The Effects and Mechanism of Atorvastatin on Pulmonary Hypertension Due to Left Heart Disease

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Abstract

Background

Pulmonary hypertension due to left heart disease (PH-LHD) is one of the most common forms of PH, termed group 2 PH. Atorvastatin exerts beneficial effects on the structural remodeling of the lung in ischemic heart failure. However, few studies have investigated the effects of atorvastatin on PH due to left heart failure induced by overload.

Methods

Group 2 PH was induced in animals by aortic banding. Rats (n = 20) were randomly divided into four groups: a control group (C), an aortic banding group (AOB ₆₃), an atorvastatin prevention group (AOB ₆₃/ATOR ₆₃) and an atorvastatin reversal group (AOB ₆₃/ATOR _50-63). Atorvastatin was administered for 63 days after banding to the rats in the AOB ₆₃/ATOR ₆₃ group and from days 50 to 63 to the rats in the AOB ₆₃/ATOR _50-63 group.

Results

Compared with the controls, significant increases in the mean pulmonary arterial pressure, pulmonary arteriolar medial thickening, biventricular cardiac hypertrophy, wet and dry weights of the right middle lung, percentage of PCNA-positive vascular smooth muscle cells, inflammatory infiltration and expression of RhoA and Rho-kinase II were observed in the AOB ₆₃ group, and these changes concomitant with significant decreases in the percentage of TUNEL-positive vascular smooth muscle cells. Treatment of the rats in the AOB ₆₃/ATOR ₆₃ group with atorvastatin at a dose of 10 mg/kg/day significantly decreased the mean pulmonary arterial pressure, right ventricular hypertrophy, pulmonary arteriolar medial thickness, inflammatory infiltration, percentage of PCNA-positive cells and pulmonary expression of RhoA and Rho-kinase II and significantly augmented the percentage of TUNEL-positive cells compared with the AOB ₆₃ group. However, only a trend of improvement in pulmonary vascular remodeling was detected in the AOB ₆₃/ATOR _50-63 group.

Conclusions

Atorvastatin prevents pulmonary vascular remodeling in the PH-LHD model by down-regulating the expression of RhoA/Rho kinase, by inhibiting the proliferation and increasing the apoptosis of pulmonary arterial smooth muscle cells, and by attenuating the inflammation of pulmonary arteries.

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Most cited references 16

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Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study.

Ross Arena, Marco Guazzi, M Guazzi … (2011)

The prevalence of heart failure with preserved ejection fraction is increasing. The prognosis worsens with pulmonary hypertension and right ventricular (RV) failure development. We targeted pulmonary hypertension and RV burden with the phosphodiesterase-5 inhibitor sildenafil. Forty-four patients with heart failure with preserved ejection fraction (heart failure signs and symptoms, diastolic dysfunction, ejection fraction ≥50%, and pulmonary artery systolic pressure >40 mm Hg) were randomly assigned to placebo or sildenafil (50 mg thrice per day). At 6 months, there was no improvement with placebo, but sildenafil mediated significant improvements in mean pulmonary artery pressure (-42.0±13.0%) and RV function, as suggested by leftward shift of the RV Frank-Starling relationship, increased tricuspid annular systolic excursion (+69.0±19.0%) and ejection rate (+17.0±8.3%), and reduced right atrial pressure (-54.0±7.2%). These effects may have resulted from changes within the lung (reduced lung water content and improved alveolar-capillary gas conductance, +15.8±4.5%), the pulmonary vasculature (arteriolar resistance, -71.0±8.2%), and left-sided cardiac function (wedge pulmonary pressure, -15.7±3.1%; cardiac index, +6.0±0.9%; deceleration time, -13.0±1.9%; isovolumic relaxation time, -14.0±1.7%; septal mitral annulus velocity, -76.4±9.2%). Results were similar at 12 months. The multifaceted response to phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction includes improvement in pulmonary pressure and vasomotility, RV function and dimension, left ventricular relaxation and distensibility (structural changes and/or ventricular interdependence), and lung interstitial water metabolism (wedge pulmonary pressure decrease improving hydrostatic balance and right atrial pressure reduction facilitating lung lymphatic drainage). These results enhance our understanding of heart failure with preserved ejection fraction and offer new directions for therapy. URL: http://www.clinicaltrials.gov. UNIQUE IDENTIFIER: NCT01156636.

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PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.

Marco Guazzi, Marco Vicenzi, Ross Arena … (2011)

In heart failure (HF), a defective nitric oxide signaling is involved in left ventricular (LV) diastolic abnormalities and remodeling. PDE5 inhibition, by blocking degradation of nitric oxide second-messenger cyclic guanosine monophosphate, might be beneficial. In a cohort of systolic HF patients, we tested the effects of PDE5 inhibition (sildenafil) on LV ejection fraction, diastolic function, cardiac geometry, and clinical status. Forty-five HF patients (New York Heart Association class II-III) were randomly assigned to placebo or sildenafil (50 mg three times per day) for 1 year, with assessment (6 months and 1 year) of LV ejection fraction, diastolic function, geometry, cardiopulmonary exercise performance, and quality of life. In the sildenafil group only, at 6 months and 1 year, LV ejection fraction, early diastolic tissue Doppler velocities (E') at the mitral lateral (from 4.62 to 5.20 and 5.19 m/s) and septal (from 4.71 to 5.23 and 5.24 m/s) annuli significantly increased, whereas the ratio of early transmitral (E) to E' lateral decreased (from 13.1 to 9.8 to 9.4) (P<0.01). Changes were accompanied by a reverse remodeling of left atrial volume index (from 32.0 to 29.0 and 29.1 mL/m(2); P<0.01) and LV mass index (from 148.0 to 130.0 and 128.0 g/m(2); P<0.01). Furthermore, sildenafil improved exercise performance (peak Vo(2)), ventilation efficiency (ventilation to CO(2) production slope), and quality of life (P<0.01). Minor adverse effects were noted: flushing in 4 and headache in 2 treated patients. Findings confirm that in HF, sildenafil improves functional capacity and clinical status and provide the first human evidence that LV diastolic function and cardiac geometry are additional targets of benefits related to chronic PDE5 inhibition.

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Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension.

Ahmed Tawakol, Robert Gerszten, Judy Hung … (2007)

Patients with systolic heart failure (HF) who develop secondary pulmonary hypertension (PH) have reduced exercise capacity and increased mortality compared with HF patients without PH. We tested the hypothesis that sildenafil, an effective therapy for pulmonary arterial hypertension, would lower pulmonary vascular resistance and improve exercise capacity in patients with HF complicated by PH. Thirty-four patients with symptomatic HF and PH were randomized to 12 weeks of treatment with sildenafil (25 to 75 mg orally 3 times daily) or placebo. Patients underwent cardiopulmonary exercise testing before and after treatment. The change in peak VO2 from baseline, the primary end point, was greater in the sildenafil group (1.8+/-0.7 mL x kg(-1) x min(-1)) than in the placebo group (-0.27 mL x kg(-1) x min(-1); P=0.02). Sildenafil reduced pulmonary vascular resistance and increased cardiac output with exercise (P<0.05 versus placebo for both) without altering pulmonary capillary wedge or mean arterial pressure, heart rate, or systemic vascular resistance. The ability of sildenafil treatment to augment peak VO2 correlated directly with baseline resting pulmonary vascular resistance (r=0.74, P=0.002) and indirectly with baseline resting right ventricular ejection fraction (r=-0.64, P=0.01). Sildenafil treatment also was associated with improvement in 6-minute walk distance (29 m versus placebo; P=0.047) and Minnesota Living With Heart Failure score (-14 versus placebo; P=0.01). Subjects in the sildenafil group experienced fewer hospitalizations for HF and a higher incidence of headache than those in the placebo group without incurring excess serious adverse events. Phosphodiesterase 5 inhibition with sildenafil improves exercise capacity and quality of life in patients with systolic HF with secondary PH.

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Author and article information

Contributors

Yunchao Su: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 7 July 2016

Publication date Collection: 2016

Volume: 11

Issue: 7

Electronic Location Identifier: e0157171

Affiliations

[1 ]Department of Cardiology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

[2 ]Department of Hepatic Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China

Augusta University, UNITED STATES

Author notes

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: WJZ KLC QW. Performed the experiments: QW YZG YTZ JJX. Analyzed the data: QW YZG WJZ ZCC. Contributed reagents/materials/analysis tools: QW YZG YTZ JJX ZCC SYC MDO. Wrote the paper: QW YZG WJZ KLC.

* E-mail: zengwj2011@ 123456126.com (WJZ); chengkangling@ 123456126.com (KLC)

Article

Publisher ID: PONE-D-16-01804

DOI: 10.1371/journal.pone.0157171

PMC ID: 4936674

PubMed ID: 27388289

SO-VID: 793a278f-1c99-4bb0-9543-cd3f01243eea

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 14 February 2016

Date accepted : 25 May 2016

Page count

Figures: 9, Tables: 1, Pages: 14

Funding

Funded by: Young of natural science funds

Award ID: 81400301

Award Recipient : Weijie Zeng

Funded by: Fundamental Research Funds for the Central Universities

Award ID: 21612312

Award Recipient : Weijie Zeng

This work was supported by the National Natural Science Foundation of China (81400301) and the Fundamental Research Funds for the Central Universities (21612312). The funders had no role in study design, decision to publish and preparation of manuscript.

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Data Availability All underlying data necessary to replicate this study are within the paper.

The Effects and Mechanism of Atorvastatin on Pulmonary Hypertension Due to Left Heart Disease

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Abstract

Background

Methods

Results

Conclusions

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Most cited references 16

Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study.

PDE5 inhibition with sildenafil improves left ventricular diastolic function, cardiac geometry, and clinical status in patients with stable systolic heart failure: results of a 1-year, prospective, randomized, placebo-controlled study.

Sildenafil improves exercise capacity and quality of life in patients with systolic heart failure and secondary pulmonary hypertension.

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