Serum S100A8 and S100A9 as prognostic biomarkers in acute exacerbation of idiopathic pulmonary fibrosis

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a devastating and life-threatening condition during its clinical course. Biomarkers for precisely anticipating the prognosis of AE-IPF remain to be fully established. The objective of this study was to clarify whether S100A8 and S100A9, which are calcium-binding proteins mainly produced by activated neutrophils, are significant prognostic biomarkers in AE-IPF.MethodsThirty-seven patients with AE-IPF who were diagnosed and treated at our hospital were retrospectively evaluated. The serum levels of S100A8 and S100A9 were measured using enzyme-linked immunosorbent assay, and the relationships between these levels and clinical parameters or prognosis were evaluated.ResultsThe serum levels of S100A8 (median 386.5 ng/mL) and S100A9 (median 60.2 ng/mL) in patients with AE-IPF were significantly higher than those in age-matched healthy controls and in patients at IPF diagnosis (p < 0.001 for all combinations). The serum levels of S100A8 negatively correlated with percent forced vital capacity (r = −0.356, p = 0.049) and positively correlated with peripheral white blood cell number (r = 0.509, p = 0.002). Immunohistochemical staining of autopsy lung specimens showed that neutrophils, present mainly in the alveolar septum, were positive for S100A8 and S100A9. Patients with AE-IPF with higher levels of S100A8 or S100A9 showed significantly worse 3-month survival than those with lower levels (log-rank test, both p = 0.028). Finally, in multivariate analysis, the serum levels of both S100A8 and S100A9 were significant prognostic factors (hazard ratio 4.032, p = 0.023 and hazard ratio 4.327, p = 0.012).ConclusionThe serum levels of S100A8 and S100A9 at AE were significant prognostic biomarkers in patients with AE-IPF.     

A Cardiac Computed Tomography–Based Score to Categorize Mitral Annular Calcification Severity and Predict Valve Embolization

ObjectivesThis study aims to establish a computed tomography (CT)–based scoring system for grading mitral annular calcification (MAC) severity and potentially aid in predicting valve embolization during transcatheter mitral valve (MV) replacement using balloon-expandable aortic transcatheter heart valves.BackgroundTranscatheter MV replacement is emerging as an alternative treatment for patients with severe MAC who are not surgical candidates. Although cardiac CT is the imaging modality of choice in the evaluation of candidates for valve-in-MAC (ViMAC), a standardized grading system to quantify MAC severity has not been established.MethodsWe performed a multicenter retrospective review of cardiac CT and clinical outcomes of patients undergoing ViMAC. A CT-based MAC score was created using the following features: average calcium thickness (mm), degrees of annulus circumference involved, calcification at one or both fibrous trigones, and calcification of one or both leaflets. Features were assigned points according to severity (total maximum score = 10) and severity grade was assigned based on total points (mild ≤3, moderate 4 to 6, and severe ≥7 points). The association between MAC score and device migration/embolization was evaluated.ResultsOf 117 patients in the TMVR in MAC registry, 87 had baseline cardiac CT of adequate quality. Of these, 15 were treated with transatrial access and were not included. The total cohort included 72 (trans-septal = 37, transapical = 35). Mean patient age was 74 ± 12 years, 66.7% were female, and the mean Society of Thoracic Surgery risk score was 15.4 ± 10.5%. The mean MAC score was 7.7 ± 1.4. Embolization/migration rates were lower in higher scores: Patients with a MAC score of 7 had valve embolization/migration rate of 12.5%, MAC score ≥8 had a rate of 8.7%, and a MAC score of ≥9 had zero (p = 0.023). Patients with a MAC score of ≤6 had 60% embolization/migration rate versus 9.7% in patients with a MAC score ≥7 (p < 0.001). In multivariable analysis, a MAC score ≤6 was in independent predictor of valve embolization/migration (odds ratio [OR]: 5.86 [95% CI: 1.00 to 34.26]; p = 0.049).ConclusionsThis cardiac CT–based score provides a systematic method to grade MAC severity which may assist in predicting valve embolization/migration during trans-septal or transapical ViMAC procedures.     

Fractal dimension in CT low attenuation areas is predictive of long-term oxygen therapy initiation in COPD patients: Results from two observational cohort studies

BackgroundSome chronic obstructive pulmonary disease (COPD) patients develop hypoxemia with disease progression, with some even requiring long-term oxygen therapy (LTOT). Lung function, especially diffusing capacity, and the annual decline in PaO₂, are reported to be predictive factors of chronic respiratory failure. However, the association between lung morphometry evaluated using computed tomography (CT) images and LTOT initiation is unknown.MethodsWe retrospectively evaluated the relationship between clinical indices, including pulmonary function, body mass index (BMI), and CT parameters, at baseline and LTOT initiation in two prospective COPD cohorts. In the Nara Medical University cohort (n = 76), the low attenuation area (LAA) and its fractal dimension (fractal D) were adapted as the indices for parenchymal destruction in CT images. The association between these CT measurements and LTOT initiation was replicated in the Kyoto University cohort (n = 130).ResultsIn the Nara Medical University cohort, lower BMI (hazard ratio [HR]:0.70, p = 0.006), lower % diffusing capacity (%DLCO) (HR: 0.92, p = 0.006), lower %DLCO/VA (HR, 0.90, p = 0.008), higher RV/TLC (HR, 1.26, p = 0.012), higher LAA% (HR: 1.18, p = 0.001), and lower fractal D (HR: 3.27 × 10^?8, p < 0.001) were associated with LTOT initiation. Multivariate analysis in the Kyoto University cohort confirmed that lower %DLCO and lower fractal D were independently associated with LTOT initiation, whereas LAA% was not.ConclusionFractal D, which is the index for morphometric complexity of LAA in CT analysis, is predictive of LTOT initiation in COPD patients.     

Combined Tricuspid and Mitral Versus Isolated Mitral Valve Repair for Severe MR and TR: An Analysis From the TriValve and TRAMI Registries

ObjectivesThe aim of this study was to retrospectively compare the characteristics, procedural courses, and outcomes of patients presenting with concomitant mitral regurgitation (MR) and tricuspid regurgitation (TR) in the TriValve (Transcatheter Tricuspid Valve Therapies) and TRAMI (Transcatheter Mitral Valve Interventions) registries.BackgroundTranscatheter mitral edge-to-edge valve repair (TMVR) has been shown to be successful in patients with severe MR. Lately, edge-to-edge repair has also emerged as a possible treatment for severe TR in patients at high risk for cardiac surgery. In patients with both severe MR and TR, the yield of concomitant transcatheter mitral and tricuspid valve repair (TMTVR) for patients at high surgical risk is unknown.MethodsThe characteristics, procedural data, and 1-year outcomes of all patients in the international multicenter TriValve registry and the German multicenter TRAMI registry, who presented with both severe MR and TR, were retrospectively compared. Patients in TRAMI (n = 106) underwent isolated TMVR, while those in TriValve (n = 122) additionally underwent concurrent TMTVR in compassionate and/or off-label use.ResultsAll 228 patients (mean age 77 ± 8 years, 44.3% women) presented with significant dyspnea at baseline (New York Heart Association functional class III or IV in 93.9%), without any differences in the rates of pulmonary hypertension and chronic pulmonary disease. The proportion of patients with left ventricular ejection fraction <30% was higher in the TMVR group (34.9% vs. 18.0%; p < 0.001), while patients in the TMTVR group had lower glomerular filtration rates. At discharge, MR was comparably reduced in both groups. At 1 year, overall all-cause mortality was 34.0% in the TMVR group and 16.4% in the TMTVR group (p = 0.035, Cox regression). On multivariate analysis, TMTVR was associated with a 2-fold lower mortality rate (hazard ratio: 0.52; p = 0.02). The rate of patients in New York Heart Association functional class ≤II at 1 year did not differ (69.4% vs. 67.0%; p = 0.54).ConclusionsConcurrent TMTVR was associated with a higher 1-year survival rate compared with isolated TMVR in patients with both MR and TR. Further randomized trials are needed to confirm these results.     

Association between abdominal fat distribution and coronary plaque instability in patients with acute coronary syndrome

Background and aimsThis study aimed to assess possible association of detailed abdominal fat profiles with coronary plaque characteristics in patients with acute coronary syndrome (ACS).Methods and resultsIn 60 patients with ACS, culprit arteries were evaluated at 1-mm intervals (length analyzed: 66 ± 28 mm) by grayscale and integrated backscatter intravascular ultrasound (IB-IVUS) before percutaneous coronary intervention. Standard IVUS indexes (as a volume index: volume/length), plaque components (as percent tissue volume) and fibrous cap thickness (FCT) were assessed by IB-IVUS. Plain abdominal computed tomography was performed to evaluate subcutaneous adipose tissue (SAT) area, visceral adipose tissue (VAT) area, and VAT/SAT ratio. While SAT area only correlated with vessel volume (r = 0.27, p = 0.04), VAT area correlated positively with vessel (r = 0.30, p = 0.02) and plaque (r = 0.33, p = 0.01) volumes and negatively with FCT (r = −0.26, p = 0.049), but not with percent plaque volume and plaque tissue components. In contrast, higher VAT/SAT ratio significantly correlated with higher percent lipid (r = 0.34, p = 0.008) and lower percent fibrous (r = −0.34, p = 0.007) volumes with a trend toward larger percent plaque volume (r = 0.19, p = 0.15), as well as thinner FCT (r = −0.53, p < 0.0001). In the multiple regression analysis, higher VAT/SAT ratio was independently associated with higher percent lipid with lower percent fibrous volumes (p = 0.03 for both) and thinner fibrous cap thickness (p = 0.0001).ConclusionCoronary plaque vulnerability, defined as increased lipid content with thinner fibrous cap thickness, appears to be more related to abnormal abdominal fat distribution, or so-called hidden obesity, compared with visceral or subcutaneous fat amount alone in patients with ACS.     

Treatment strategies with alternative treatment options for patients with Mycobacterium avium complex pulmonary disease

Diseases caused by Mycobacterium avium complex (MAC) infection in the lungs are increasing worldwide. The recurrence rate of MAC-pulmonary disease (PD) has been reported to be as high as 25–45%. A significant percentage of recurrences occurs because of reinfection with a new genotype from the environment. A focus on reducing exposure to MAC organisms from the environment is therefore an essential component of the management of this disease as well as standard MAC-PD treatment. A macrolide-containing three-drug regimen is recommended over a two-drug regimen as a standard treatment, and azithromycin is recommended rather than clarithromycin. Both the 2007 and 2020 guidelines recommend a treatment duration of MAC-PD of at least one year after the culture conversion. Previous clinical studies have reported that ethambutol could prevent macrolide resistance. Furthermore, the concomitant use of aminoglycoside, amikacin liposomal inhalation, clofazimine, linezolid, bedaquiline, and fluoroquinolone with modification of guideline-based therapy has been studied.Long-term management of MAC-PD remains challenging because of the discontinuation of multi-drug regimens and the acquisition of macrolide resistance. Moreover, the poor compliance of guideline-based therapy for MAC-PD treatment worldwide is concerning since it causes macrolide resistance.Therefore, in this review, we focus on MAC-PD treatment and summarize various treatment options when standard treatment cannot be maintained, with reference to the latest ATS/ERS/ESCMID/IDSA clinical practice guidelines revised in 2020.     

Comparison of Management Strategies for Neonates With Symptomatic Tetralogy of Fallot

BackgroundNeonates with tetralogy of Fallot and symptomatic cyanosis (sTOF) require early intervention.ObjectivesThis study sought to perform a balanced multicenter comparison of staged repair (SR) (initial palliation [IP] and subsequent complete repair [CR]) versus primary repair (PR) treatment strategies.MethodsConsecutive neonates with sTOF who underwent IP or PR at ≤30 days of age from 2005 to 2017 were retrospectively reviewed from the Congenital Cardiac Research Collaborative. The primary outcome was death. Secondary outcomes included component (IP, CR, PR) and cumulative (SR): hospital and intensive care unit lengths of stay; durations of cardiopulmonary bypass, anesthesia, ventilation, and inotrope use; and complication and reintervention rates. Outcomes were compared using propensity score adjustment.ResultsThe cohort consisted of 342 patients who underwent SR (IP: surgical, n = 256; transcatheter, n = 86) and 230 patients who underwent PR. Pre-procedural ventilation, prematurity, DiGeorge syndrome, and pulmonary atresia were more common in the SR group (p ≤0.01). The observed risk of death was not different between the groups (10.2% vs 7.4%; p = 0.25) at median 4.3 years. After adjustment, the hazard of death remained similar between groups (hazard ratio: 0.82; 95% confidence interval: 0.49 to 1.38; p = 0.456), but it favored SR during early follow-up (<4 months; p = 0.041). Secondary outcomes favored the SR group in component analysis, whereas they largely favored PR in cumulative analysis. Reintervention risk was higher in the SR group (p = 0.002).ConclusionsIn this multicenter comparison of SR or PR for management of neonates with sTOF, adjusted for patient-related factors, early mortality and neonatal morbidity were lower in the SR group, but cumulative morbidity and reinterventions favored the PR group, findings suggesting potential benefits to each strategy.     

Effect of Ticagrelor on Left Ventricular Remodeling in Patients With ST-Segment Elevation Myocardial Infarction (HEALING-AMI)

ObjectivesThe aim of this study was to evaluate the effect of ticagrelor versus clopidogrel on left ventricular (LV) remodeling after reperfusion of ST-segment elevation myocardial infarction (STEMI) in humans.BackgroundAnimal studies have demonstrated that ticagrelor compared with clopidogrel better protects myocardium against reperfusion injury and improves remodeling after myocardial infarction.MethodsIn this investigator-initiated, randomized, open-label, assessor-blinded trial performed at 10 centers in Korea, patients were enrolled if they had naive STEMI successfully treated with primary percutaneous coronary intervention (PCI) and at least 6-month planned duration of dual-antiplatelet treatment. The coprimary endpoints were LV remodeling index (LVRI) (a relative change of LV end-diastolic volume) measured on 3-dimensional echocardiography and N-terminal pro–B-type natriuretic peptide level at 6 months.ResultsAmong initially enrolled patients with STEMI (n = 336), 139 in each group completed the study. LVRI at 6 months was numerically lower with ticagrelor versus clopidogrel (0.6 ± 18.6% vs. 4.5 ± 16.5%; p = 0.095). Ticagrelor significantly reduced the 6-month level of N-terminal pro–B-type natriuretic peptide (173 ± 141 pg/ml vs. 289 ± 585 pg/ml; p = 0.028). These differences were prominent in patients with pre-PCI TIMI (Thrombolysis In Myocardial Infarction) flow grade 0. By multivariate analysis, ticagrelor versus clopidogrel reduced the risk for positive LV remodeling (LVRI >0%) (odds ratio: 0.56; 95% confidence interval: 0.33 to 0.95; p = 0.030). The LV end-diastolic volume index remained unchanged during ticagrelor treatment (from 54.7 ± 12.2 to 54.2 ± 12.2 ml/m²; p = 0.629), but this value increased over time during clopidogrel treatment (from 54.6 ± 11.3 to 56.4 ± 13.9 ml/m²; p = 0.056) (difference −2.3 ml/m²; 95% confidence interval: −4.8 to 0.2 ml/m²; p = 0.073). Ticagrelor reduced LV end-systolic volume index (from 27.0 ± 8.5 to 24.7 ± 8.4 ml/m²; p < 0.001), whereas no reduction was seen with clopidogrel (from 26.2 ± 8.9 to 25.6 ± 11.0 ml/m²; p = 0.366) (difference −1.8 ml/m²; 95% confidence interval: −3.5 to −0.1 ml/m²; p = 0.040).ConclusionsTicagrelor was superior to clopidogrel for LV remodeling after reperfusion of STEMI with primary PCI. (High Platelet Inhibition With Ticagrelor to Improve Left Ventricular Remodeling in Patients With ST Segment Elevation Myocardial Infarction [HEALING-AMI]; NCT02224534)     

Right-to-Left Shunt Through Iatrogenic Atrial Septal Defect After MitraClip Procedure

ObjectivesThe aim of this study was to investigate the incidence, characteristics, hemodynamic conditions, and clinical significance of right-to-left (R-L) shunt through an iatrogenic atrial septal defect (iASD) after the MitraClip procedure.BackgroundR-L shunt through an iASD after the MitraClip procedure has not been well investigated.MethodsFrom 2014 to 2017, 385 consecutive patients with mitral regurgitation underwent the MitraClip procedure. iASD was assessed using intraprocedural transesophageal echocardiography. Right and left heart catheterization was used to assess the hemodynamic status of patients. All patients provided written informed consent for the procedure. All data for this study were collected from an established interventional cardiology laboratory database approved by the Cedars-Sinai Medical Center Institutional Review Board.ResultsR-L shunt was observed in 20 patients (5%). In 7 of these patients (35%), R-L shunt was accompanied by acute deoxygenation. Prevalence of severe tricuspid regurgitation (55% vs. 20%; p = 0.001), serum B-type natriuretic peptide (664 pg/ml [434 to 1,169 pg/ml] vs. 400 pg/ml [195 to 699 pg/ml]; p = 0.006), mean pulmonary artery pressure (38 mm Hg [34 to 45 mm Hg] vs. 29 mm Hg [22 to 37 mm Hg]; p < 0.001), and right atrial pressure (19 mm Hg [13 to 20 mm Hg] vs. 10 mm Hg [7 to 14 mm Hg]; p < 0.001) were significantly higher in patients with R-L shunt than in those with left-to-right shunt. Patients with R-L shunt also showed a more prominent reduction in the left atrial V-wave and mean pressure from baseline to post-procedure compared with those with left-to-right shunt (−22.8 ± 2.6 mm Hg vs. −11.8 ± 0.9 mm Hg [p = 0.002] and −7.9 ± 0.8 mm Hg vs. −4.0 ± 0.4 mm Hg [p = 0.003], respectively).ConclusionsR-L shunt through an iASD was observed in 5% of patients who underwent the MitraClip procedure and in one-third of patients with R-L shunt presented acute deoxygenation. Elevated right atrial pressure concomitant with pulmonary hypertension and significant reduction in left atrial pressure after MitraClip deployment were associated with R-L shunt.     

What is the impact of zinc deficiency for pancreatectomies in patients with pancreatic ductal adenocarcinoma?

Backgroundand purpose: Zinc is an essential element for human health and plays an important role in metabolic, immunological and other biological processes. The present study was conducted to investigate the association between zinc deficiency (ZD) and the perioperative clinical course in patients with pancreatic ductal adenocarcinoma (PDAC).MethodsOf 216 patients with PDAC who underwent elective pancreatectomy between 2013 and 2017 at our institution, 206 patients with sufficient clinical data were retrospectively reviewed. The perioperative variables were compared and the risk factors associated with infectious complications were identified.ResultsZD was preoperatively present in 36 (17.5%) of 206 patients with PDAC. In the patients of the ZD group, a higher proportion of males, higher preoperative modified Glasgow prognostic scores, a higher neutrophil-to-lymphocyte ratio, and a higher occurrence of postoperative infectious complications after pancreatectomy were observed, compared to the non-ZD group. By a univariate analysis, three risk factors were significantly associated with infectious complications after pancreatectomy: ZD (vs non-ZD: p = 0.002), serum albumin <3.5 g/dl (vs ≥ 3.5 g/dl: p = 0.005), and the procedure of pancreaticoduodenectomy (vs others: p = 0.013). By multivariate logistic regression analysis, the occurrence of infectious complications was significantly associated with ZD (OR 3.430, 95%CI 1.570 to 7.490, p = 0.002) and the procedure of pancreaticoduodenectomy (OR 2.030, 95%CI 1.090 to 3.770, p = 0.025).ConclusionsThe current study newly demonstrated that ZD could serve as a preoperative predictor of infectious complications after pancreatectomies in the patients with PDAC.     

Mechanical ventilation for acute exacerbation of fibrosing interstitial lung diseases

BackgroundAcute exacerbation of fibrosing interstitial lung diseases, including idiopathic pulmonary fibrosis, is associated with poor prognosis. Accordingly, tracheal intubation and invasive mechanical ventilation are generally avoided in such patients. However, the efficacy of invasive mechanical ventilation for acute exacerbation of fibrosing interstitial lung diseases remains unclear. Therefore, we aimed to investigate the clinical course of patients with acute exacerbation of fibrosing interstitial lung diseases who were treated with invasive mechanical ventilation.MethodsWe retrospectively analyzed 28 patients with acute exacerbation of fibrosing interstitial lung diseases who underwent invasive mechanical ventilation at our hospital.ResultsOf the 28 included patients (20 men, 8 women; mean age, 70.6 years), 13 (46.4%) were discharged alive and 15 died. Ten patients (35.7%) had idiopathic pulmonary fibrosis. Univariate analysis revealed that longer survival was significantly associated with lower partial pressure of arterial carbon dioxide (hazard ratio [HR] 1.04 [1.01–1.07]; p = 0.002) and higher pH (HR 0.0002 [0–0.02] levels; p = 0.0003) and less severe general status according to the Acute Physiology and Chronic Health Evaluation II score (HR 1.13 [1.03–1.22]; p = 0.006) at the time of mechanical ventilation initiation. In addition, the univariate analysis indicated that patients without long-term oxygen therapy use had significantly longer survival (HR 4.35 [1.51–12.52]; p = 0.006).ConclusionsInvasive mechanical ventilation may effectively treat acute exacerbation of fibrosing interstitial lung diseases if good ventilation and general conditions can be maintained.     

Impact of Pulmonary Hypertension Hemodynamic Status on Long-Term Outcome After Transcatheter Aortic Valve Replacement

ObjectivesThe aim of this study was to investigate the prognostic impact and development of pulmonary hypertension (PH) in the different hemodynamic subtypes of PH in patients with severe aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR).BackgroundPH is a frequent finding in patients with severe AS and predicts outcome after TAVR. Nevertheless, outcomes among PH subtypes and the impact of residual PH after TAVR are controversial.MethodsA total of 1,400 patients with symptomatic AS and full invasive hemodynamic assessment before and after TAVR were included. Patients were stratified into 4 groups: no PH (n = 658); isolated pre-capillary PH (n = 139), isolated post-capillary PH (Ipc-PH; n = 534), and combined post-capillary and pre-capillary PH (n = 69).ResultsThe mean overall patient age was 81.5 ± 6.8 years, and 46.3% were men. Acute device success was achieved in 94.9%. Patients without PH showed significantly lower mortality rates compared with patients with PH (1 year, 13.8% vs. 22.4% [p < 0.001]; 4 years, 37.2% vs. 51.5% [p < 0.001]). Patients with pre-capillary PH showed 1.9-fold increased 1-year mortality and those with Ipc-PH showed 1.5-fold increased 1-year mortality compared with patients without pH (p = 0.001). No differences regarding survival were found among the subgroups. Only in patients with Ipc-PH, residual PH was associated with 2.1-fold increased mortality (p = 0.010). All patients benefited in terms of functional capacity after TAVR.ConclusionsPatients with pre-capillary PH and those with Ipc-PH showed significantly higher risk for death after TAVR compared with those without PH. Reversible PH had no benefit for survival except in patients with Ipc-PH. Hemodynamic stratification of PH is helpful for risk and response prediction in patients with AS undergoing TAVR.     

Severe Atrial Functional Mitral Regurgitation: Clinical and Echocardiographic Characteristics,Management and Outcomes

ObjectivesThis study was designed to compare the clinical and echocardiographic characteristics, management, and outcomes of severe atrial functional mitral regurgitation (AFMR) to primary mitral regurgitation (PMR).BackgroundAFMR remains poorly defined clinically.MethodsConsecutive patients who underwent transesophageal echocardiography at our institution between 2011 and 2018 for severe mitral regurgitation with preserved left ventricular function were screened. We excluded patients with endocarditis, any form of cardiomyopathy, or prior mitral intervention. The absence of leaflet pathology defined AFMR. Outcomes included death and heart failure hospitalizations.ResultsA total of 283 patients were included (AFMR = 14%, PMR = 86%). Compared to PMR, patients with AFMR had more comorbidities, including hypertension (94.9% vs. 76.2%; p = 0.015), diabetes mellitus (46.2% vs. 18.4%; p < 0.001), long-standing atrial fibrillation (28.2% vs. 13.1%; p = 0.015), prior nonmitral cardiac surgery (25.6% vs. 9.8%; p = 0.004), and pacemaker placement (33.3% vs. 13.5%; p = 0.002). They also had higher average E/e’ (median [interquartile range]:16.04 [13.1 to 22.46] vs. 14.1 [10.89 to 19]; p = 0.036) and worse longitudinal left atrial strain peak positive value (16.86 ± 12.15% vs. 23.67 ± 14.09%; p = 0.002) compared to PMR. During follow-up (median: 22 months), patients with AFMR had worse survival (log-rank p = 0.009) and more heart failure hospitalizations (log-rank p = 0.002). They were also less likely to undergo mitral valve intervention (59.0% vs. 83.6%; p = 0.001), although surgery was associated with improved survival (log-rank p = 0.021). On multivariable regression analysis, AFMR was independently associated with mortality [adjusted odds ratio: 2.61, 95% confidence interval: 1.17 to 5.83; p = 0.02].ConclusionsAFMR constitutes an under-recognized high-risk group, with significant comorbidities, limited therapeutic options, and poor outcomes.     

Clinical characteristics,outcomes, and factors associated with mortality in Nocardia pneumonia: 18 years' real-world data from a tertiary care hospital in Karachi,Pakistan

BackgroundPulmonary nocardiosis is a rare pulmonary infection with high morbidity and mortality. Limited real-world data on pulmonary nocardiosis patients are available from developing countries like Pakistan.MethodsThis retrospective observational study was conducted at the Aga Khan University Hospital, Karachi, Pakistan, from August 2003 to June 2020. Demographics, immune status, underlying diseases, laboratory data, treatment, and outcomes of all nocardiosis patients were recorded in predesigned proforma.ResultsSixty-six patients with smear/culture-proven pulmonary nocardiosis were identified. Most patients (83.3%) were treated with trimethoprim-sulfamethoxazole alone or in combination with other medicines. The overall mortality rate in our study was 33.3% (n = 22/66). Factors significantly associated with mortality were respiratory failure (p < 0.001), raised procalcitonin levels (p = 0.01), concomitant fungal infections (p = 0.01), concomitant TB (p = 0.03), and patients on combination therapy (p < 0.001).Respiratory failure (odds ratio [OR] 46.94 [95% confidence intervals [CI]: 5.01–439.03] p < 0.001), concomitant fungal infection (OR 17.09 [95% CI: 1.47–197.88] p- = 0.02) and patients on combination therapy (OR 6.90 [95% CI: 1.23–38.61] p = 0.02) were also identified as independent risk factors for mortality on multivariate analysis.ConclusionsThis study provides essential information on the clinical characteristics and risk factors, outcomes, and factors associated with mortality for pulmonary nocardial infections.     

Reduction in CMR Derived Extracellular Volume With Patisiran Indicates Cardiac Amyloid Regression

ObjectivesThe purpose of this study was to determine the effect of patisiran on the cardiac amyloid load as measured by cardiac magnetic resonance and extracellular volume (ECV) mapping in cases of transthyretin cardiomyopathy (ATTR-CM).BackgroundAdministration of patisiran, a TTR-specific small interfering RNA (siRNA), has been shown to benefit neuropathy in patients with hereditary ATTR amyloidosis, but its effect on ATTR-CM remains uncertain.MethodsPatisiran was administered to 16 patients with hereditary ATTR-CM who underwent assessment protocols at the UK National Amyloidosis Centre. Twelve of those patients concomitantly received diflunisal as a “TTR-stabilizing” drug. Patients underwent serial monitoring using cardiac magnetic resonance, echocardiography, cardiac biomarkers, bone scintigraphy, and 6-min walk tests (6MWTs). Findings of amyloid types and extracellular volumes were compared with those of 16 patients who were retrospectively matched based on cardiac magnetic resonance results.ResultsPatisiran was well tolerated. Median serum TTR knockdown among treated patients was 86% (interquartile range [IQR]: 82% to 90%). A total of 82% of cases showed >80% knockdown. Patisiran therapy was typically associated with a reduction in ECV (adjusted mean difference between groups: ?6.2% [95% confidence interval [CI]: ?9.5% to ?3.0%]; p = 0.001) accompanied by a fall in N-terminal pro–B-type natriuretic peptide concentrations (adjusted mean difference between groups: ?1,342 ng/l [95% CI: ?2,364 to ?322]; p = 0.012); an increase in 6MWT distances (adjusted mean differences between groups: 169 m [95% CI: 57 to 2,80]; p = 0.004) after 12 months of therapy; and a median reduction in cardiac uptake by bone scintigraphy of 19.6% (IQR: 9.8% to 27.1%).ConclusionsReductions in ECV by cardiac magnetic resonance provided evidence for ATTR cardiac amyloid regression in a proportion of patients receiving patisiran.     

Proposed Stages of Myocardial Phenotype Development in Fabry Disease

ObjectivesThis study sought to explore the Fabry myocardium in relation to storage, age, sex, structure, function, electrocardiogram changes, blood biomarkers, and inflammation/fibrosis.BackgroundFabry disease (FD) is a rare, x-linked lysosomal storage disorder. Mortality is mainly cardiovascular with men exhibiting cardiac symptoms earlier than women. By cardiovascular magnetic resonance, native T1 is low in FD because of sphingolipid accumulation.MethodsA prospective, observational study of 182 FD (167 adults, 15 children; mean age 42 ± 17 years, 37% male) who underwent cardiovascular magnetic resonance including native T1, late gadolinium enhancement (LGE), and extracellular volume fraction, 12-lead electrocardiogram, and blood biomarkers (troponin and N-terminal pro-brain natriuretic peptide).ResultsIn children, T1 was never below the normal range, but was lower with age (9 ms/year, r = −0.78 children; r = −0.41 whole cohort; both p < 0.001). Over the whole cohort, the T1 reduction with age was greater and more marked in men (men: −1.9 ms/year, r = −0.51, p < 0.001; women: −1.4 ms/year, r = −0.47 women, p < 0.001). Left ventricular hypertrophy (LVH), LGE, and electrocardiogram abnormalities occur earlier in men. Once LVH occurs, T1 demonstrates major sex dimorphism: with increasing LVH in women, T1 and LVH become uncorrelated (r = −0.239, p = 0.196) but in men, the correlation reverses and T1 increases (toward normal) with LVH (r = 0.631, p < 0.001), a U-shaped relationship of T1 to indexed left ventricular mass in men.ConclusionsThese data suggest that myocyte storage starts in childhood and accumulates faster in men before triggering 2 processes: a sex-independent scar/inflammation regional response (LGE) and, in men, apparent myocyte hypertrophy diluting the T1 lowering of sphingolipid.     

Right Atrial/Pulmonary Arterial Wedge Pressure Ratio in Primary and Mixed Constrictive Pericarditis

BackgroundCardiac filling pressures may be elevated due to abnormalities in the myocardium, heightened pericardial restraint, or both. The authors hypothesized that the relative contributions due to myocardium and pericardium could be estimated by the ratio between right atrial pressure and pulmonary arterial wedge pressure (RAP/PAWP), which would enable better discrimination of the extent of myocardial disease in patients with constrictive pericarditis (CP).ObjectivesThis study investigated the relationships between RAP/PAWP and the pericardial thickness as well as echocardiographic parameters of myocardial function and assessed the prognostic implications of RAP/PAWP for long-term mortality in primary and mixed CP patients who underwent pericardiectomy.MethodsA total of 113 surgically confirmed CP patients who underwent echocardiography and cardiac catheterization within 7 days of each other between 2005 and 2013 were included in the study. The patients were classified into a high RAP/PAWP group (≥0.77; n = 56) or a low RAP/PAWP group (<0.77; n = 57) according to the median RAP/PAWP value. The primary outcome was prognostic implication of RAP/PAWP on long-term mortality and assessment of the relationship between RAP/PAWP and Doppler echocardiographic parameters in primary and mixed CP. In addition, the relationship between RAP/PAWP and the pericardial thickness was assessed.ResultsRAP/PAWP was directly correlated with pericardial thickness (regression coefficient [β] = 8.34; p < 0.001). RAP/PAWP had a significant direct correlation with early diastolic velocity of medial mitral annulus (eʹ) (β = 10.69; p < 0.001) and inverse relationship with early transmitral diastolic velocity (E) (β = −105.15; p < 0.001), resulting in an inverse relationship with the ratio of E/eʹ (β = −23.53; p < 0.001). Patients with high RAP/PAWP ratio had a better survival rate compared with those with low RAP/PAWP ratio (p = 0.01). Its prognostic value was significant in primary CP (p = 0.03) but not in mixed CP with concomitant myocardial disease (p = 0.89).ConclusionsThe RAP/PAWP ratio can reflect the degree of pericardial restraint versus restrictive myocardium and was associated with the long-term survival after pericardiectomy.     

Exercise Pulmonary Hypertension Predicts Clinical Outcomes in Patients With Dyspnea on Effort

BackgroundAbnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear.ObjectivesThis study sought to investigate the association of exPH with clinical determinants and outcomes.MethodsThe authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality.ResultsAmong 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 ± 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p < 0.001). The association of abnormal PAP/CO slope with outcomes remained significant after excluding rest PH (n = 146, hazard ratio: 1.75; 95% confidence interval: 1.21 to 2.54; p = 0.003). Both pre- and post-capillary contributions to exPH independently predicted adverse events (p < 0.001 for both).ConclusionsExercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation.     

Combination of F-ASO and Targeted Medical Therapy in Patients With Secundum ASD and Severe PAH

ObjectivesThis study was conducted to investigate the combined use of fenestrated atrial septal occluder (F-ASO) and targeted medical therapy (TMT) in patients with secundum atrial septal defect (ASD) and severe pulmonary arterial hypertension (PAH).BackgroundTreatment of patients with ASD and severe PAH is still challenging.MethodsAfter ethical approval was obtained, 56 consecutive patients with ASD with severe PAH were included (7 men, 49 women; median age 50.5 years; mean ASD size 26.9 ± 4.6 mm). After 3 months of TMT, transcatheter closure was performed using F-ASO in patients with ratios of pulmonary to systemic blood flow ≥1.5. TMT was continued post-operatively together with 6 months of dual-antiplatelet therapy. The hemodynamic variables during baseline, TMT alone, and combined treatment with F-ASO were compared.ResultsAfter only TMT, systolic pulmonary arterial pressure (−14.5 mm Hg; p < 0.001), pulmonary vascular resistance (−3.9 Wood units; p < 0.001), and exercise capacity (+72.0 m; p < 0.001) improved. Ratio of pulmonary to systemic blood flow increased by 0.9 (p < 0.001), with adverse cardiac remodeling (right ventricular dimension +3.5 mm; p < 0.001). Closure with F-ASO (median size 34.0 mm) led to further decrease in systolic pulmonary artery pressure (−6.0 mm Hg; p < 0.001). Follow-up (median duration 10 months) revealed further improvement in exercise capacity (+60.5 m; p < 0.001), with favorable cardiac remodeling (right ventricular dimension −9.9 mm; p < 0.001). In addition, all fenestrations were stable (p = 0.699), with negligible shunt (median ratio of pulmonary to systemic blood flow 1.1) and no complications. One year later, pulmonary artery pressure was normalized in 8 of 19 patients, and PAH recurred in 5 patients after discontinuation of TMT.ConclusionsIn patients with ASD and severe PAH, combination of F-ASO and TMT was a safe and effective procedure. Compared with TMT alone, the combined treatment further improved exercise capacity, with favorable cardiac remodeling.     

Cardiopulmonary Hemodynamic Profile Predicts Mortality After Transcatheter Tricuspid Valve Repair in Chronic Heart Failure

ObjectivesThis study was designed to assess hemodynamic changes in response to transcatheter tricuspid valve edge-to-edge repair (TTVR) and to identify hemodynamic predictors associated with mortality.BackgroundSevere tricuspid regurgitation (TR) is associated with high mortality. TTVR effectively alleviates heart failure symptoms, but comprehensive hemodynamic characterization of patients undergoing TTVR is currently lacking.MethodsThis international, multicenter study included 236 patients undergoing TTVR. Data from clinical assessment, echocardiography, intraprocedural right heart catheterization, and noninvasive cardiac output measurement were analyzed. Hemodynamic predictors for mortality were identified using linear Cox regression analysis and were used for stratification of patients with subsequent analysis of survival time.ResultsPatients (median age 78 years, 53% women) were symptomatic (89% in New York Heart Association functional class III or IV) because of severe TR (grade ≥3+ in 100%). TTVR significantly reduced TR at discharge (grade ≥3+ in 16%; p < 0.001), with a corresponding 19% reduction of the right atrial v wave (21 mm Hg vs. 16 mm Hg; p < 0.001) and an improvement in cardiac output (from 3.5 to 4.0 l/min; p < 0.01). Invasive mean pulmonary artery pressure, transpulmonary gradient, pulmonary vascular resistance, and right ventricular stroke work were significant predictors of 1-year mortality (p < 0.05 for all). Hemodynamic stratification by mean pulmonary artery pressure and transpulmonary gradient best predicted 1-year survival (p < 0.001). Although patients with pre-capillary dominant pulmonary hypertension showed an unfavorable prognosis (1-year survival 38%), patients without or with post-capillary pulmonary hypertension had favorable outcome (1-year survival 92% or 78%, respectively).ConclusionsInvasive assessment of cardiopulmonary hemodynamic status predicts survival after TTVR. Invasive hemodynamic characterization may help identify patients profiting most from TTVR.