Right and Left Ventricular Myocardial Perfusion Reserves Correlate with Right Ventricular Function and Pulmonary Hemodynamics in Patients with Pulmonary Arterial Hypertension

Vogel‐Claussen, Jens; Skrok, Jan; Shehata, Monda L.; Singh, Sukhminder; Sibley, Christopher T.; Boyce, Danielle; Lechtzin, Noah; Girgis, Reda E.; Mathai, Steven C.; Goldstein, Thomas; Zheng, Jie; Lima, João A.C.; Bluemke, David A.; Hassoun, Paul M.

doi:10.1148/radiol.10100725

Cited by 108 publications

(94 citation statements)

References 36 publications

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“…Disruption of the myocardial-microvascular balance would predictably impact on RV function, clinical severity of disease, and outcomes. Clinical support of such a principle in PAH comes from adenosine magnetic resonance imaging data, which demonstrate decreased RV myocardial perfusion reserve index in PAH (10). The RV myocardial perfusion reserve index is inversely associated with RV systolic function and RV remodeling (i.e., RV mass).…”

Section: Discussionmentioning

confidence: 99%

“…In preclinical models of disease, the transition from RV adaptation to RVF is linked to diminished angiogenesis within the hypertrophic RV (8) and decreased myocardial capillary density in the failed RV (9). In humans, studies using adenosine coupled with cardiac magnetic resonance imaging (cMRI) indicate that RV myocardial perfusion reserve is reduced in patients with PAH and is linked to poor RV function (10). Thus, we predict that disruption, or direct antagonism, of the microcirculatory balance within the RV would predispose to RV dysfunction, negatively impacting on outcomes in PAH.…”

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confidence: 99%

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Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Damico

Kolb

Valera

et al. 2015

Am J Respir Crit Care Med

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102

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Rationale: Pulmonary arterial hypertension (PAH) is a medically incurable disease resulting in death from right ventricular (RV) failure. Both pulmonary vascular and RV remodeling are linked to dynamic changes in the microvasculature. Therefore, we hypothesized that circulating angiostatic factors could be linked to outcomes and represent novel biomarkers of disease severity in PAH.Objectives: We sought to determine the relationship of a potent angiostatic factor, endostatin (ES), with disease severity and mortality in PAH. Furthermore, we assessed genetic predictors of ES expression and/or function and their association with outcomes in PAH.Methods: We measured levels of serum ES in two independent cohorts of patients with PAH. Contemporaneous clinical data included New York Heart Association functional class, 6-minutewalk distance, invasive hemodynamics, and laboratory chemistries.Measurements and Main Results: Serum ES correlated with poor functional status, decreased exercise tolerance, and invasive hemodynamics variables. Furthermore, serum ES was a strong predictor of mortality. A loss-of-function, missense variant in the gene encoding ES, Col18a1, was linked to lower circulating protein and was independently associated with reduced mortality.Conclusions: Our data link increased expression of ES to disease severity in PAH and demonstrate a significant relationship with adverse outcomes. Circulating ES levels can be genetically influenced, implicating ES as a genetically determined modifier of disease severity impacting on survival. These observations support serum ES as a potential biomarker in PAH with the capacity to predict poor outcomes. More importantly, this study implicates Col18a1/ES as a potential new therapeutic target in PAH.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Damico

Kolb

Valera

et al. 2015

Am J Respir Crit Care Med

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102

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“…Coronary flow reserve has shown to be decreased in PAH patients and correlated to the degree of RV dysfunction. 42,43 Decreased cardiomyocyte/fibrosis ratio, reduced capillary density in the myocardium and increased diastolic stiffness are known characteristics of our PTB model. 21 Given that the prostacyclin mimetics are dependent on increase in coronary flow to improve RV function, reduced coronary flow reserve, micro-vascular dysfunction, reduced capillary density…”

Section: A C C E P T E Dmentioning

confidence: 99%

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure

Holmboe

Andersen

Johnsen

et al. 2017

Journal of Cardiovascular Pharmacology

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Background:Prostacyclin mimetics are vasodilatory agents used in the treatment of pulmonary arterial hypertension. The direct effects of prostanoids on right ventricular (RV) function are unknown.We aimed to investigate the direct effects of prostacyclin mimetics on RV function in hearts with and without RV hypertrophy and failure. Methods:Wistar rats were subjected to pulmonary trunk banding to induce compensated RV hypertrophy (n=32) or manifest RV failure (n=32). Rats without banding served as healthy controls (n=30).The hearts were excised and perfused in a Langendorff system and subjected to iloprost, treprostinil, epoprostenol or MRE-269 in increasing concentrations. The effect on RV function was evaluated using a balloon-tipped catheter inserted into the RV. Results:In control hearts iloprost, treprostinil and MRE-269, improved RV function. The effect was, however, absent in hearts with RV hypertrophy and failure. Treprostinil and MRE-269 even impaired RV function in hearts with manifest RV failure.Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. A C C E P T E D 3 Conclusion:Iloprost, treprostinil and MRE-269 improved RV function in the healthy rat heart. RV hypertrophy abolished the positive inotropic effect and in the failing right ventricle, MRE-269 and treprostinil impaired RV function. This may be related to changes in prostanoid receptor expression and reduced coronary flow reserve in the hypertrophic and failing right ventricle.

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“…Whether decreased myocardial perfusion reserve is characteristic of SSc-PAH or, rather, associated with PAH in general needs further evaluation. 96 …”

Section: Role Of Sponsorsmentioning

confidence: 99%

Systemic Sclerosis-associated Pulmonary Arterial Hypertension

Pavec

Humbert

Mouthon

et al. 2010

Am J Respir Crit Care Med

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Systemic sclerosis (SSc) is a complex, multisystem disease characterized by fi brosis and excessive collagen deposition within the skin and internal organs, chronic infl ammation, autoimmune dysregulation, and microvascular endothelial dysfunction. There are two forms of SSc that are characterized by the extent of skin involvement. Limited cutaneous SSc predominantly involves the skin of the hands, arms, and face, and diffuse SSc involves large areas of skin and multiple organs. 1 Both forms are systemic diseases associated with signifi cant morbidity and mortality. Historically, mortality was largely caused by renal disease. With the advent of angiotensin-converting enzyme inhibitors to treat SSc renal crisis, SSc-associated pulmonary arterial hypertension (SSc-PAH) has emerged as a leading cause of morbidity and mortality, accounting for up to 30% of premature deaths. 2 Although SSc-PAH represents a signifi cant proportion of the pulmonary arterial hypertension (PAH) population (15%-30%), 3,4 much of what we know about PAH is derived from studies of idiopathic PAH (IPAH).Pulmonary arterial hypertension (PAH) is the leading cause of death in systemic sclerosis (SSc ) and affects up to 12% of all patients with SSc, with a 50% mortality rate within 3 years of PAH diagnosis. Compared with the idiopathic form of PAH (IPAH), patients with SSc-associated PAH (SSc-PAH) have a threefold increased risk of death and may receive a diagnosis late in the course of disease because of insidious onset and the high prevalence of cardiac, musculoskeletal, and pulmonary parenchymal comorbidities. Treatment with conventional forms of PAH therapy often yield poor results compared with IPAH cohorts; unfortunately, the exact reasons behind this remain poorly understood but likely include variations in the pathologic mechanisms, differences in cardiovascular response to increasing afterload, and inadequate strategies to detect and treat SSc-PAH early in its course. Current methods for screening and longitudinal evaluation of SSc-PAH, such as the 6-min walk test, transthoracic echocardiography, and MRI, each have notable advantages and disadvantages. We provide an up-to-date, focused review of SSc-PAH and how it differs from IPAH, including pathogenesis, appropriate screening for disease onset, and new approaches to treatment and longitudinal assessment of this disease. CHEST 2013; 144(4):1346-1356Abbreviations: 6MWD 5 6-min walk distance; CCB 5 calcium channel blocker; CTD 5 connective tissue disease; D lco 5 diffusing capacity of lung for carbon monoxide; EIPAH 5 exercise-induced pulmonary arterial hypertension; ERA 5 endothelin receptor antagonist; FC 5 functional class; ILD 5 interstitial lung disease; IPAH 5 idiopathic pulmonary arterial hypertension; LV 5 left ventricular; mPAP 5 mean pulmonary artery pressure; PAH 5 pulmonary arterial hypertension; PASP 5 pulmonary artery systolic pressure; PDE-5I 5 phosphodiesterase type 5 inhibitor; PFT 5 pulmonary function test; PH 5 pulmonary hypertension; pro-BNP 5 pro-brain natriuretic pe...

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Right and Left Ventricular Myocardial Perfusion Reserves Correlate with Right Ventricular Function and Pulmonary Hemodynamics in Patients with Pulmonary Arterial Hypertension

Cited by 108 publications

References 36 publications

Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Serum Endostatin Is a Genetically Determined Predictor of Survival in Pulmonary Arterial Hypertension

Inotropic Effects of Prostacyclins on the Right Ventricle Are Abolished in Isolated Rat Hearts With Right-Ventricular Hypertrophy and Failure

Systemic Sclerosis-associated Pulmonary Arterial Hypertension

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