Impact of insulin resistance on ventricular function in pulmonary arterial hypertension

Brunner, Nathan W.; Skhiri, Mehdi; Fortenko, Olga; Hsi, Andrew; Haddad, François; Khazeni, Nayer; Zamanian, Roham T.

doi:10.1016/j.healun.2014.02.016

Cited by 24 publications

(20 citation statements)

References 22 publications

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“…Metabolic changes as reflected by decreased levels of HDL-C and increased insulin resistance have been described previously in the PAH population 4 5 6 7 . Low HDL-C in PAH patients has been associated with worse clinical outcomes and higher mortality.…”

Section: Discussionsupporting

confidence: 60%

“…Till now some prognostic factors, including clinical signs of right heart failure, impaired exercise capacity, right ventricular dysfunction and impaired pulmonary hemodynamics have been associated with poor outcome 1 2 3 . Recently, more focus has been placed on the prognostic role of alterations in the glucose and lipid metabolism 4 5 6 7 . Low high-density lipoprotein cholesterol (HDL-C) in PAH patients has been associated with worse clinical outcomes and higher mortality.…”

mentioning

confidence: 99%

“…This finding was independent of cardiovascular risk factors, insulin resistance and severity of the disease. It was hypothesized that anti-inflammatory properties of HDL-C, its ability to enhance prostacyclin half-life and its protective role in endothelium could explain its impact on prognosis in PAH 4 5 6 7 .…”

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confidence: 99%

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Low-density lipoprotein cholesterol and survival in pulmonary arterial hypertension

Kopeć

Waligóra

Tyrka

et al. 2017

Sci Rep

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Low-density lipoprotein cholesterol(LDL-C) is a well established metabolic marker of cardiovascular risk, however, its role in pulmonary arterial hypertension (PAH) has not been determined. Therefore we assessed whether LDL-C levels are altered in PAH patients, if they are associated with survival in this group and whether pulmonary hypertension (PH) reversal can influence LDL-C levels. Consecutive 46 PAH males and 94 females were age matched with a representative sample of 1168 males and 1245 females, respectively. Cox regression models were used to assess the association between LDL-C and mortality. The effect of PH reversal on LDL-C levels was assessed in 34 patients with chronic thromboembolic pulmonary hypertension (CTEPH) undergoing invasive treatment. LDL-C was lower in both PAH (2.6 ± 0.8 mmol/l) and CTEPH (2.7 ± 0.7 mmol/l) patients when compared to controls (3.2 ± 1.1 mmol/l, p < 0.001). In PAH patients lower LDL-C significantly predicted death (HR:0.44/1 mmol/l, 95%CI:0.26–0.74, p = 0.002) after a median follow-up time of 33(21–36) months. In the CTEPH group, LDL-C increased (from 2.6[2.1–3.2] to 4.0[2.8–4.9]mmol/l, p = 0.01) in patients with PH reversal but remained unchanged in other patients (2.4[2.2–2.7] vs 2.3[2.1–2.5]mmol/l, p = 0.51). We concluded that LDL-C level is low in patients with PAH and is associated with an increased risk of death. Reversal of PH increases LDL-C levels.

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Section: Discussionsupporting

confidence: 60%

mentioning

confidence: 99%

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Low-density lipoprotein cholesterol and survival in pulmonary arterial hypertension

Kopeć

Waligóra

Tyrka

et al. 2017

Sci Rep

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“…We have recently demonstrated that in HPAH and IPAH, patients with a diagnosis of DM had worse outcomes that appeared to correlate with markers of worse RV function, suggesting a negative impact of DM on RV stress response [80]. Interestingly, while the presence of IR was not associated with echocardiographic RV dysfunction in PAH in Brunner et al’s recent analysis, diastolic dysfunction of the LV was noted [81]. …”

Section: Human Studies Involving Metabolic Disease and The Pulmonary mentioning

confidence: 99%

Metabolic Dysfunction in Pulmonary Arterial Hypertension

Assad

Hemnes

2015

Curr Hypertens Rep

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Previously considered a disease isolated to the pulmonary circulation, pulmonary arterial hypertension is now being recognized as a systemic disorder that is associated with significant metabolic dysfunction. Numerous animal models have demonstrated the development of pulmonary arterial hypertension following the onset of insulin resistance, indicating that insulin resistance may be causal. Recent publications highlighting alterations in aerobic glycolysis, fatty acid oxidation, and the tricarboxylic acid cycle in the pulmonary circulation and right ventricle have expanded our understanding of the complex pathobiology of this disease. By targeting these derangements in metabolism, numerous researchers are investigating noninvasive techniques to monitor disease activity and therapeutics that address the underlying metabolic condition. In the following review, we will explore pre-clinical and clinical studies investigating the metabolic dysfunction seen in pulmonary arterial hypertension.

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“…17 With regard to the role of BMPR2 in metabolism, recent data suggest that enhanced estrogenic activity decreases BMP signaling in a susceptible host, whereas altered BMP signaling modifies estrogenic activity. 30 BMPR2 is involved in the regulation of hepcidin gene expression and iron metabolism, 31 and most recently has been shown to be associated with insulin resistance 32,33 and impaired fatty acid oxidation in experimental PH. 34 In addition, metabolic reprogramming in PAH occurs downstream of BMPR2, 35 which is supported by studies in mice with a disease-causing mutation in BMPR2 that are more susceptible to oxidant injury in mitochondrial membranes compared to wild-type animals.…”

Section: The Importance Of Bmpr2 Signaling As a Potential "Master Swimentioning

confidence: 99%

Repurposing FK506 to Increase BMPR2 Signaling and Improve Pulmonary Arterial Hypertension: A Fast Track From Cells to People

Spiekerkoetter

Zamanian

2014

Advances in Pulmonary Hypertension

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To improve long-term survival in pulmonary arterial hypertension (PAH), new treatment approaches that target occlusive vasculopathy instead of vasoconstriction of pulmonary arteries are necessary. Identifying genes or pathways that unify different pathologies and etiologies in PAH is a crucial first step for drug development. The bone morphogenetic protein receptor 2 (BMPR2) pathway, originally described as the cause of familial PAH, has gained significant interest over the past few years as a potential master switch in PAH, and therefore presents a promising treatment target in PAH. FK506 (tacrolimus) was found in a high-throughput screen of US Food and Drug Administration (FDA)-approved drugs to significantly increase BMPR2 signaling. Low-dose FK506 was able to restore normal BMPR2 signaling and function in patient pulmonary artery (PA) endothelial cells, inhibit proliferation and induce apoptosis in PA smooth muscle cells, and prevent and reverse pulmonary hypertension (PH) in 3 experimental rodent models of PH. As an FDA-approved drug, it was possible to relatively quickly (in approximately 2 years) translate the basic science discoveries from the bench to the clinic. A Phase 2 proof-of-concept safety and tolerability trial is underway (ClinicalTrials.gov Identifier: NCT01647945) to evaluate the use of low-dose FK506 in PAH and to identify patients who might respond best to FK506 depending on their impairment in BMPR2 signaling.

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Impact of insulin resistance on ventricular function in pulmonary arterial hypertension

Cited by 24 publications

References 22 publications

Low-density lipoprotein cholesterol and survival in pulmonary arterial hypertension

Low-density lipoprotein cholesterol and survival in pulmonary arterial hypertension

Metabolic Dysfunction in Pulmonary Arterial Hypertension

Repurposing FK506 to Increase BMPR2 Signaling and Improve Pulmonary Arterial Hypertension: A Fast Track From Cells to People

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