Pulmonary Hypertension Induced by Right Pulmonary Artery Occlusion: Hemodynamic Consequences of Bmpr2 Mutation.

BACKGROUND: The primary genetic risk factor for heritable pulmonary arterial hypertension is the presence of monoallelic mutations in the BMPR2 gene. The incomplete penetrance of BMPR2 mutations implies that additional triggers are necessary for pulmonary arterial hypertension occurrence. Pulmonary artery stenosis directly raises pulmonary artery pressure, and the redirection of blood flow to unobstructed arteries leads to endothelial dysfunction and vascular remodeling. We hypothesized that right pulmonary artery occlusion (RPAO) triggers pulmonary hypertension (PH) in rats with Bmpr2 mutations. METHODS AND RESULTS: Male and female rats with a 71 bp monoallelic deletion in exon 1 of Bmpr2 and their wild-type siblings underwent acute and chronic RPAO. They were subjected to full high-fidelity hemodynamic characterization. We also examined how chronic RPAO can mimic the pulmonary gene expression pattern associated with installed PH in unobstructed territories. RPAO induced precapillary PH in male and female rats, both acutely and chronically. Bmpr2 mutant and male rats manifested more severe PH compared with their counterparts. Although wild-type rats adapted to RPAO, Bmpr2 mutant rats experienced heightened mortality. RPAO induced a decline in cardiac contractility index, particularly pronounced in male Bmpr2 rats. Chronic RPAO resulted in elevated pulmonary IL-6 (interleukin-6) expression and decreased Gdf2 expression (corrected P value<0.05 and log2 fold change>1). In this context, male rats expressed higher pulmonary levels of endothelin-1 and IL-6 than females. CONCLUSIONS: Our novel 2-hit rat model presents a promising avenue to explore the adaptation of the right ventricle and pulmonary vasculature to PH, shedding light on pertinent sex- and gene-related effects.

Pulsatile pulmonary artery pressure in a large animal model of chronic thromboembolic pulmonary hypertension: Similarities and differences with human data.

A striking feature of the human pulmonary circulation is that mean (mPAP) and systolic (sPAP) pulmonary artery pressures (PAPs) are strongly related and, thus, are essentially redundant. According to the empirical formula documented under normotensive and hypertensive conditions (mPAP = 0.61 sPAP + 2 mmHg), sPAP matches ~160%mPAP on average. This attests to the high pulsatility of PAP, as also witnessed by the near equality of PA pulse pressure and mPAP. Our prospective study tested if pressure redundancy and high pulsatility also apply in a piglet model of chronic thromboembolic pulmonary hypertension (CTEPH). At baseline (Week-0, W0), Sham (n = 8) and CTEPH (n = 27) had similar mPAP and stroke volume. At W6, mPAP increased in CTEPH only, with a two- to three-fold increase in PA stiffness and total pulmonary resistance. Seven CTEPH piglets were also studied at W16 at baseline, after volume loading, and after acute pulmonary embolism associated with dobutamine infusion. There was a strong linear relationship between sPAP and mPAP (1) at W0 and W6 (n = 70 data points, r² = 0.95); (2) in the subgroup studied at W16 (n = 21, r² = 0.97); and (3) when all data were pooled (n = 91, r² = 0.97, sPAP range 9-112 mmHg). The PA pulsatility was lower than that expected based on observations in humans: sPAP matched ~120%mPAP only and PA pulse pressure was markedly lower than mPAP. In conclusion, the redundancy between mPAP and sPAP seems a characteristic of the pulmonary circulation independent of the species. However, it is suggested that the sPAP thresholds used to define PH in animals are species- and/or model-dependent and thus must be validated.

Induction and Phenotyping of Acute Right Heart Failure in a Large Animal Model of Chronic Thromboembolic Pulmonary Hypertension.

The development of acute right heart failure (ARHF) in the context of chronic pulmonary hypertension (PH) is associated with poor short-term outcomes. The morphological and functional phenotyping of the right ventricle is of particular importance in the context of hemodynamic compromise in patients with ARHF. Here, we describe a method to induce ARHF in a previously described large animal model of chronic PH, and to phenotype, dynamically, right ventricular function using the gold standard method (i.e., pressure-volume PV loops) and with a non-invasive clinically available method (i.e., echocardiography). Chronic PH is first induced in pigs by left pulmonary artery ligation and right lower lobe embolism with biological glue once a week for 5 weeks. After 16 weeks, ARHF is induced by successive volume loading using saline followed by iterative pulmonary embolism until the ratio of the systolic pulmonary pressure over systemic pressure reaches 0.9 or until the systolic systemic pressure decreases below 90 mmHg. Hemodynamics are restored with dobutamine infusion (from 2.5 µg/kg/min to 7.5 µg/kg/min). PV-loops and echocardiography are performed during each condition. Each condition requires around 40 minutes for induction, hemodynamic stabilization and data acquisition. Out of 9 animals, 2 died immediately after pulmonary embolism and 7 completed the protocol, which illustrates the learning curve of the model. The model induced a 3-fold increase in mean pulmonary artery pressure. The PV-loop analysis showed that ventriculo-arterial coupling was preserved after volume loading, decreased after acute pulmonary embolism and was restored with dobutamine. Echocardiographic acquisitions allowed to quantify right ventricular parameters of morphology and function with good quality. We identified right ventricular ischemic lesions in the model. The model can be used to compare different treatments or to validate non-invasive parameters of right ventricular morphology and function in the context of ARHF.

Extrapleural cervico-manubriotomy and clavicular swing for the management of a mesenchymal tumour of the middle scalenus: an adapted anterior thoracic inlet approach.

Surgical approach for resection of tumours involving the thoracic inlet has largely been developed in the context of lung cancer of the superior sulcus. Therefore, initial anterior approaches included a thoracotomy associated with a longitudinal cervicotomy. Here, we describe a variation of the previously described anterior surgical approaches of the thoracic inlet that we performed for the resection of a primary mesenchymal tumour of the left middle scalenus muscle secreting fibroblast growth factor-23 responsible for tumour-induced osteomalacia. This approach allowed a safe control of the great vessels phrenic nerve and brachial plexus as well as a comfortable access to the middle scalenus muscle through an L-shaped incision with a cervico-manubriotomy without thoracotomy. The tumour was resected entirely with the middle scalenus. After 3 months of follow-up, the symptoms resolved entirely.

Study of abdominal wall muscle innervation applied to large-defect closure in congenital diaphragmatic hernia.

In large congenital diaphragmatic hernias (CDHs), direct suture of the diaphragm is impossible. Surgeons can use a triangular internal oblique muscle (IOM) plus transverse abdominis muscle (TAM) flap. Its caudal limit faces the medial extremity of the 11th rib. Clinical studies show that the flap is not hypotonic but that the procedure could expose patients already presenting a hypoplastic lung to external oblique muscle (EOM) hypotonia. The aims of this study were to study EOM innervation by the 10th intercostal nerve (ICN) and ICN innervation to the IOM and TAM. Forty cadaveric abdominal hemi-walls were dissected. The number of branches and the trajectory of each specimen's 10th ICN were studied medially to the medial extremity of the 11th rib (MEK11) using surgical goggles and a microscope (Carl Zeiss®). The 10th ICN was consistently found between the IOM and TAM. There was a median of nine branches from the 10th ICN to the EOM, 77% of them medial to the MEK11. Median values of nine and 12 branches for the IOM and TAM were found, 60% and 51%, respectively, medial to the MEK11. These results argue in favor of good innervation to the IOM plus TAM flap but also indicate postoperative abdominal weakness exposing patients to herniation risks, as more than 75% of the branches from the 10th ICN to the EOM were sectioned or pulled away during flap detachment. Clin. Anat., 33:759-766, 2020. © 2019 Wiley Periodicals, Inc.