scholarly journals Apelin decreases myocardial injury and improves right ventricular function in monocrotaline-induced pulmonary hypertension

2009 ◽  
Vol 296 (6) ◽  
pp. H2007-H2014 ◽  
Author(s):  
Inês Falcão-Pires ◽  
Nádia Gonçalves ◽  
Tiago Henriques-Coelho ◽  
Daniel Moreira-Gonçalves ◽  
Roberto Roncon-Albuquerque ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pressure Rise ◽  
Chronic Administration ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Peak Rate ◽  
Male Wistar Rats ◽  
Neurohumoral Activation

We investigated the endogenous production of apelin and the cardiac and pulmonary effects of its chronic administration in monocrotaline (MCT)-induced pulmonary hypertension (PH). Male Wistar rats were injected with MCT (60 mg/kg sc) or vehicle ( day 0). One week later, these animals were randomly treated during 17 days with pyroglutamylated apelin-13 (Pyr-AP13; 200 μg·kg−1·day−1 ip) or a similar volume of saline, resulting in four groups: sham ( n = 11), sham-AP ( n = 11), MCT ( n = 16), and MCT-AP ( n = 13). On day 25, right ventricular (RV) and left ventricular (LV) hemodynamic and morphometric parameters were assessed. Tissue and plasma samples were collected for histological and molecular analysis. When compared with sham, the MCT group presented a significant increase of RV mass (166 ± 38%), diameter of cardiomyocyte (40 ± 10%), myocardial fibrosis (95 ± 20%), peak systolic pressure (99 ± 22%), peak rate of ventricular pressure rise (dP/d tmax; 74 ± 24%), peak rate of ventricular pressure decline (dP/d tmin; 73 ± 19%), and time constant τ (55 ± 16%). In these animals, RV expression of apelin (−73 ± 10%) and its receptor APJ (−61 ± 20%) was downregulated, whereas mRNA expression of type B natriuretic peptide (9,606 ± 713%), angiotensinogen (191 ± 147%), endothelin-1 (RV, 497 ± 156%; and LV, 799 ± 309%), plasmatic levels of apelin (104 ± 48%), and angiotensin 1-7 (161 ± 151%) were increased. Chronic treatment with Pyr-AP13 significantly attenuated or normalized these changes, preventing apelin-APJ mRNA downregulation and PH-induced neurohumoral activation of several vasoconstrictors, which exacerbates apelin-APJ vasodilator effects. Therefore, apelin delayed the progression of RV hypertrophy and diastolic dysfunction. Together, these observations suggest that the apelin-APJ system may play an important role in the pathophysiology of PH, representing a potential therapeutic target since it significantly attenuates RV overload and PH-induced neurohumoral activation.

Abstract 13973: Impaired Right Ventricular Hemodynamics Suggest Preclinical Pulmonary Hypertension in Patients With Metabolic Syndrome

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Deepa M Gopal ◽  
Yi-Chih Wang ◽  
Nir Ayalon ◽  
Courtney Donohue ◽  
Rajalakshmi Santhanakrishnan ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Systolic Function ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Doppler Measurement ◽  
Ejection Time ◽  
Pulsed Wave Doppler ◽  
Lv Diastolic Dysfunction

Introduction: Metabolic syndrome (MetS) is associated with preclinical metabolic heart disease (MHD) as reflected by left ventricular (LV) diastolic dysfunction. Very little is known about right ventricular (RV) function and/or pulmonary hypertension in MetS or early MHD. Hypothesis: We tested the hypothesis that that MetS is associated with subclinical RV dysfunction and pulmonary hypertension. Methods: A total of 164 subjects with MetS but without cardiovascular disease (mean age 45 years, 71% women, mean BMI 41 kg/m 2 ), 40 similarly obese controls without MetS, and 36 non-obese healthy controls underwent echocardiography, including pulsed-wave Doppler measurement of pulmonary artery acceleration time (PAAT) and ejection time (ET). PA systolic pressure was estimated from PAAT using validated equations. Results: MetS was associated with lower tricuspid valve e', shorter PAAT, shorter ET, and larger PA diameter compared with controls (Table). A total of 24% of individuals with MetS had an abnormal PAAT (<100 msec). Estimated PA systolic pressure based on PAAT was 42±10 mmHg in MetS compared with 32±10 and 32±9 mmHg in healthy and obese controls (P for ANOVA <0.0001). In contrast, RV structure and systolic function were similar in MetS compared with controls ( Table ). After adjustment for age, sex, hypertension, diabetes, and body-mass index, MetS remained associated with shorter PAAT (P=0.03 vs healthy; P=0.0005 vs obese). Among MetS, PAAT was correlated with mitral mean e’ (r=0.20, P=0.004), E/A ratio (r=0.21, P=0.008), and tricuspid e’ (r=0.20, P=0.04). A total of 40% of participants with abnormal PAAT also had low mean e’ (<8 cm/s). Conclusions: MetS is associated with abnormal RV hemodynamics as evidenced by shorter PAAT, which correlates with measures of LV diastolic function. Estimated PA systolic pressures are significantly higher in preclinical MetS and MHD, and raise the possibility that pulmonary hypertension contributes to the pathophysiology of MHD.

scholarly journals Tofogliflozin improved pulmonary hypertension due to heart failure with preserved ejection fraction in mice

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
Y J Joki ◽  
H K Konishi ◽  
K T Takasu ◽  
T M Minamino
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Right Ventricular ◽  
Heart Diseases ◽  
Sglt2 Inhibitor ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Chow Diet ◽  
Normal Chow

Abstract Introduction Pulmonary hypertension (PH) caused by left heart diseases is categorized as the group 2 (PH-LHD). PH-LHD due to heart failure with preserved LV ejection fraction (HFpEF) is more prevalent in patients with metabolic syndrome and shows poorer prognosis than LHD without PH. Tofogliflozin (TOFO) is an SGLT2 inhibitor utilized for diabetic treatment. Recent studies revealed that the SGLT2 inhibitor has a beneficial effect on heart failure; however, it remains unclear whether the SGLT2 inhibitor is effective for the treatment of PH-LHD. Hypothesis We hypothesized that TOFO has a protective effect on PH with HFpEF. Methods We generated two murine models for PH-LHD due to HFpEF, a transverse aortic constriction (TAC) model and a high fat diet (HFD) model. C57BL/6J mice were subjected to TAC and treated with TOFO (3 mg/kg) for 4weeks. In another model, AKR/J mice were fed HFD or normal chow diet and treated with TOFO (3mg/kg in water) for 20 weeks. We then measured physical data including body weight (BW), left ventricular weight (LV), right ventricular weight (RV), and right ventricular systolic pressure (RVSP) and performed echocardiography. Results Mice treated with TOFO demonstrated increased urine glucose level. TAC induced left ventricular hypertrophy and increased RVSP. TOFO treatment improved RV/LV ratio and RVSP in TAC mice (Figure 1). HFD fed AKR/J mice demonstrated increased BW and PH as demonstrated by increased RV/LV ratio and RVSP compared with the normal chow group. TOFO treatment ameliorated the increases of BW, RV/LV ratio, and RVSP in HFD fed AKR/J mice (Figure 2). Conclusions TOFO treatment improved pulmonary hypertension in two models for PH-LHD due to HFpEF, suggesting that the SGLT2 inhibitor is effective for the treatment of this condition. FUNDunding Acknowledgement Type of funding sources: None. Figure 2. TOFO reduced RVSP caused by HFD

scholarly journals Angiotensin-II type 1 receptor mediates pulmonary hypertension and right ventricular remodeling induced by inhaled nicotine.

2021 ◽  
Author(s):  
Nicholas D. Fried ◽  
Tamara M. Morris ◽  
Anna Whitehead ◽  
Eric Lazartigues ◽  
Xinping Yue ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Angiotensin Ii ◽  
Right Ventricular ◽  
Ventricular Remodeling ◽  
Electronic Cigarettes ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Serum Cotinine

Use of electronic cigarettes is rapidly increasing among youth and young adults, but little is known regarding the long-term cardiopulmonary health impacts of these nicotine-containing devices. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension (PH) and right ventricular (RV) remodeling in mice. These changes were associated with upregulated RV angiotensin-converting enzyme (ACE). Angiotensin-II receptor blockers (ARBs) have been shown to reverse cigarette smoking-induced PH in rats. ACE inhibitor and ARB use in a large retrospective PH patient cohort is associated with improved survival. Here, we utilized losartan (an ARB specific for angiotensin-II type 1 receptor) to further explore nicotine-induced PH. Male C57BL/6 mice received nicotine vapor for 12 hours per day, and exposure was assessed using serum cotinine to achieve levels comparable to human smokers or electronic cigarette users. Mice were exposed to nicotine for 8 weeks and a subset was treated with losartan via osmotic minipump. Cardiac function was assessed using echocardiography and catheterization. Although nicotine exposure increased angiotensin-II in the RV and lung, this finding was non-significant. Chronic, inhaled nicotine significantly increased RV systolic pressure and RV free wall thickness versus air control. These parameters were significantly lower in mice receiving both nicotine and losartan. Nicotine significantly increased RV internal diameter, with no differences seen between the nicotine and nicotine-losartan group. Neither nicotine nor losartan effect left ventricular structure or function. These findings provide the first evidence that antagonism of the angiotensin-II type 1 receptor can ameliorate chronic, inhaled nicotine-induced PH and RV remodeling.

Abstract 16307: Tofogliflozin Improves Pulmonary Hypertension With Heart Failure With Preserved Ejection Fraction Mice

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Yusuke Joki ◽  
Hakuoh Konishi ◽  
Kiyoshi Takasu ◽  
Tohru Minamino
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Ejection Fraction ◽  
Beneficial Effect ◽  
Right Ventricular ◽  
Sglt2 Inhibitor ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Sglt2 Inhibitors ◽  
Urine Glucose

Introduction: Pulmonary hypertension (PH) is a syndrome of increased pulmonary artery pressure and often leads to death. Left heart diseases(LHD) are frequently complicated by PH (PH-LHD), classified group2. In particular, PH with heart failure with preserved LV ejection fraction (HFpEF) is higher prevalence metabolic syndrome and poor prognosis than LHD without PH. Tofogliflozin (TOFO) is SGLT2 inhibitor as a therapeutic agent for diabetes. Recent study revealed SGLT2 inhibitors have a beneficial effect on heart failure. However it has not been clarified that SGLT2 inhibitors affect PH-LHD. This study examined whether TOFO improved for PH-LHD. Hypothesis: We hypothesis TOFO has a protective effect for PH with HFpEF. Methods: We used two HFpEF mice models, induced by transverse aortic constriction (TAC) surgery and high fat diet (HFD). TAC model: C57BL/6J mice were subjected to TAC. Sham and TAC mice were treated with TOFO 3mg/kg in water by day or only water. After 4weeks, each mouse was measured physical data, Body weight (BW), Left ventricular weight (LV), Right ventricular weight (RV), right ventricular systolic pressure (RVSP), UCG, collected blood and urine glucose. HFD model: AKR/J mice fed a HFD for 20weeks. Regular diet and HFD mice were treated with TOHO 3mg/kg in water by day or only water. 20weeks later each mouse measured above data. Results and Conclusions: Mice treated with TOFO had significantly higher urine glucose concentrations. TAC induced left ventricular hypertrophy, increased HW/BW ratio and RVSP. However TAC+TOFO mice were reduced hypertrophy and LV/BW ratio than TAC group. Moreover TAC+TOFO mice were improved RV/LV ratio and RVSP (Figure). AKR/J+HFD groups substantially higher BW and occurred PH than RFD groups. In contrast with HFD, TOFO treated group ameliorated BW, RW/LW ratio, moreover normal RVSP. These results showed Tofogliflozin had a beneficial effect for PH with HFpEF.

Impaired Left Ventricular Filling Due to Right Ventricular Pressure Overload in Primary Pulmonary Hypertension

CHEST Journal ◽  
2001 ◽  
Vol 119 (6) ◽  
pp. 1761-1765 ◽  
Author(s):  
J. Tim Marcus ◽  
Anton Vonk Noordegraaf ◽  
Roald J. Roeleveld ◽  
Pieter E. Postmus ◽  
Rob M. Heethaar ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Primary Pulmonary Hypertension ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Left Ventricular Filling ◽  
Ventricular Pressure ◽  
Ventricular Filling

Reflex cardiovascular depression induced by capsaicin injection into canine liver

1982 ◽  
Vol 242 (6) ◽  
pp. H955-H960
Author(s):  
J. H. Ashton ◽  
G. A. Iwamoto ◽  
J. C. Longhurst ◽  
J. H. Mitchell
Keyword(s):  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Afferent Fiber ◽  
Pressure Rise ◽  
Left Ventricular Pressure ◽  
Cardiovascular Responses ◽  
Left Ventricular ◽  
Ventricular Pressure ◽  
Ventricular Systolic Pressure ◽  
Cardiovascular Depression

Capsaicin was injected into the portal circulation of 29 dogs after a blood delay pathway was constructed between the liver and right heart, through which capsaicin-contaminated blood could be replaced while systemic hemodynamics were maintained constant. Capsaicin (500 micrograms) rapidly decreased left ventricular systolic pressure (-10%), mean arterial pressure (-12%), heart rate (-4%), renal vascular resistance (-7%), maximal rate of left ventricular pressure rise (dP/dtmax) (-12%), and dP/dt at 25 mmHg developed left ventricular pressure (-15%) in animals with paced hearts. Left ventricular end-diastolic pressure did not change. Vagus nerve interruption at the level of the diaphragm did not alter hemodynamic changes occurring during capsaicin injections, but anterior hepatic nerve interruption eliminated the changes, suggesting that the cardiovascular responses were reflex in origin and that the principal afferent pathway traverses the hepatic nerve. This study demonstrates that activation of afferent fiber receptors within the liver tissue can contribute to neural regulation of the cardiovascular system, but the natural stimulus for these receptors is not known.

Abstract 325: Administration Of Apelin Modulates Myocardial Expression Of Apelin-apj And Improves Right Ventricular Performance In Mct-induced Pulmonary Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Inês Falcao-Pires ◽  
Nadia Gonçalves ◽  
Tiago Henriques-Coelho ◽  
Roberto Roncon-Albuquerque ◽  
Moreira-Gonçalves Daniel ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Chronic Administration ◽  
List Type ◽  
Down Regulation ◽  
Ventricular Performance ◽  
Beneficial Effects ◽  
Male Wistar Rats ◽  
Decreasing Ph ◽  
And Function

Background: Apelin (AP) is the endogenous vasoactive ligand of APJ receptor. It is widely expressed in the heart and lungs and has important cardiovascular functions such as endothelium-dependent vasodilatation and positive inotropic effect. However, the role of apelin-APJ system in pulmonary hypertension (PH) remains to be clarified. Objective: To evaluate the chronic effects of apelin in: right ventricular (RV) myocardial function; cardiac expression of apelin and APJ in healthy and MCT-PH rats Methods: Male Wistar rats were randomly injected with MCT (60mg/Kg, sc) or vehicle (CTR, day 0). One week later, half of these animals were randomly treated with Pyr-apelin-13 (200μg/Kg/day, ip) or a similar volume of vehicle. The study resulted in 4 groups: CTR; AP; MCT and MCT+ AP. At day 24, animals were instrumented to record RV peak systolic (Pmax) pressures, dP/dtmax, dP/dtmin and time constant Tau. Also, heart and lungs were weighted and transmural RV samples were collected for relative quantification of mRNA by real-time RT-PCR. Results are on table . Conclusions: In healthy rats, exogenous apelin potentiates its endogenous production with no significant changes in APJ. MCT-induced PH resulted in a significant down-regulation of apelin-APJ system, which might play a role in the systolic and diastolic dysfunction observed in this model. This down-regulation was completely reverted by chronic administration of exogenous apelin. Therefore, apelin upregulates the cardiac apelin-APJ system exerting beneficial effects on cardiac remodeling and function, namely, by decreasing PH, RV diastolic function and hypertrophy. These results reveal the importance of apelin-APJ system in the pathophysiology of PH, suggesting that apelin is a potential therapeutic target in this disease. Results table

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