Anthony R. Cucci

Estradiol Improves Right Ventricular Function In Rats With Severe Angioproliferative Pulmonary Hypertension: Effects Of Endogenous And Exogenous Sex Hormones

Estrogens are disease modifiers in PAH. Even though female patients exhibit better right ventricular (RV) function than men, estrogen effects on RV function (a major determinant of survival in PAH) are incompletely characterized. We sought to determine whether sex differences exist in RV function in the SuHx model of PAH, whether hormone depletion in females worsens RV function, and whether E2 repletion improves RV adaptation. Furthermore, we studied the contribution of ERs in mediating E2s RV effects. SuHx-induced pulmonary hypertension (SuHx-PH) was induced in male and female Sprague-Dawley rats as well as OVX females with or without concomitant E2 repletion (75 μg·kg(-1)·day(-1)). Female SuHx rats exhibited superior CI than SuHx males. OVX worsened SuHx-induced decreases in CI and SuHx-induced increases in RVH and inflammation (MCP-1 and IL-6). E2 repletion in OVX rats attenuated SuHx-induced increases in RV systolic pressure (RVSP), RVH, and pulmonary artery remodeling and improved CI and exercise capacity (V̇o2max). Furthermore, E2 repletion ameliorated SuHx-induced alterations in RV glutathione activation, proapoptotic signaling, cytoplasmic glycolysis, and proinflammatory cytokine expression. Expression of ERα in RV was decreased in SuHx-OVX but was restored upon E2 repletion. RV ERα expression was inversely correlated with RVSP and RVH and positively correlated with CO and apelin RNA levels. RV-protective E2 effects observed in females were recapitulated in male SuHx rats treated with E2 or with pharmacological ERα or ERβ agonists. Our data suggest significant RV-protective ER-mediated effects of E2 in a model of severe PH.

Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure.

The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0-4 or 0-10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults.

Acute Right Ventricular Failure

Acute right ventricular (RV) failure is a devastating syndrome caused by a variety of common diseases and conditions. Acute RV failure is caused by acute alterations in preload, afterload, and/or contractility. Ventricular interdependence and decreases in perfusion pressure make the RV particularly prone to acute failure. Histologic and biochemical correlates of RV failure are inflammation, oxidative stress, mitochondrial dysfunction, and cardiomyocyte death. The most common causes are pulmonary hypertension, pulmonary embolism, left heart failure, acute right-sided myocardial infarction, and sepsis as well as acute respiratory distress syndrome. Invasive hemodynamic assessment and echocardiography remain the most valuable methods to diagnose and manage acute RVF in critically ill patients. In more stable patients, cardiac MRI can be used as an alternative or complementary imaging method. These strategies are complemented by biomarker assessment, radiographic studies, and incorporation of clinical parameters into validated risk scores. The key principle in the management of acute RV failure focuses on treatment of the underlying etiology, complemented by supportive strategies focused on improving RV function via optimization of volume status and oxygenation, enhancing contractility, and reducing afterload. The latter two are achieved through use of vasopressors (e.g., norepinephrine), inotropes (e.g., dobutamine, milrinone), pulmonary vasodilators (e.g., inhaled nitric oxide, parenteral prostacyclins, phosphodiesterase type 5 inhibitors), and interventional or surgical therapies (e.g., extracorporeal membrane oxygenation). This chapter will provide a definition of acute RV failure and review its pathophysiology, etiologies, diagnosis and risk stratification as well as treatment.

Right heart failure

Right ventricular failure (RVF) is a frequent and formidable clinical challenge in the intensive care unit, the operating room, the general ward, and the outpatient setting. The presence of RVF (1) carries substantial morbidity and mortality and (2) complicates the use of commonly employed treatment strategies in both inpatients and outpatients. In contrast to the left ventricle (LV), the right ventricle (RV) remains relatively understudied, and none of the major professional societies have published any guidelines on how to approach patients with RVF. Due to embryological, anatomical, physiological, biochemical, and electrophysiological differences between the RV and LV, paradigms that are important for the treatment of the failing LV cannot be extrapolated to RVF. However, with pulmonary hypertension (PH) having become a major area of scientific and clinical interest, recent studies have shed more light on the physiology of the normal RV and the pathophysiology of its failure. Using a comprehensive and evidence-based approach, this chapter will (1) highlight the pathophysiology of the failing RV; (2) discuss the etiologies of acute, chronic, and acute-on-chronic RVF; (3) describe invasive and noninvasive approaches that assist in diagnosis and risk stratification; and (4) emphasize treatment strategies for stable (chronic) and decompensated (acute) RVF.

A patient with severe hypoxia secondary to a large iatrogenic pulmonary artery to pulmonary vein fistula

Pulmonary arteriovenous malformations are uncommon communications between the pulmonary arteries and veins, most commonly associated with hereditary haemorrhagic telangiectasia. They can also be associated with a variety of other conditions, and can be single or multiple. We present a case of a female patient with a history of coronary artery bypass grafting and mitral valve repair, who presented to the hospital with severe hypoxia. She was found to have a large pulmonary artery to superior pulmonary vein fistula that was successfully repaired using a septal occluder. To our knowledge, this is the first case of a large pulmonary artery to superior pulmonary vein fistula following mitral valve repair.