The Extent of Late Gadolinium Enhancement Can Predict Adverse Cardiac Outcomes in Patients with Non-Ischemic Cardiomyopathy with Reduced Left Ventricular Ejection Fraction: A Prospective Observational Study

Objective@#The clinical course of an individual patient with heart failure is unpredictable with left ventricle ejection fraction (LVEF) only. We aimed to evaluate the prognostic value of cardiac magnetic resonance (CMR)-derived myocardial fibrosis extent and to determine the cutoff value for event-free survival in patients with non-ischemic cardiomyopathy (NICM) who had severely reduced LVEF. @*Materials and Methods@#Our prospective cohort study included 78 NICM patients with significantly reduced LV systolic function (LVEF < 35%). CMR images were analyzed for the presence and extent of late gadolinium enhancement (LGE). The primary outcome was major adverse cardiac events (MACEs), defined as a composite of cardiac death, heart transplantation, implantable cardioverter-defibrillator discharge for major arrhythmia, and hospitalization for congestive heart failure within 5 years after enrollment. @*Results@#A total of 80.8% (n = 63) of enrolled patients had LGE, with the median LVEF of 25.4% (19.8–32.4%). The extent of myocardial scarring was significantly higher in patients who experienced MACE than in those without any cardiac events (22.0 [5.5–46.1] %LV vs. 6.7 [0–17.1] %LV, respectively, p = 0.008). During follow-up, 51.4% of patients with LGE ≥ 12.0 %LV experienced MACE, along with 20.9% of those with LGE ≤ 12.0 %LV (log-rank p = 0.001). According to multivariate analysis, LGE extent more than 12.0 %LV was independently associated with MACE (adjusted hazard ratio, 6.71; 95% confidence interval, 2.54–17.74; p < 0.001). @*Conclusion@#In NICM patients with significantly reduced LV systolic function, the extent of LGE is a strong predictor for longterm adverse cardiac outcomes. Event-free survival was well discriminated with an LGE cutoff value of 12.0 %LV in these patients.

The mortality benefit of carvedilol versus bisoprolol in patients with heart failure with reduced ejection fraction

BACKGROUND/AIMS@#It is unknown whether different β-blockers (BBs) have variable effects on long-term survival of patients with heart failure with reduced ejection fraction (HFrEF). This study compares the effects of two BBs, carvedilol and bisoprolol, on survival in patients with HFrEF.@*METHODS@#The Korean Acute Heart Failure (KorAHF) registry is a prospective multicenter cohort that includes 5,625 patients who were hospitalized for acute heart failure (AHF). We selected 3,016 patients with HFrEF and divided this study population into two groups: BB at discharge (n = 1,707) or no BB at discharge (n = 1,309). Among patients with BB at discharge, subgroups were formed based on carvedilol prescription (n = 831), or bisoprolol prescription (n = 553). Propensity score matching analysis was performed.@*RESULTS@#Among patients who were prescribed a BB at discharge, 60.5% received carvedilol and 32.7% received bisoprolol. There was a significant reduction in all-cause mortality in those patients with HFrEF prescribed a BB at discharge compared to those who were not (BB vs. no BB, 26.1% vs. 40.8%; hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.52 to 0.67; p < 0.001). However, there was no significant difference in the rate of all-cause mortality between those receiving different types of BB (carvedilol vs. bisoprolol, 27.5% vs. 23.5%; HR, 1.21; 95% CI, 0.99 to 1.47; p = 0.07). Similar results were observed after propensity score matching analysis (508 pairs, 26.2% vs. 23.8%; HR, 1.10; 95% CI, 0.86 to 1.40; p = 0.47).@*CONCLUSIONS@#In the treatment of AHF with reduced EF after hospitalization, mortality benefits of carvedilol and bisoprolol were comparable.

Characteristics of South Korean Patients with Hereditary Transthyretin Amyloidosis

BACKGROUND AND PURPOSE: This retrospective cross-sectional study included 18 patients from unrelated families harboring mutations of the transthyretin gene (TTR), and analyzed their characteristics and geographical distribution in South Korea. METHODS: The included patients had a diagnosis of systemic amyloidosis, clinical symptoms, such as amyloid neuropathy or cardiomyopathy, and confirmation of a TTR gene mutation using genetic analysis recorded between April 1995 and November 2014. RESULTS: The mean age at disease onset was 49.6 years, and the mean disease duration from symptom onset to diagnosis was 3.67 years. Fifteen of the 18 patients were classified as mixed phenotype, 2 as the neurological phenotype, and only 1 patient as the cardiac phenotype. The most-common mutation pattern in South Korea was Asp38Ala, which was detected in eight patients. Thirteen patients reported their family hometowns, and five of the eight harboring the Asp38Ala mutation were from the Gyeongsang province in southeast Korea. The other eight patients exhibited a widespread geographical distribution. A particularly noteworthy finding was that the valine at position 30 (Val30Met) mutation, which was previously reported as the most-common TTR mutation worldwide and also the most common in the Japanese population, was not detected in the present South Korean patients. CONCLUSIONS: South Korean patients with hereditary TTR amyloidosis exhibited heterogeneous TTR genotypes and clinical phenotypes. The findings of this study suggest that the distribution of TTR amyloidosis in South Korea is due to de novo mutations and/or related to the other countries in East Asia.

Prognostic Significance of Left Axis Deviation in Acute Heart Failure Patients with Left Bundle branch block: an Analysis from the Korean Acute Heart Failure (KorAHF) Registry

BACKGROUND AND OBJECTIVES@#The prognostic impact of left axis deviation (LAD) on clinical outcomes in acute heart failure syndrome (AHFS) with left bundle branch block (LBBB) is unknown. The aim of this study was to determine the prognostic significance of axis deviation in acute heart failure patients with LBBB.@*METHODS@#Between March 2011 and February 2014, 292 consecutive AHFS patients with LBBB were recruited from 10 tertiary university hospitals. They were divided into groups with no LAD (n=189) or with LAD (n=103) groups according to QRS axis <−30 degree. The primary outcome was all-cause mortality.@*RESULTS@#The median follow-up duration was 24 months. On multivariate analysis, the rate of all-cause death did not significantly differ between the normal axis and LAD groups (39.7% vs. 46.6%, adjusted hazard ratio, 1.01; 95% confidence interval, 0.66, 1.53; p=0.97). However, on the multiple linear regression analysis to evaluate the predictors of the left ventricular ejection fraction (LVEF), presence of LAD significantly predicted a worse LVEF (adjusted beta, −3.25; 95% confidence interval, −5.82, −0.67; p=0.01). Right ventricle (RV) dilatation was defined as at least 2 of 3 electrocardiographic criteria (late R in lead aVR, low voltages in limb leads, and R/S ratio < 1 in lead V5) and was more frequent in the LAD group than in the normal axis group (p < 0.001).@*CONCLUSIONS@#Among the AHFS with LBBB patients, LAD did not predict mortality, but it could be used as a significant predictor of worse LVEF and RV dilatation (Trial registry at KorAHF registry, ClinicalTrial.gov, NCT01389843).

Prognostic Significance of Left Axis Deviation in Acute Heart Failure Patients with Left Bundle branch block: an Analysis from the Korean Acute Heart Failure (KorAHF) Registry

BACKGROUND AND OBJECTIVES: The prognostic impact of left axis deviation (LAD) on clinical outcomes in acute heart failure syndrome (AHFS) with left bundle branch block (LBBB) is unknown. The aim of this study was to determine the prognostic significance of axis deviation in acute heart failure patients with LBBB. METHODS: Between March 2011 and February 2014, 292 consecutive AHFS patients with LBBB were recruited from 10 tertiary university hospitals. They were divided into groups with no LAD (n=189) or with LAD (n=103) groups according to QRS axis < −30 degree. The primary outcome was all-cause mortality. RESULTS: The median follow-up duration was 24 months. On multivariate analysis, the rate of all-cause death did not significantly differ between the normal axis and LAD groups (39.7% vs. 46.6%, adjusted hazard ratio, 1.01; 95% confidence interval, 0.66, 1.53; p=0.97). However, on the multiple linear regression analysis to evaluate the predictors of the left ventricular ejection fraction (LVEF), presence of LAD significantly predicted a worse LVEF (adjusted beta, −3.25; 95% confidence interval, −5.82, −0.67; p=0.01). Right ventricle (RV) dilatation was defined as at least 2 of 3 electrocardiographic criteria (late R in lead aVR, low voltages in limb leads, and R/S ratio < 1 in lead V5) and was more frequent in the LAD group than in the normal axis group (p < 0.001). CONCLUSIONS: Among the AHFS with LBBB patients, LAD did not predict mortality, but it could be used as a significant predictor of worse LVEF and RV dilatation (Trial registry at KorAHF registry, ClinicalTrial.gov, NCT01389843).

Risk factors for poor prognosis in nosocomial infective endocarditis

BACKGROUND/AIMS@#The aim of our study was to compare the characteristics of nosocomial infective endocarditis (NIE) with community-acquired infective endocarditis (CIE) and to determine independent risk factors for in-hospital death.@*METHODS@#We retrospectively reviewed the medical records of 560 patients diagnosed with infective endocarditis. NIE was defined by a diagnosis made > 72 hours after hospital admission or within 2 months of hospital discharge.@*RESULTS@#Among the 560 cases reviewed, 121 were classified as NIE. Compared with patients with CIE, patients with NIE were older (mean ± SD, 51.30±18.01 vs. 59.76±14.87, p < 0.001). The in-hospital death rate of the NIE group was much higher than that of the CIE group (27.3% vs. 5.9%, p < 0.001). More patients with NIE had central intravenous catheters, and were undergoing hemodialysis (p < 0.001). Methicillin-resistant Staphylococcus aureus (MRSA) was the most common causal microorganism of NIE, and MRSA (p < 0.001) and fungus (p = 0.002) were more common in NIE compared with CIE. On multiple analysis, age, liver cirrhosis, cancer chemotherapy, central intravenous catheter, hemodialysis, and genitourinary tract manipulation were independent clinical risk factors for NIE. Among the patients with NIE, 33 died during their hospital admission. The independent risk factors for in-hospital death were older age (adjusted odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01 to 1.07; p = 0.037) and chemotherapy for malignancy (adjusted OR, 3.89; 95% CI, 1.18 to 12.87; p = 0.026).@*CONCLUSIONS@#Because of the considerable incidence of NIE and its poor prognosis, we should pay attention to early diagnosis and active management of NIE, especially for older patients and patients receiving chemotherapy.

Effects of Decreased Annular Height and Annular Saddle-Shaped Non-Planarity in Degenerative Severe Mitral Regurgitation with Normal Left Ventricular Ejection Fraction: Real-Time 3D Transesophageal Echocardiography

BACKGROUND: The extent of mitral annular (MA) remodeling and dysfunction is correlated with the severity of mitral regurgitation (MR) as well as left atrial (LA) and left ventricular (LV) dilation. MA dysfunction may be a useful prognostic factor for operative timing and MR recurrence after successful mitral valve (MV) repair. The aim of this study was to evaluate additive prognostic factors of MA non-planarity using real-time 3D transesophageal echocardiography (RT3D-TEE) analysis in patients with chronic severe MR and preserved LV systolic function. METHODS: Forty-seven patients with chronic severe MR and preserved LV systolic function scheduled for MV repair were prospectively enrolled. Echocardiographic studies were performed before surgery and postoperatively within 2 weeks and at least 6 months after surgery. RT3D-TEE was performed before the operation and immediately post-operative. RESULTS: Mean age was 55.4 ± 15.1 years and 24 were male. Annulus height/body surface area (BSA) obtained via RT3D-TEE was correlated with the degree of postoperative LA remodeling. Patients were divided into two groups by average baseline annulus height/BSA. Patients with normal annular height had a smaller postoperative LV end-diastolic dimension, LV end-systolic dimension and LA volume index than patients with decreased annular height. Preoperative annulus height/BSA values strongly predicted postoperative LA remodeling. CONCLUSION: MA height may be a useful prognostic factor for determining the timing of surgery in patients with chronic primary MR. Annulus height/BSA assessed via RT3D-TEE may provide additional information predictive of postoperative LA remodeling after successful MV repair.

Reversible Cerebral Vasoconstriction Syndrome after Heart Transplantation

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe headaches with or without other acute neurological symptoms, and diffuse segmental constriction of cerebral arteries that resolves spontaneously within 3 months. A 44-year-old woman underwent heart transplantation due to primary amyloidosis with heart involvement. She started to have a seizure after three hours after the heart transplantation, and her consciousness was not recovered. Computed tomography and transcranial doppler sonography were used to diagnose RCVS, and contracted vessels were recovered after oral nimodipine administration.

Association of ADRβ2 Haplotypes with Coronary Artery Disease in Korean Patients

BACKGROUND: Beta₂-adrenergic receptor (ADRβ2) gene variations seem to be correlated with disease progression, prognosis, and drug response to β-blockers in cardiovascular events. In this study, we investigated the genotypes and haplotypes of ADRβ2 in Korean patients and analysed their association with coronary artery disease (CAD). METHODS: One hundred five patients diagnosed with stable angina (SA), 109 patients with acute coronary syndrome (ACS), and 88 controls were enrolled. Five single nucleotide polymorphisms (SNPs) were determined at positions 46, 79, 252, 491, and 523 nucleotides, using the polymerase chain reaction and direct sequencing analysis. The haplotype reconstruction was carried out using genotype data, and analyses of the association between the genetic variation and CAD were performed. RESULTS: There were significant differences in the allele frequencies for the 79CG SNPs among the three groups. Relative to the control group, the distribution of 79CG genotypes was significantly different in both the SA group (P=0.0003) and the ACS group (P=0.0056). Compared with the CC genotype of 79CG, subjects with CG or GG had a higher risk of CAD (adjusted odds ratio [OR], 12.851; P=0.014). The frequencies of specific ACGCA, GCACC, and GGGCC haplotypes were 6.4% vs. 0%, 8.3% vs. 0%, and 6.9% vs. 0.6%, respectively, in the ACS group and controls. The GGGCC haplotype was significantly associated with CAD (adjusted OR, 12.266; P=0.016). CONCLUSIONS: Although there are large ethnic differences in the distribution of ADRβ2 SNPs and their association with CAD, the 79G polymorphism and GGGCC haplotype in ADRβ2 might specifically contribute to CAD pathogenesis in Korean patients.

Role of Soluble ST2 as a Marker for Rejection after Heart Transplant

BACKGROUND AND OBJECTIVES: Endomyocardial biopsy is obligatory during the first year after heart transplant (HTx) for the surveillance of acute rejection. Previous attempts using cardiac biomarkers for the detection of rejection failed to show enough evidence to substitute endomyocardial biopsy. Therefore, this study sought the possibility of using soluble ST2 (sST2), a novel cardiovascular marker, as a surrogate marker for acute allograft rejection after HTx. SUBJECTS AND METHODS: A total of 494 blood samples acquired at the time of endomyocardial biopsy were analyzed in 67 HTx cases from September 2006 to August 2014. Significant rejection was defined as International Society of Heart and Lung Transplant (ISHLT) score ≥2R and humoral rejection accompanied by hemodynamic instability. RESULTS: Twenty cases of HTx with 22 blood samples showed significant rejection in endomyocardial biopsy at 4.0 (2.0-9.0) months after HTx. The level of sST2 showed positive correlation with cardiac troponin I, and N-terminal pro-B-type natriuretic peptide (all p<0.001), and negative correlation with post-HTx months (p<0.001). The levels of sST2 according to the ISHLT scores were 36 (19-98), 28 (18-62), 15 (16-37), and 191 (85-343) ng/mL, consecutively 0R, 1R, 2R, and 3R+ (3R plus hemodynamically-unstable humoral rejection) (p=0.003). However, when we studied within-subject effects of sST2 using a mixed model, the sST2 level according to the predefined time point was not different according to the presence of significant rejection (p for interaction=0.94). CONCLUSION: Although sST2 is known as a promising predictor for cardiovascular events, its role in HTx patients to predict acute allograft rejection seems to be limited.

Heart Retransplantation to Treat a Case of Refractory Cardiac Allograft Vasculopathy / 대한내과학회지

Cardiac allograft vasculopathy is one of the most important causes of poor long-term survival after heart transplantation. The condition tends to be diffuse, usually affecting the mid-to-distal portions of the coronary artery. Reperfusion therapy is ineffective. Everolimus, an inhibitor of proliferation signaling, has been reported to prevent development of the condition; however, the efficacy thereof has not yet been fully accepted. The only definitive treatment for cardiac allograft vasculopathy is retransplantation. Herein, we describe the case of a 15-year-old boy who underwent heart retransplantation because of rapidly progressive cardiac allograft vasculopathy.

Clinical features and outcomes of systemic amyloidosis with gastrointestinal involvement: a single-center experience

BACKGROUND/AIMS: The gastrointestinal (GI) tract often becomes involved in patients with systemic amyloidosis. As few GI amyloidosis data have been reported, we describe the clinical features and outcomes of patients with pathologically proven GI amyloidosis. METHODS: We identified 155 patients diagnosed with systemic amyloidosis between April 1995 and April 2013. Twenty-four patients (15.5%) were diagnosed with GI amyloidosis using associated symptoms, and the diagnoses were confirmed by direct biopsy. RESULTS: Among the 24 patients, 20 (83.3%) had amyloidosis light chain (AL), three (12.5%) had amyloid A, and one (4.2%) had transthyretin-related type amyloidosis. Their median age was 57 years (range, 37 to 72), and 10 patients were female (41.7%). The most common symptoms of GI amyloidosis were diarrhea (11 patients, 45.8%), followed by anorexia (nine patients, 37.5%), weight loss, and nausea and/or vomiting (seven patients, 29.2%). The histologically confirmed GI tract site in AL amyloidosis was the stomach in 11 patients (55.0%), the colon in nine (45.0%), the rectum in seven (35.0%), and the small bowel in one (5.0%). Patients with GI involvement had a greater frequency of organ involvement (p = 0.014). Median overall survival (OS) in patients with GI involvement was shorter (7.95 months; range, 0.3 to 40.54) than in those without GI involvement (15.84 months; range, 0.0 to 114.53; p = 0.069) in a univariate analysis. A multivariate analysis of prognostic factors for AL amyloidosis revealed that GI involvement was not a significant predictor of OS (p = 0.447). CONCLUSIONS: The prognosis of patients with AL amyloidosis and GI involvement was poorer than those without GI involvement, and they presented with more organ involvement and more advanced disease than those without organ involvement.

Clinical Features of Right-Sided Infective Endocarditis Occurring in Non-Drug Users

Right-sided infective endocarditis (RIE) occurs predominantly in intravenous drug users in western countries, and it has a relatively good prognosis. Clinical features and prognosis of RIE occurring in non-drug users are not well known. We investigated the clinical findings of RIE in non-drug users. We retrospectively reviewed 345 cases diagnosed with IE. Cases with RIE or left-sided infective endocarditis (LIE) defined by the vegetation site were included and cases having no vegetation or both-side vegetation were excluded. Clinical findings and in-hospital outcome of RIE were compared to those of LIE. Among the 245 cases, 39 (16%) cases had RIE and 206 (84%) cases had LIE. RIE patients were younger (40+/-19 yr vs 50+/-18 yr, P=0.004), and had a higher incidence of congenital heart disease (CHD) (36% vs 13%, P<0.001) and central venous catheter (CVC) (21% vs 4%, P=0.001) compared to LIE patients. A large vegetation was more common in RIE (33% vs 9%, P<0.001). Staphylococcus aureus was the most common cause of RIE, while Streptococcus viridans were the most common cause of LIE. In-hospital mortality and cardiac surgery were not different between the two groups. CHD and use of CVC were common in non-drug users with RIE. The short-term clinical outcome of RIE is not different from that of LIE.

Percutaneous Suture-Based Closure Device for Management of Inadvertent Subclavian Artery Catheterization / 대한내과학회지

Central venous catheterization is performed to secure pathways for large amounts of saline, drug infusion, parenteral nutrition support, and hemodialysis. Accidental subclavian artery cannulation is a possible complication of central venous catheterization. Here, we report two cases of 8 Fr. chemoports inadvertently inserted in subclavian arteries during internal jugular venous catheterizations. The chemoports were removed successfully, and puncture sites were repaired using suture-based closure devices (Perclose). One patient experienced minor neurological complications after the procedure. With effective management, the patient was treated with no sequelae. To our knowledge, this is the first report of stroke after procedures using suture-based devices.

The Successful Implantation of Continuous-Flow Left Ventricular Assist Device as a Destination Therapy in Korea: Echocardiographic Assessment

Left ventricular assist device (LVAD) is a good treatment option for the patients ineligible for cardiac transplantation. Several studies have demonstrated that a ventricular assist device improves the quality of life and prognosis of the patients with end-stage heart failure. A 75-yr-old man debilitated with New York Heart Association (NYHA) functional class III-IV due to severe left ventricular systolic dysfunction received LVAD implantation as a destination therapy. The patient was discharged with improved functional status (NYHA functional class II) after appropriate cardiac rehabilitation and education about how to manage the device and potential emergency situations. This is the first case of successful continuous-flow LVAD implantation as a destination therapy in Korea.

Adjunctive Cilostazol versus High Maintenance Dose of Clopidogrel in Patients with Hyporesponsiveness to Chronic Clopidogrel Therapy

PURPOSE: Whether addition of cilostazol is superior to increasing dose of clopidogrel in patients with hyporesponsiveness to chronic clopidogrel therapy is unknown. MATERIALS AND METHODS: We studied 73 patients with hyporesponsiveness to clopidogrel on standard dual antiplatelet therapy for more than 2 weeks. Clopidogrel hyporesponsiveness was defined as percent inhibition of P2Y12 reaction units (PRU) <30% on VerifyNow P2Y12 assay. Patients were randomly assigned to increased dose of clopidogrel (aspirin 100 mg+clopidogrel 150 mg daily: group A, n=38) or to receiving additional cilostazol (aspirin 100 mg+clopidogrel 75 mg+cilostazol 100 mg bid daily: group B, n=35). RESULTS: Baseline percent inhibition of PRU and PRU was similar between 2 groups (13.0+/-10.2% versus 11.8+/-9.7%, p=0.61, and 286.3+/-54.7 versus 295.7+/-53.7, p=0.44, respectively). At follow-up, percent inhibition of PRU was higher and PRU was lower significantly in group B than in group A (38.5+/-17.9% versus 28.3+/-16.6%, p=0.02, and 207.3+/-68.2 versus 241.3+/-76.7, p=0.050, respectively). Among those still showing hyporesponsiveness to clopidogrel at follow-up (21 patients in group A, 10 patients in group B), 12 patients completed further crossover study. Compared to the baseline, magnitude of change in percent inhibition of PRU and PRU showed an improved tendency after the crossover (from 2.7+/-8.7% to 15.8+/-18.4%, p=0.08, and from -18.6+/-58.0 to -61.9+/-84.3, p=0.08). CONCLUSION: Adjunctive cilostazol improved clopidogrel responsiveness better than the higher maintenance dose of clopidogrel in hyporesponsive patients with chronic clopidogrel therapy.

Cardiac Amyloidosis Determines the Prognosis of Systemic Amyloidosis; Roles and Responsibilities of Cardiologist

No abstract available.

Acute Recurrent Pericarditis Accompanied by Graves' Disease

The etiology of acute pericarditis is often thought to be autoimmune, and Graves' disease has been reported in a few series to manifest as acute pericarditis. Since the etiology of recurrent pericarditis is known to be more associated with autoimmune causes, recurrent acute pericarditis may be a potential cardiovascular complication of Graves' disease. We report a case of recurrent acute pericarditis that was presumed to be associated with Graves' disease which was controlled after management of the problem of the thyroid.

A Case of Swallow Syncope Associated With Cold Beverage Ingestion

Swallow syncope (also known as deglutition syncope) is a relatively rare type of syncope that is treatable if diagnosed correctly. We report a case of a 39-year-old man with recurrent swallow syncope. The patient did not have structural heart disease. He developed a complete atrioventricular block upon drinking a cold beverage (Chilsung cider) while undergoing a repeated head-up tilt test. The patient was advised to avoid cold beverages and has been symptom free for 5 months.

A Case of Pulmonary Alveolar Proteinosis that Improved with GM-CSF Inhalation Therapy / 대한내과학회지

Pulmonary alveolar proteinosis (PAP) is a rare condition that is treated using whole lung lavage. A recent study suggested that granulocyte-macrophage colony stimulating factor (GM-CSF) plays roles in both the pathogenesis and treatment of PAP. We present a 69-year-old man with PAP who deteriorated despite bilateral whole lung lavage; that said, his symptoms, chest X-ray findings, and pulmonary function test improved after GM-CSF inhalation therapy over 12 months. GM-CSF therapy is an effective treatment modality for PAP.