The low-density lipoprotein receptor (LDLR) gene family includes LDLR, very LDLR, and LDL receptor-related proteins (LRPs) such as LRP1, LRP1b (aka LRP-DIT), LRP2 (aka megalin), LRP4, and LRP5/6, and LRP8 (aka ApoER2). LDLR family members constitute a class of closely related multifunctional, transmembrane receptors, with diverse functions, from embryonic development to cancer, lipid metabolism, and cardiovascular homeostasis. While LDLR family members have been studied extensively in the systemic circulation in the context of atherosclerosis, their roles in pulmonary arterial hypertension (PAH) are understudied and largely unknown. Endothelial dysfunction, tissue infiltration of monocytes, and proliferation of pulmonary artery smooth muscle cells are hallmarks of PAH, leading to vascular remodeling, obliteration, increased pulmonary vascular resistance, heart failure, and death. LDLR family members are entangled with the aforementioned detrimental processes by controlling many pathways that are dysregulated in PAH; these include lipid metabolism and oxidation, but also platelet-derived growth factor, transforming growth factor β1, Wnt, apolipoprotein E, bone morpohogenetic proteins, and peroxisome proliferator-activated receptor gamma. In this paper, we discuss the current knowledge on LDLR family members in PAH. We also review mechanisms and drugs discovered in biological contexts and diseases other than PAH that are likely very relevant in the hypertensive pulmonary vasculature and the future care of patients with PAH or other chronic, progressive, debilitating cardiovascular diseases.

UNASSIGNED: Stroke is one of the leading causes of morbidity and mortality with a significant percentage classified as cryptogenic. Left atrial (LA) remodelling, a substrate for atrial fibrillation (AF) and stroke development, may play a role in identification of the aetiology of cryptogenic stroke. We aimed to examine LA function to gain mechanistic insights into the pathophysiology of cryptogenic stroke in young patients otherwise at low risk for cardiovascular disease.
UNASSIGNED: Patients aged <60 years without traditional cardiovascular risk factors and who were diagnosed with ischaemic cryptogenic stroke or TIA were evaluated and compared to healthy controls and patients with paroxysmal AF with a CHA2DS2-VA score of 0. Conventional and novel left ventricular (LV) and LA echocardiographic parameters between the three groups were assessed.
UNASSIGNED: Each group consisted of thirty patients. There were no significant differences in LV parameters (LVEF, LV endoGLS) between groups. LA strain in stroke patients was significantly lower compared to the controls (median 33%; interquartile range (IQ) [32/39] vs 31 [27/34]; p = 0.008). LA strain was significantly lower in AF patients compared to stroke patients (median 21% [19/22] vs 31% [27/34]; p < 0.0001).
UNASSIGNED: A stepwise reduction in measures of LA function was appreciated between controls, young stroke and paroxysmal AF groups. This may indicate dynamic LA remodelling occurring in the young stroke population and suggest a shared causal mechanism for stroke development in this group. LA strain may further refine the risk for cardioembolic stroke.

BACKGROUND: Prevalence of pacemaker-induced cardiomyopathy (PICM) in adults with congenital heart disease is unknown. Tetralogy of Fallot (TOF) is a common diagnosis in the adult congenital heart disease population, and the purpose of this study was to determine association between frequent right ventricular (RV) pacing and temporal decrease in left ventricular ejection fraction (LVEF) from pre-implantation to 2-years post-implantation (LVEFpost-pre) in TOF patients.
METHODS: We studied TOF patients that received RV leads only (N = 51) and a reference group of 7 patients with atrial pacing or biventricular pacing. We defined PICM as a ≥10% decrease in LVEF resulting in LVEF <50%. Linear regression was used to assess relationship between frequent RV pacing (≤20%, 21-40%, >40%) and LVEFpost-pre.
RESULTS: PICM occurred in 2 (4%) of 51 patients in RV pacing group. LVEFpost-pre was +3% (95% confidence interval [CI] 0% to +5%) in the reference group and -4% (95% CI -11% to +2%) in RV pacing group. No significant difference occured in LVEFpost-pre between the reference group (LVEFpost-pre +3%) vs RV pacing ≤20% (LVEFpost-pre +1%) vs RV pacing 21-40% (LVEFpost-pre -3%) vs RV pacing >40% (LVEFpost-pre -5%), p = 0.318. There was also no association between frequent RV pacing and LVEFpost-pre, R 2 = 0.307, p = 0.10.
CONCLUSIONS: PICM occurred in 4% of TOF patients receiving RV pacing, and there was no association between frequent RV pacing and temporal decline in LVEF. Further studies are required to determine the long-term impact of RV pacing in the TOF population, and explore optimal treatment strategies.

UNASSIGNED: To evaluate the safety and efficacy of balloon pulmonary angioplasty (BPA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) seen at a US medical center.
UNASSIGNED: Patients with inoperable or residual postendarterectomy CTEPH who underwent BPA at Mayo Clinic in Rochester, Minnesota, between August 11, 2014, and May 17, 2018, were included. Invasive hemodynamic, clinical, laboratory, and echocardiographic data were collected and analyzed retrospectively.
UNASSIGNED: We identified 31 patients (26 with inoperable CTEPH and 5 with residual postendarterectomy CTEPH) who underwent 75 BPA procedures performed in a staged manner to reduce complications. The median number of sessions was 2 (interquartile range [IQR], 1-3) per patient, and the number of vessels treated per session was 3 (IQR, 2-3). Of the 31 patients, 24 (77.4%) were taking pulmonary vasodilators and 22 (71.0%) were taking riociguat. The mean pulmonary arterial pressure decreased from 40 mm Hg (IQR, 29-48 mm Hg) to 29 mm Hg (IQR, 25-37 mm Hg; P<.001); pulmonary vascular resistance decreased from 5.5 Wood units (WU) (IQR, 3.0-7.6 WU) to 3.3 WU (2.2-5.2 WU; P<.001). The follow-up 6-minute walk test was performed in 13 patients and improved from 402 m (IQR, 311-439 m) to 439 m (366-510 m; P=.001). Of the 31 patients, 19 (61.3%) had improvement in New York Heart Association functional class. The mean ± SD nadir of minute ventilation/carbon dioxide production decreased by 3.4±5.5 (P=.03), reflecting improved ventilatory efficiency. Complications included hemoptysis requiring overnight intensive care unit observation (n=1) and cardiac tamponade requiring pericardiocentesis (n=1). One patient had reperfusion injury requiring intubation, recovered, and was dismissed to home but died unexpectedly within less than 30 days of the procedure. Serious complications occurred in 3 of the 75 BPA procedures (4.0%).
UNASSIGNED: Our experience with BPA revealed that this procedure has acceptable risk and improves hemodynamics, functional class, and exercise tolerance in patients with inoperable or residual CTEPH.

Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure.

The present article reports three clinical cases in order to elucidate the diversity of the pathophysiological mechanisms that underlie rheumatoid arthritis associated pulmonary hypertension. The condition\'s three major causes are: interstitial lung disease, vasculitis, and chronic thromboembolic disease, but it should be noted that the multiple pulmonary manifestations of rheumatoid arthritis, can all contribute to chronic lung disease or hypoxia. The first patient in this report suffered from moderate restriction due to fibrosis and was diagnosed with pulmonary hypertension during an episode of life threatening hypoxia. Early upfront combination therapy prevented intubation and reversed hypoxia to adequate levels. The second presented patient was a case of isolated pulmonary hypertension attributable to vasculopathy. The patient maintained normal lung volumes but low diffusion capacity and echocardiography dictated the need for right heart catheterization. Finally, the third patient presented severe functional limitation due to several manifestations of rheumatoid arthritis, but a past episode of acute pulmonary embolism was also reported although it had never been evaluated. Chronic thromboembolic disease was eventually proved to be one major cause of the patient\'s pulmonary hypertension. The importance of early identification of pulmonary hypertension in patients with rheumatoid arthritis is therefore emphasized, especially since multiple treatment options are available, symptoms can be treated, and right heart failure can be avoided.

Adult onset Still\'s disease (AOSD) is an autoimmune disease characterized by systemic inflammation and is a rarely reported cause of pulmonary arterial hypertension (PAH). We describe the clinical course of a 40-year-old woman who presented with PAH 19 months after a diagnosis of AOSD. Sildenafil and immunosuppressive therapy with cyclosporine resulted in clinical and hemodynamic improvement with long-term survival 15 years after her initial presentation of AOSD. We review the literature for published cases of PAH due to AOSD and discuss the potential mechanisms relating inflammatory diseases and PAH.

BACKGROUND: Pulmonary vascular resistance (PVR) is an important hemodynamic parameter in patients with congenital heart disease (CHD). Noninvasive estimation of PVR represents an attractive alternative to invasive measurements.
METHODS: The study included 175 patients with pulmonary hypertension (PH) secondary to CHD. All patients underwent full echocardiographic study and invasive hemodynamic measurements. The study population was then subdivided into four subgroups. Each of the following Doppler indices was measured in one of these four subgroups: peak tricuspid regurgitant velocity (TRV), the ratio of the TRV to the velocity time integral of the right ventricular outflow tract (TRV/TVIRVOT), peak velocity of tricuspid annular systolic motion (TSm), heart rate corrected acceleration time and infliction time of the proximal left pulmonary artery (ATc, InTc). The data obtained was correlated with invasive PVR measurement. An ROC curve analysis was done to generate cutoff points with the highest balanced sensitivity and specificity to predict PVR > 6WU/m(2). The receiver operating characteristics (ROC) curves were compared with each other to determine the most reliable cutoff point in predicting elevated PVR > 6WU/m(2).
RESULTS: There was a significant correlation between both the TRV and TSm and invasive measurement of PVR (r = -0.511, 0.387 and P value = 0.0002, 0.006 respectively). The TSm and TRV cutoff values were the most reliable to predict elevated PVR > 6 WU/m(2). A TSm cutoff value of ⩽16.16 cm/s provided the best balanced sensitivity (85.7%) and specificity (66.7%) to determine PVRCATH > 6 WU/m(2). A cutoff value less than 7.62 cm/s had 100% specificity to predict PVRCATH > 6 WU/m(2). A TRV cutoff value of >3.96 m/s provided the best balanced sensitivity (66.7%) and specificity (100%) to determine PVRCATH > 6 WU/m(2). Both TRV and TSm had the highest area under the ROC curve among the 5 DOPPLER indices studied.
CONCLUSIONS: Prediction of elevated PVR in children with PH secondary to CHD could be achieved noninvasively using a number of Doppler indices. Among the five Doppler indices examined in the current study, the peak TRV and the TSm of the lateral tricuspid annulus had the highest balanced sensitivity and specificity to predict PVRI > 6 WU/m(2).

BACKGROUND: Balloon pulmonary valvuloplasty (BPV) represents the standard of management for all patients with severe pulmonary stenosis (PS) irrespective of their age. Nevertheless neonates and infants with critical PS represent a high-risk group that needs to be studied.
METHODS: The study population included 72 infants with severe congenital valvular PS and four infants with imperforate pulmonary valve (PV) who were subjected to detailed history taking, full clinical examination, resting 12-lead ECG, Chest roentgenogram and transthoracic echocardiography. BPV was attempted in all infants with a peak-to-peak gradient across the PV of 50 mmHg or greater at catheterization-laboratory. Full echocardiographic evaluation was done 24 hours after the procedure as well as 3 and 6 months later.
RESULTS: Seventy-six infants with severe PS or imperforate PV with a mean age of 5.63 ± 2.99 months were subjected to BPV with or without wire perforation. Immediately after the procedure patients had a significant reduction of the right ventricular systolic pressure (RVSP) (104.69 ± 24.98 mm Hg Vs 43.6 ± 13 mm Hg, p < 0.001) and RV-PA systolic pressure gradient (PG) (82.5 ± 23.76 mm Hg Vs 17.35 ± 8.96 mm Hg, p < 0.001). The immediate success rate defined as the drop in the RVSP to less than or equal to 50% of the baseline measurement was achieved in 85% of the cases. There was a progressive drop in the PG across the PV by Doppler echocardiogram throughout a follow-up period of six months from a mean of 93.3 ± 28.2 mm Hg to a mean of 17.4 ± 10.42 mm Hg (p < 0.001). There was a significant increase of the mean PV annulus diameter after balloon dilatation (p < 0.001). There was also a highly significant inverse correlation between the growth of the pulmonary annulus and the annular size at the baseline before dilatation (r = -0.74, p value <0.001). The incidence of PR significantly increased immediately after BPV to 64% followed by a progressive decline over a 6 months period of follow-up to 20%. There was a significant decrease in the incidence of tricuspid regurgitation (TR) over the same period of follow-up (from 55.6% at baseline to less than 20% at follow-up).
CONCLUSIONS: BPV is safe and effective to relieve critical PS in infants during the first year of life. The balloon promotes advantageous changes in both, pulmonary annulus and PG across the RVOT. In addition, the Doppler gradient observations during the follow-up support the expectation that BPV is a \"curative\" therapy.