Echocardiographic Ratio Shows Pre- and Post-Capillary Pulmonary Hypertension - The Cardiology Advisor

Posted: 25 Jun 2019 01:00 AM PDT

In patients with pulmonary hypertension (PH), echocardiographic pulmonary to left atrial global strain ratio accurately discriminated between pre-capillary and post-capillary PH, according to a study published in the International Journal of Cardiology.

Researchers evaluated the ability of echocardiographic pulmonary to left atrial global strain ratio to differentiate pre-capillary and post-capillary PH to see whether echocardiographic pulmonary to left atrial ratio or echocardiographic pulmonary to left atrial global strain ratio had a superior diagnostic capacity. Patients with unexplained dyspnea or heart failure who were referred for right heart catheterization were included in this study.

Transthoracic echocardiography measured left ventricular ejection fraction, wave Doppler measured max tricuspid regurgitation peak velocity, and speckle tracking echocardiography measured left atrial global strain. These measurements were used to calculate echocardiographic pulmonary to left atrial global strain ratio. Right heart catheterization was used to measure mean right atrial pressure and pulmonary artery pressure.

Of the 130 patients included in this study, 64 demonstrated pre-capillary PH, 66 demonstrated post-capillary PH, with 39 classified as isolated post-capillary PH, and 27 demonstrated combined post- and pre-capillary PH.

When analyzing the baseline characteristics, echocardiographic pulmonary to left atrial global strain ratio was lower in pre-capillary PH than post-capillary PH (0.19 vs 0.45; P =.02), and echocardiographic pulmonary to left atrial ratio was higher in pre-capillary PH compared with post-capillary PH (0.37 vs 0.20; P <.001). Echocardiographic pulmonary to left atrial global strain ratio differentiated between isolated post-capillary PH and combined post- and pre-capillary PH (0.62 vs 0.32; P =.04) and was associated with pulmonary vascular resistance (r =0.28; P =.02) and transpulmonary gradient (r =0.30; P =.01).

The diagnostic capability to distinguish pre-capillary and post-capillary PH favored echocardiographic pulmonary to left atrial global strain ratio (area under the curve [AUC] 0.80; 95% CI, 0.72-0.89; P <.001) over echocardiographic pulmonary to left atrial ratio (AUC 0.70; 95% CI, 0.61-0.80; P <.001).

Limitations of this study included a lack of standard image acquisition, the absence of a control cohort, potential errors in the variable used to calculate echocardiographic pulmonary to left atrial global strain ratio, and the inclusion of symptomatic patients in the post-capillary PH cohort.

The researchers concluded that "[t]he novel [echocardiographic pulmonary to left atrial global strain] ratio distinguishes pre-capillary from post-capillary PH and demonstrates a stronger differentiating capability as compared to [echocardiographic pulmonary to left atrial ratio]."

Reference

Venkateshvaran A, Manouras A, Kjellström B, Lund LH. The addi t ive value of echocardiographic pulmonary to left atrial global strain ratio in the diagnosis of pulmonary hypertension [published online May 31, 2019]. Int J Cardiol. doi:10.1016/j.ijcard.2019.05.025

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Pulmonary Hypertension Pulmonary Vasculature

Mouse Study Finds Causal Link Between Iron Levels and Pulmonary Hypertension - Pulmonary Hypertension News

Posted: 14 Jun 2019 05:30 AM PDT

A new study in mice demonstrated that a lack of iron in muscle cells lining the circulatory system in the lungs — termed pulmonary arterial smooth muscle cells (PASMCs) — sets off a chain of events that result in pulmonary hypertension (PH).

These results suggest a cause-and-effect link between iron deficiency and PH.

The study, titled "Intracellular iron deficiency in pulmonary arterial smooth muscle cells induces pulmonary arterial hypertension in mice," was published in the journal Proceedings of the National Academy of Sciences.

Iron deficiency has a well-established link to PH, and iron supplementation has proven to be beneficial for some patients with the disease. Yet, the reasons for this connection have remained elusive.

Regulation of iron in the body is governed in large part by two proteins: ferroportin and hepcidin.

Ferroportin is a transport protein that can move iron from within a cell to the outside of a cell (i.e., into the bloodstream), allowing iron to be moved from organs like the gut and liver, where it is absorbed and stored, respectively, into the blood.

Hepcidin regulates this process by essentially turning ferroportin "off," causing iron to remain within cells. Controlling the levels of this protein allows for the indirect control of iron released from cells.

PASMCs express both of these proteins, prompting the researchers to wonder if this might be the link between PH and iron regulation.

To find out, researchers developed mice that expressed a mutant version of ferroportin in their PASMCs (and only their PASMCs, so as to avoid off-target effects from systemic iron dysregulation). This mutant version is unresponsive to hepcidin; essentially, it is stuck in a perpetual "on" state of moving iron out of the cells. Indeed, researchers confirmed that PASMCs in these mice had lower levels of iron within the cell than did normal mice.

Importantly, these mice developed PH and right-sided heart failure, suggesting that decreasing the amount of iron in these cells contributes to PH development.

Further supporting this association, mice with the mutation that were given injections of iron — which was able to restore iron in PASMCs to near-normal levels — had fewer signs of PH and heart failure. This "rescue effect" was more pronounced when iron was given earlier, suggesting that, while iron supplementation can help prevent the development of PH in these mice, it cannot reverse the damage already done.

Having identified this relationship, the researchers next wondered how iron levels in PASMCs might actually cause PH. They found that another protein, ET-1, was present at higher levels in iron-deficient PASMCs, leading them to hypothesize that this protein might be the culprit.

To test this, the team treated the aforementioned mice with mutant ferroportin with an inhibitor of ET-1. This produced a similar prevention-but-not-reversal result, as with iron injections, supporting ET-1 as a mechanism by which iron deficiency can cause PH.

Finally, the researchers asked whether this dysregulation in iron levels also could cause some familial cases of PH. Specifically, they were interested in BMPR2, a protein that is involved in regulating the production of hepcidin levels. Some mutations in the BMPR2 gene are known to be associated with familial PH.

Testing one such mutation (R899X) in mouse and human cells, researchers found that cells with this mutation made less hepcidin and, consequently, produced more ferroportin and ET-1. This supports a link between mutations in BMPR2 and the development of PH via iron-based pathways.

Overall, "this study presents evidence that intracellular iron deficiency specifically within PASMCs alters pulmonary vascular function," the researchers wrote.

"We also provide evidence that BMPR2 mutations are associated with reduced hepcidin expression in PASMCs, and consequently increased FPN [ferroportin] and ET-1 levels. These effects could constitute an additional mechanistic link between BMPR2 mutations" and familial PH, the team added.

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