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Abstract Rationale In the CLAIM study, dual bronchodilation with indacaterol/glycopyrronium (IND/GLY) significantly reduced hyperinflation, which translated into improved cardiac function, measured by left ventricular end-diastolic volume and cardiac output. Pulmonary microvascular blood flow (PMBF) is reduced in chronic obstructive pulmonary disease (COPD); however, the effect of reduced lung hyperinflation on PMBF remains unknown. Objectives To determine the effect of lung deflation with IND/GLY on PMBF and regional pulmonary ventilation using magnetic resonance imaging (MRI) in hyperinflated patients with COPD. Methods In this double-blind, randomized, two-period crossover study, gadolinium-enhanced MRI and phase-resolved functional lung MRI were used to measure PMBF and regional ventilation, respectively, in patients with COPD receiving IND/GLY versus placebo. Measurements and Main Results Sixty-two patients were randomized to receive once-daily IND/GLY (110/50 μg) for 14 days, followed by 14 days of placebo, or vice versa. Treatment periods were separated by a 14-day washout. Sixty patients were included in the per-protocol analysis. MRI measurements showed significant improvements in total PMBF (P = 0.006) and regional PMBF (P values for individual lobes were between 0.004 and 0.022) in response to IND/GLY versus placebo. Regional ventilation was also significantly improved with IND/GLY, as evidenced by a 12.4% increase versus placebo (P = 0.011), a 14.3% relative decrease in ventilation defect percentage of nonventilated/hypoventilated lung tissue (cutoff was defined as 0.075 regional ventilation; P = 0.0002), and a 15.7% reduction in the coefficient of variation of regional ventilation compared with placebo (P < 0.0001). Conclusions Pharmacologic intervention with IND/GLY improves pulmonary microvascular blood flow and regional ventilation in patients with COPD with hyperinflation. Clinical trial registered with www.clinicaltrials.gov (NCT02442206).

Abstract Rationale Exercise tolerance is decreased in patients with pulmonary hypertension (PH). It is unknown whether exercise intolerance in PH coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility. Objectives To investigate in patients with PH the RV exertional contractile reserve, defined as the rest-to-exercise response in end-systolic elastance (ΔEes), and the effects of exercise on the matching of Ees and RV afterload (Ea) (i.e., RV–arterial coupling; Ees/Ea). In addition, we compared ΔEes with a recently proposed surrogate, the rest-to-exercise change in pulmonary artery pressure (ΔPAP). Methods We prospectively included 17 patients with precapillary PH and 7 control subjects without PH who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and July 2014. Ees and Ees/Ea were assessed using single-beat pressure–volume loop analysis. Measurements and Main Results Exercise data in 16 patients with PH and 5 control subjects were of sufficient quality for analysis. Ees significantly increased from rest to exercise in control subjects but not in patients with PH. Ea significantly increased in both groups. As a result, exercise led to a decrease in Ees/Ea in patients with PH, whereas Ees/Ea was unaffected in control subjects (Pinteraction = 0.009). In patients with PH, ΔPAP was not related to ΔEes but significantly correlated to the rest-to-exercise change in heart rate. Conclusions In contrast to control subjects, patients with PH were unable to increase Ees during submaximal exercise. Failure to compensate for the further increase in Ea during exercise led to deterioration in Ees/Ea. Furthermore, ΔPAP did not reflect ΔEes but rather the change in heart rate.

Abstract Rationale Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension (PAH), monotherapy with these agents has not been conclusively shown to reduce clinical worsening events. Objectives To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH. Methods In a randomized, double-blind, placebo-controlled study, 66 patients with PAH were randomized 2:1 to vardenafil (5 mg once daily for 4 wk then 5 mg twice daily; n = 44) or placebo (n = 22) for 12 weeks. Patients completing this phase were then treated with open-label vardenafil (5 mg twice daily) for a further 12 weeks. Measurements and Main Results At Week 12, the mean placebo-corrected 6-minute walking distance was increased with vardenafil (69 m; P < 0.001), and this improvement was maintained for at least 24 weeks. Vardenafil also increased the mean placebo-corrected cardiac index (0.39 L·min−1·m−2; P = 0.005) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance (−5.3 mm Hg, P = 0.047; −4.7 Wood U, P = 0.003; respectively) at Week 12. Four patients in the placebo group (20%) and one in the vardenafil group (2.3%) had clinical worsening events (hazard ratio 0.105; 95% confidence interval, 0.012–0.938; P = 0.044). Vardenafil was associated with only mild and transient adverse events. Conclusions Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily.

The large-conductance Ca 2+ -activated K + (BK) channel is widely expressed in the pulmonary blood vessels and plays a significant role in regulating pulmonary vascular tonus. It opens under membrane depolarization, increased intracellular Ca +2 concentration, and chronic hypoxia, resulting in massive K + efflux, membrane hyperpolarization, decreased L-type Ca +2 channel opening, and smooth muscle relaxation. Several reports have demonstrated an association between BK channel dysfunction and pulmonary hypertension (PH) development. Decreased BK channel subunit expression and impaired regulation by paracrine hormones result in decreased BK channel opening, increased pulmonary vascular resistance, and pulmonary arterial pressure being the cornerstone of PH. The resulting right ventricular pressure overload ultimately leads to ventricular remodeling and failure. Therefore, it is unsurprising that the BK channel has arisen as a potential target for treating PH. Recently, a series of selective, synthetic BK channel agonists have proven effective in attenuating the pathophysiological progression of PH without adverse effects in animal models.

Pulmonary fibrosis induced by repetitive chemical injury in mice involves cross talk among macrophages, endothelial cells and fibroblasts. Macrophages induce expression of the Notch ligand Jag1 in pulmonary capillary endothelial cells, leading to Notch pathway activation in perivascular fibroblasts and fibrosis. Although the lung can undergo self-repair after injury, fibrosis in chronically injured or diseased lungs can occur at the expense of regeneration. Here we study how a hematopoietic-vascular niche regulates alveolar repair and lung fibrosis. Using intratracheal injection of bleomycin or hydrochloric acid in mice, we show that repetitive lung injury activates pulmonary capillary endothelial cells (PCECs) and perivascular macrophages, impeding alveolar repair and promoting fibrosis. Whereas the chemokine receptor CXCR7, expressed on PCECs, acts to prevent epithelial damage and ameliorate fibrosis after a single round of treatment with bleomycin or hydrochloric acid, repeated injury leads to suppression of CXCR7 expression and recruitment of vascular endothelial growth factor receptor 1 (VEGFR1)-expressing perivascular macrophages. This recruitment stimulates Wnt/β-catenin–dependent persistent upregulation of the Notch ligand Jagged1 (encoded by Jag1 ) in PCECs, which in turn stimulates exuberant Notch signaling in perivascular fibroblasts and enhances fibrosis. Administration of a CXCR7 agonist or PCEC-targeted Jag1 shRNA after lung injury promotes alveolar repair and reduces fibrosis. Thus, targeting of a maladapted hematopoietic-vascular niche, in which macrophages, PCECs and perivascular fibroblasts interact, may help to develop therapy to spur lung regeneration and alleviate fibrosis.

In recent years, the study of right ventricular (RV) to pulmonary circulation (PC) coupling in heart failure with preserved ejection fraction (HFpEF) has been a matter of special interest. Tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP) ratio has emerged as a reliable noninvasive index of RV to PC coupling. Thus, we hypothesized that TAPSE/PASP would be a predictor of readmission burden in HFpEF. One thousand one hundred and twenty seven consecutive HFpEF patients discharged for acute HF were included. In 367 patients (32.6%), PASP could not be accurately measured by echocardiography, leaving the final sample size to be 760 patients. Negative binomial regression method was used to evaluate the association between TAPSE/PASP ratio and recurrent admissions. Mean age of the cohort was 75.6 ± 9.7 years and 68.3% were women. At a median (interquartile range) follow-up of 2.0 (2.9) years, 352 (46.3%) patients died and 1,214 readmissions were registered in 482 patients (63.4%), being 506 of them HF-related. There was a stepwise increase in the rates of all-cause and HF readmissions by decreasing TAPSE/PASP ratio. After multivariable adjustment, TAPSE/PASP <0.36 was associated with a higher risk of HF-related recurrent admissions (incidence rate ratio [IRR] 1.51, 95% confidence interval [CI], 1.01 to 2.24; p = 0.040), whereas patients in the lowest quintile (TAPSE/PASP <0.28) exhibited the highest risk of both all-cause and HF-related recurrent admissions (IRR 1.40, 95% CI 1.04 to 1.87, p = 0.025; and IRR 1.85, 95% CI 1.22 to 2.80, p = 0.004, respectively). In conclusion, TAPSE/PASP ratio, as a noninvasive index of RV-PC coupling, emerges as a strong predictor of recurrent hospitalizations in HFpEF.

Objectives To evaluate whether careful exercise training improves pulmonary perfusion and blood flow in patients with pulmonary hypertension (PH), as assessed by magnetic resonance imaging (MR). Methods Twenty patients with pulmonary arterial hypertension or inoperable chronic thromboembolic PH on stable medication were randomly assigned to control ( n  = 10) or training groups ( n  = 10). Training group patients received in-hospital exercise training; patients of the sedentary control group received conventional rehabilitation. Medication remained unchanged during the study period. Changes of 6-min walking distance (6MWD), MR pulmonary flow (peak velocity) and MR perfusion (pulmonary blood volume) were assessed from baseline to week 3. Results After 3 weeks of training, increases in mean 6MWD ( P  = 0.004) and mean MR flow peak velocity ( P  = 0.012) were significantly greater in the training group. Training group patients had significantly improved 6MWD ( P  = 0.008), MR flow (peak velocity −9.7 ± 8.6 cm/s, P  = 0.007) and MR perfusion (pulmonary blood volume +2.2 ± 2.7 mL/100 mL, P  = 0.017), whereas the control group showed no significant changes. Conclusion The study indicates that respiratory and physical exercise may improve pulmonary perfusion in patients with PH. Measurement of MR parameters of pulmonary perfusion might be an interesting new method to assess therapy effects in PH. The results of this initial study should be confirmed in a larger study group. Key Points • Quantification of magnetic resonance perfusion is feasible in patients with pulmonary hypertension. • Quantified magnetic resonance perfusion may become useful for non-invasive monitoring of treatment. • Quantification of lung perfusion allows new insights into lung (patho-)physiology of PH. • Careful exercise training improves pulmonary perfusion and blood flow in patients with PH.

Background Management of pulmonary atresia with ventricular septal defect and ductal-dependent pulmonary circulation (PA/VSD/PDA) varies according to pulmonary artery morphology and institutional surgical strategy. We adopted a range of initial palliative surgical options for patients with PA/VSD/PDA and evaluated the effectiveness of our management strategy. Methods Twenty-five patients with PA/VSD/PDA were enrolled between May 2015 and July 2023. Patients with major aortopulmonary collateral arteries were excluded. The mean age at initial surgery was 14.9 ± 13.7 days, and the mean weight was 3.17 ± 0.35 kg. Twenty-two (88%) patients were neonates. Nineteen patients underwent initial palliative systemic-to-pulmonary shunt, while six underwent an initial definitive Rastelli operation depending on the main pulmonary artery morphology and branch pulmonary arteries size. Results One patient died of postoperative brain hemorrhage following the initial definitive Rastelli operation. The mean follow-up duration was 58.5 ± 28.4 months. During follow-up, one patient died suddenly two months after the initial central shunt procedure. All surviving patients with a shunt, except two, underwent biventricular repair: ten with the Rastelli operation and six with the transannular patch (TAP) procedure. The staged TAP group demonstrated a significantly larger freedom from reoperation rate than that of the initial Rastelli operation group ( p  = 0.022) and a significantly lower catheter-based reintervention rate than that of the other two management groups ( p  = 0.011). Conclusions A management strategy using an initial definitive Rastelli operation or systemic-to-pulmonary shunt based on main pulmonary artery development and branch pulmonary arteries size is safe and effective for PA/VSD/PDA treatment. The staged TAP procedure could be a viable option for patients with PA/VSD/PDA and a well-developed main pulmonary artery segment. Trial registration Not applicable. Graphical Abstract

The autonomic regulation of the pulmonary vasculature has been under‐appreciated despite the presence of sympathetic and parasympathetic neural innervation and adrenergic and cholinergic receptors on pulmonary vessels. Recent clinical trials targeting this innervation have demonstrated promising effects in pulmonary hypertension, and in this context of reignited interest, we review autonomic pulmonary vascular regulation, its integration with other pulmonary vascular regulatory mechanisms, systemic homeostatic reflexes and their clinical relevance in pulmonary hypertension. The sympathetic and parasympathetic nervous systems can affect pulmonary vascular tone and pulmonary vascular stiffness. Local afferents in the pulmonary vasculature are activated by elevations in pressure and distension and lead to distinct pulmonary baroreflex responses, including pulmonary vasoconstriction, increased sympathetic outflow, systemic vasoconstriction and increased respiratory drive. Autonomic pulmonary vascular control interacts with, and potentially makes a functional contribution to, systemic homeostatic reflexes, such as the arterial baroreflex. New experimental therapeutic applications, including pulmonary artery denervation, pharmacological cholinergic potentiation, vagal nerve stimulation and carotid baroreflex stimulation, have shown some promise in the treatment of pulmonary hypertension. What is the topic of this review? This review examines our understanding of the autonomic control of pulmonary circulation, with an emphasis on its clinical relevance and potential therapeutic targeting in pulmonary hypertension. What advances does it highlight? The sympathetic and parasympathetic nervous systems both regulate pulmonary vascular tone and stiffness, in integration with systemic autonomic homeostasis. Pulmonary vascular afferents responsive to pulmonary arterial pressure produce distinct pulmonary baroreflex responses. Dysfunction in autonomic control both to and from the pulmonary vasculature might contribute to pulmonary hypertension, and new approaches targeting this have demonstrated early success.

Evaluating pulmonary circulation parameters (PCP) with cardiovascular magnetic resonance (CMR) is a relatively new approach with the potential for complex evaluation of the cardio-pulmonary system. Its impact might complement clinical assessment through right heart catheterization (RHC), the gold standard in evaluating pulmonary hypertension (PH) and hemodynamics, and transthoracic echocardiography (TTE). The study aims to examine the correlation between PCP and diastolic and systolic function, as well as PH, in patients with recent-onset dilated cardiomyopathy (RODCM). Eighty-four patients with RODCM were retrospectively included. All patients had a CMR examination, RHC (including pulmonary capillary wedge pressure (PCWP) and pulmonary vascular resistance (PVR)), and TTE. The pulmonary transit time (PTT), corrected pulmonary transit time (PTTc), systolic and diastolic function, and PH were assessed. Patients were divided into groups according to the PH and the diastolic function. PTT and PTTc correlated with PCWP, cardiac index, PVR, and E/e'. Patients with a restrictive filling pattern showed significantly longer PTT. The receiver operating characteristic curves for PTT, PTTc, and PH were assessed with areas under the curve of 72.7% for PTT and 75.3% for PTTc, and cut-off values of 8.62 s (PTT) and 8.52 s (PTTc). To our knowledge, this is the first study focused on CMR-derived PCP in an RODCM group. Our findings show that PTT and PTTc are prolonged in patients with impaired systolic and diastolic function, and PH. Therefore, PCP might offer critical information to evaluate the cardio-pulmonary system comprehensively.