Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks.Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation.Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.

scholarly journals Promoting PGC-1α-driven mitochondrial biogenesis is detrimental in pressure-overloaded mouse hearts

2014 ◽  
Vol 307 (9) ◽  
pp. H1307-H1316 ◽  
Author(s):  
Georgios Karamanlidis ◽  
Lorena Garcia-Menendez ◽  
Stephen C. Kolwicz ◽  
Chi Fung Lee ◽  
Rong Tian
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Mitochondrial Biogenesis ◽  
Citrate Synthase ◽  
Mitochondrial Gene ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Wild Type ◽  
Term Survival ◽  
Fractional Shortening

Mitochondrial dysfunction in animal models of heart failure is associated with downregulation of the peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α pathway. To test whether PGC-1α is an appropriate therapeutic target for increasing mitochondrial biogenesis and improving function in heart failure, we used a transgenic (TG) mouse model of moderate overexpression of PGC-1α (∼3-fold) in the heart. TG mice had small increases in citrate synthase activity and mitochondria size in the heart without alterations in myocardial energetics or cardiac function at baseline. In vivo dobutamine stress increased fractional shortening in wild-type mice, but this increase was attenuated in TG mice, whereas ex vivo isolated perfused TG hearts demonstrated normal functional and energetic response to high workload challenge. When subjected to pressure overload by transverse aortic constriction (TAC), TG mice displayed a significantly greater acute mortality for both male and female mice; however, long-term survival up to 8 wk was similar between the two groups. TG mice also showed a greater decrease in fractional shortening and a greater increase in left ventricular chamber dimension in response to TAC. Mitochondrial gene expression and citrate synthase activity were mildly increased in TG mice compared with wild-type mice, and this difference was also maintained after TAC. Our data suggest that a moderate level of PGC-1α overexpression in the heart compromises acute survival and does not improve cardiac function during chronic pressure overload in mice.

scholarly journals A Protective Role of SOD1 Overexpression in Central Mediation of Bradycardia Following Chronic Intermittent Hypoxia in Mice

2020 ◽  
Author(s):  
Jin Chen ◽  
He Gu ◽  
Robert D Wurster ◽  
Zixi Jack Cheng
Keyword(s):  
Transgenic Mice ◽  
Intermittent Hypoxia ◽  
Baroreflex Sensitivity ◽  
Cardiovascular Complications ◽  
Protective Role ◽  
Chronic Intermittent Hypoxia ◽  
Wild Type ◽  
Baroreflex Control ◽  
Aortic Depressor Nerve ◽  
Obstructive Sleep

Obstructive sleep apnea (OSA) is a highly prevalent sleep disorder that is associated with many cardiovascular complications. Similar to OSA, chronic intermittent hypoxia (CIH) (a model for OSA) leads to oxidative stress and impairs baroreflex control of the heart rate (HR) in rodents. The baroreflex arc includes the aortic depressor nerve (ADN), vagal efferent, and central neurons. In this study, we used mice as a model to examine the effects of CIH on baroreflex sensitivity, aortic baroreceptor afferents and central and vagal efferent components of the baroreflex circuitry. Furthermore, we tested whether human Cu/Zn Superoxide Dismutase (SOD1) overexpression in the transgenic mice offers protection against CIH induced deficit of the baroreflex arc. Wild-type C57BL/6J and SOD1 mice were exposed to room air (RA) or CIH and were then anesthetized, ventilated and catheterized for measurement of mean arterial pressure (MAP) and HR. Compared with wild-type RA control, CIH impaired baroreflex sensitivity but increased maximum baroreceptor gain and the bradycardic response to vagal efferent stimulation. Additionally, CIH reduced the bradycardic response to ADN stimulation, indicating a diminished central regulation of bradycardia. Interestingly, SOD1 overexpression prevented CIH-induced attenuation of HR responses to ADN stimulation and preserved HR responses to vagal efferent stimulation in transgenic mice. We suggest that CIH decreased central mediation of the baroreflex and SOD1 overexpression may prevent the CIH-induced central deficit.

The role of N-terminal pro-brain natriuretic peptide (NT-pro-BNP) as a prognostic marker in older people: the impact of reduced renal function

2009 ◽  
Vol 19 (2) ◽  
pp. 71-76 ◽  
Author(s):  
Thiane Gama Axelsson ◽  
Bengt Lindholm
Keyword(s):  
Heart Failure ◽  
Older People ◽  
Brain Natriuretic Peptide ◽  
Kidney Function ◽  
Natriuretic Peptide ◽  
Ventricular Myocytes ◽  
Left Ventricular ◽  
The Impact ◽  
Circulating Levels

SummaryThe N-terminal pro-brain natriuretic peptide (NT-pro-BNP) is released in response to volume expansion and/or increased tension on left ventricular myocytes. NT-pro-BNP is a useful diagnostic and prognostic biomarker both in patients with dyspnoea of unknown aetiology, and for risk assessment of patients with established heart failure. However, impaired kidney function – a common condition in older people as well as a strong risk factor for cardiovascular disease is associated with elevated circulating levels of NT-pro-BNP. Therefore, it is important to know the kidney function when interpreting an elevated NT-pro-BNP measurement obtained in older people in order to diagnose or stage congestive heart failure.

scholarly journals The Effect of Carvedilol on B-Type Natriuretic Peptide and Cardiac Function in Patients with Heart Failure and Persistent Atrial Fibrillation

Cardiology ◽  
2015 ◽  
Vol 130 (3) ◽  
pp. 153-158 ◽  
Author(s):  
Aleem U. Khand ◽  
Pei G. Chew ◽  
Homeyra Douglas ◽  
Julia Jones ◽  
Aftab Jan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atrial Fibrillation ◽  
Heart Rate ◽  
Cardiac Function ◽  
Natriuretic Peptide ◽  
Nyha Class ◽  
Persistent Atrial Fibrillation ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Controlled Study

Objectives: We sought to determine the relationship between changes in natriuretic peptides and symptoms as a consequence of introducing beta-blocker therapy, in patients with chronic heart failure (CHF) and persistent atrial fibrillation (AF). Methods: In a randomised, double-blind, placebo-controlled study involving 47 patients with CHF and persistent AF (mean age 68 years and 62% men), we analysed the individual change (Δ) in B-type natriuretic peptide (BNP) level to the introduction of carvedilol (titrated to a target dose of 25 mg twice daily, group A) or placebo (group B) in addition to background treatment with digoxin. Symptoms score, 6-min walk distance, New York Heart Association (NYHA) class, left ventricular ejection fraction (LVEF), heart rate (24-hour ECG) and BNP were measured at baseline and at 4 months. Results: LVEF (Δ median +5 vs. +0.4, p = 0.048), symptoms score (Δ median -4 vs. 0, p = 0.04), NYHA class (Δ median -33% vs. +3% in NYHA class 3-4, p = 0.046) and heart rate [Δ median 24-hour ventricular rate (VR) -19 vs. -2, p < 0.0001] improved with combination therapy of digoxin and carvedilol compared to digoxin alone, but BNP (Δ median +28 vs. -6 , p = 0.11) trended in the opposite direction. There was no relationship between the degree of symptomatic improvement or VR control and BNP response. Conclusion: After the introduction of carvedilol, clinical outcome appears unrelated to BNP changes in patients with CHF and AF. Changes in BNP cannot be used as a marker of clinical response in terms of symptoms or cardiac function in this setting.

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