Validation of the Framingham General Cardiovascular Risk Score and Pooled Cohort Equations in a Community-Based Population: A Prospective Cohort Study Analysis 2006-2017.

Background: The 10-year atherosclerotic cardiovascular disease (ASCVD) risk - as assessed using the Framingham general cardiovascular risk score (FRS-CVD) or pooled cohort equations (PCE) - is commonly used in Western cohorts for the primary prevention of cardiovascular disease (CVD). However, the FRS-CVD and PCE have not been validated in Taiwanese cohorts. Objectives: We aimed to validate the FRS-CVD and PCE for assessing the 10-year ASCVD risk using a Taiwanese community-based population. Methods: We extracted patient data from the Landseed Integrated Outreaching Neighborhood Screening registry, a community-based prospective cohort study established in 2006. Cardiovascular events from 2006 to 2017 were determined from electronic medical records. The discriminative power and calibration of the FRS-CVD and PCE were evaluated. Results: Overall, 5,139 subjects were analyzed; the 10-year follow-up rate was 99.6%. The mean age at baseline was 52.8 ± 13.1 years, and 44.6% of the subjects were male. In total, 430 of 4,631 (9.3%) and 227 of 4,022 (5.6%) of the FRS-CVD- and PCE-like cohorts, respectively, had ASCVD events. The calibration χ2 of the FRS-CVD was 7.0267 (p = 0.6343) in males and 7.8845 (p = 0.5458) in females; the χ2 of PCE was 13.007 (p = 0.1623) in males and 38.785 (p < 0.001) in females. The area under the receiver operating characteristic curve (AUROC) of the FRS-CVD was 0.76 (0.72-0.79) in males and 0.71 (0.67-0.74) in females; the AUROC of PCE was 0.68 (0.62-0.73) in males and 0.61 (0.56-0.67) in females. Conclusions: Except for PCE in females, the FRS-CVD and PCE provided good calibration and modest discrimination in statin-naïve Taiwanese individuals without prior CVD.

Association between corrected QT interval and long-term cardiovascular outcomes in elderly patients who had undergone endovascular therapy for lower extremity arterial disease.

Background: Population-based studies have reported the association between prolonged corrected QT (QTc) intervals and an increased risk of adverse cardiovascular events. Data regarding the association between longer QTc intervals and incident cardiovascular outcomes in patients with lower extremity arterial disease (LEAD) are scarce. Objective: To examine the impact of QTc interval on long-term cardiovascular outcomes in elderly patients with symptomatic LEAD. Methods: This cohort study extracted data from the Tzu-chi Registry of ENDovascular Intervention for Peripheral Artery Disease (TRENDPAD) and enrolled 504 patients aged ≥ 70 treated with endovascular therapy for atherosclerotic LEAD from July 1, 2005, to December 31, 2019. The main outcomes of interest were all-cause mortality and major adverse cardiovascular events (MACE). Multivariate analysis was conducted using the Cox proportional hazard model to determine independent variables. We performed interaction analysis between corrected QT and other covariates and Kaplan-Meier analysis to compare the outcome of interest among the groups stratified by the tercile of QTc intervals. Results: A total of 504 patients [235 men (46.6%); mean age, 79.9 ± 6.2 years; mean QTc interval, 459 ± 33 msec] entered the final data analysis. We categorized the baseline patient characteristics according to terciles of QTc intervals. During the median follow-up time of 3.15 (interquartile ranges, 1.65-5.42) years, we noted 264 deaths and 145 MACEs. The 5-year rates of freedom from all-cause mortality (71% vs. 57% vs. 31%, P < 0.001) and MACEs (83% vs. 67% vs. 46%, P < 0.001) were significantly different among the tercile groups. Multivariate analysis showed that a 1-SD increase in the QTc interval increased the risk of all-cause mortality [hazard ratio (HR) 1.49, P < 0.001] and MACEs (HR 1.59, P < 0.001) after adjusting for other covariates. The interaction analysis showed that QTc interval and C-reactive protein levels were most strongly associated with death (HR = 4.88, 95% CI 3.09-7.73, interaction P < 0.001) and MACEs (HR = 7.83, 95% CI 4.14-14.79, interaction P < 0.001). Conclusions: In elderly patients with symptomatic atherosclerotic LEAD, a prolonged QTc interval is associated with advanced limb ischemia, multiple medical comorbidities, increased risk of MACEs, and all-cause mortality.

Repetition of Paclitaxel-Coated Devices for the Treatment of Lower Extremity Artery Disease: Mortality Outcomes and Predictors.

Background: A recent meta-analysis reported late excess mortality in patients treated with paclitaxel-coated devices (PCDs) for symptomatic femoropopliteal disease. However, this finding is controversial. Objectives: To investigate the impact on mortality and predictors of repeat exposure to PCDs in patients with lower extremity peripheral arterial disease (LE-PAD). Methods: We analyzed registry patient-level data from two centers. A total of 214 patients were enrolled, and stratified based on terciles of cumulative dose of paclitaxel. We treated 134 patients with a single PCD exposure and 80 with multiple PCD exposures. We used the follow-up index (FUI) in Kaplan-Meier survival estimates to minimize potential selection bias. We used Cox proportional hazard and splines models to determine the predictors of mortality and assess their relationships with mortality. Results: The mean cumulative dose of paclitaxel was significantly different among groups (6.40 mg vs. 15.06 mg vs. 38.57 mg, p < 0.001). The 5-year FUI (0.93 ± 0.19 vs. 0.94 ± 0.18 vs. 0.95 ± 0.15, p = 0.836) and survival rates were not different (65.4% vs. 51.9% vs. 72.0%, p = 0.148). There was no dose-response association between paclitaxel dosage and death (p = 0.297). The predictors of death were congestive heart failure, stroke, dialysis dependence, neutrophil-lymphocyte ratio (NLR) > 3, age > 71 years, and body mass index (BMI) < 20 kg/m2. Spline model analysis validated the non-linear associations between mortality, age, BMI, and NLR. Conclusions: Repeated PCD exposure for LE-PAD did not result in excess late mortality. Predictors of mortality might change over time, and continuous variables had non-linear relationships with death.

Targeting the Phosphatidylserine-Immune Checkpoint with a Small-Molecule Maytansinoid Conjugate.

Ligand-targeting drug delivery systems have made significant strides for disease treatments with numerous clinical approvals in this era of precision medicine. Herein, we report a class of small molecule-based immune checkpoint-targeting maytansinoid conjugates. From the ligand targeting ability, pharmacokinetics profiling, in vivo anti-pancreatic cancer, triple-negative breast cancer, and sorafenib-resistant liver cancer efficacies with quantitative mRNA analysis of treated-tumor tissues, we demonstrated that conjugate 40a not only induced lasting regression of tumor growth, but it also rejuvenated the once immunosuppressive tumor microenvironment to an "inflamed hot tumor" with significant elevation of gene expressions that were not accessible in the vehicle-treated tumor. In turn, the immune checkpoint-targeting small molecule drug conjugate from this work represents a new pharmacodelivery strategy that can be expanded with combination therapy with existing immune-oncology treatment options.

Synthesis and Evaluation of Small Molecule Drug Conjugates Harnessing Thioester-Linked Maytansinoids.

Ligand-targeting drug conjugates are a class of clinically validated biopharmaceutical drugs constructed by conjugating cytotoxic drugs with specific disease antigen targeting ligands through appropriate linkers. The integrated linker-drug motif embedded within such a system can prevent the premature release during systemic circulation, thereby allowing the targeting ligand to engage with the disease antigen and selective accumulation. We have designed and synthesized new thioester-linked maytansinoid conjugates. By performing in vitro cytotoxicity, targeting ligand binding assay, and in vivo pharmacokinetic studies, we investigated the utility of this new linker-drug moiety in the small molecule drug conjugate (SMDC) system. In particular, we conjugated the thioester-linked maytansinoids to the phosphatidylserine-targeting small molecule zinc dipicolylamine and showed that Zn8_DM1 induced tumor regression in the HCC1806 triple-negative breast cancer xenograft model. Moreover, in a spontaneous sorafenib-resistant liver cancer model, Zn8_DM1 exhibited potent antitumor growth efficacy. From quantitative mRNA analysis of Zn8_DM1 treated-tumor tissues, we observed the elevation of gene expressions associated with a "hot inflamed tumor" state. With the identification and validation of a plethora of cancer-associated antigens in the "omics" era, this work provided the insight that antibody- or small molecule-based targeting ligands can be conjugated similarly to generate new ligand-targeting drug conjugates.

Rejuvenating hepatic tumor microenvironment immunity with a phosphatidylserine-targeting small molecule drug conjugate.

We report the design, synthesis and evaluation of a class of phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates and show that conjugate 16b elicits immune cell infiltration and remodels the "cold" hepatic tumor microenvironment to the inflamed "hot" tumor. Structure-property relationship study via linker modifications and subsequent pharmacokinetics profiling were carried out to improve the solubility and stability of the conjugates in vivo. In a spontaneous hepatocellular carcinoma mouse model, we showed that conjugate 16b exhibited better antitumor efficacy than sorafenib. In particular, significant increase of CD8+ T cell infiltration and granzyme B level was observed, providing insights in sensitizing tumors from intrinsic immune suppressive microenvironment. Evaluation of tumor inflammation-related mRNA expression profile revealed that conjugate 16b, through inductions of key gene expressions including STAT1, CXCL9, CCL5, and PD-L1, rejuvenated tumor microenvironment with enhancement in T cell-, macrophage-, NK cell-, chemokines and cytokines'- functions. Our study establishes that an apoptosis-targeting theranostic enables enrichment of multifaceted immune cells into the tumor mass, which provides potential therapeutic strategies in the combination with immune checkpoint blockade treatment.

Clinical Outcomes of Dialysis Patients Treated with Drug-Eluting Stent for Left Main Distal Bifurcation Lesions.

AIMS: We assessed clinical outcomes after percutaneous coronary intervention (PCI) for unprotected left main coronary artery (ULMCA) distal bifurcation lesions using drug-eluting stents (DES) in hemodialysis (HD) patients compared to non-HD patients. METHODS AND RESULTS: We identified 1,858 consecutive patients who underwent PCI for ULMCA distal bifurcation lesions at 4 high-volume centers in Japan, Italy, and Taiwan between January 2005 and December 2015. Of them, 1,416 patients were treated with DES including 113 HD patients and 1,303 non-HD patients. The primary end point was target lesion failure (TLF) defined as a composite of cardiac death, target lesion revascularization (TLR), and myocardial infarction. HD patients were more likely to be younger and have diabetes mellitus, dyslipidemia, peripheral artery disease, lower ejection fraction, and higher EuroSCORE. TLF rate at 3 years was significantly higher in HD group than in non-HD group (adjusted hazard ratio [HR] 2.43 [1.75-3.38], p < 0.001). Cardiac mortality and TLR rate were also significantly higher in HD group than in non-HD group (adjusted HR 3.85 [2.34-6.34], p < 0.001, and HR 2.10 [1.41-3.14], p < 0.001, respectively). CONCLUSIONS: HD was strongly associated with adverse cardiac events after PCI for ULMCA distal bifurcation lesions with DES.

Linker Optimization and Therapeutic Evaluation of Phosphatidylserine-Targeting Zinc Dipicolylamine-based Drug Conjugates.

We report that compound 13, a novel phosphatidylserine-targeting zinc(II) dipicolylamine drug conjugate, readily triggers a positive feedback therapeutic loop through the in situ generation of phosphatidylserine in the tumor microenvironment. Linker modifications, pharmacokinetics profiling, in vivo antitumor studies, and micro-Western array of treated-tumor tissues were employed to show that this class of conjugates induced regeneration of apoptotic signals, which facilitated subsequent recruitment of the circulating conjugates through the zinc(II) dipicolylamine-phosphatidylserine association and resulted in compounding antitumor efficacy. Compared to the marketed compound 17, compound 13 not only induced regressions in colorectal and pancreatic tumor models, it also exhibited at least 5-fold enhancement in antitumor efficacy with only 40% of the drug employed during treatment, culminating in a >12.5-fold increase in therapeutic potential. Our study discloses a chemically distinct apoptosis-targeting theranostic, with built-in complementary functional moieties between the targeting module and the drug mechanism to expand the arsenal of antitumor therapy.

Targeting Tumor Associated Phosphatidylserine with New Zinc Dipicolylamine-Based Drug Conjugates.

A series of zinc(II) dipicolylamine (ZnDPA)-based drug conjugates have been synthesized to probe the potential of phosphatidylserine (PS) as a new antigen for small molecule drug conjugate (SMDC) development. Using in vitro cytotoxicity and plasma stability studies, PS-binding assay, in vivo pharmacokinetic studies, and maximum tolerated dose profiles, we provided a roadmap and the key parameters required for the development of the ZnDPA based drug conjugate. In particular, conjugate 24 induced tumor regression in the COLO 205 xenograft model and exhibited a more potent antitumor effect with a 70% reduction of cytotoxic payload compared to that of the marketed irinotecan when dosed at the same regimen. In addition to the validation of PS as an effective pharmacodelivery target for SMDC, our work also provided the foundation that, if applicable, a variety of therapeutic agents could be conjugated in the same manner to treat other PS-associated diseases.

Worse Prognosis in Heart Failure Patients with 30-Day Readmission.

BACKGROUND: Heart failure (HF) readmission results in substantial expenditure on HF management. This study aimed to evaluate the readmission rate, outcome, and predictors of HF readmission. METHODS: Patients with reduced left ventricular ejection fraction (LVEF < 40%) who were admitted for acute decompensation of de novo HF were enrolled to analyze readmission rate, mortality and predictors of readmission. RESULTS: A total of 433 de novo HF patients with LVEF < 40% were enrolled during the period August 2013 to December 2014. The in-hospital and 6-month mortality rates were 3.9% and 15.2%, respectively. In those patients surviving the index HF hospitalization, the 30-day and 6-month readmission rates were 10.9% and 27%, respectively. At the end of the 6-month follow-up, the readmission group had higher mortality than the non-readmission group (27.66% vs. 10.36%; p = 0.001). The survivors of the 30-day readmission had similar mortality rates at 6 months, regardless of the cause of readmission (cardiovascular vs. non-cardiovascular: 25% vs. 30.43%, p = 0.677). Among all the parameters, prescription of beta blockers independently reduced the risk of 30-day readmission (odds ratio 0.15; 95% confidence interval 0.02-0.99; p = 0.049). CONCLUSIONS: Those HF patients who suffered from 30-day readmission had worse prognosis at the 6-month follow-up. Regardless of the readmission causes, the patients surviving the 30-day readmission had similar mortality rates at 6-month follow-up. These results underscored the importance of reducing readmission as a means to improve HF outcome.

Erectile Dysfunction Is Not a Predictor of Atrial Fibrillation: A Population-Based Propensity-Score Matched Cohort Study.

INTRODUCTION: Erectile dysfunction (ED) has been regarded a marker of cardiovascular diseases. Nevertheless, the association between ED and incident atrial fibrillation (AF) remains unknown. AIM: To determine the association between ED and incident AF. METHODS: This population-based cohort study was conducted using the National Health Insurance Research Database in Taiwan. In total, 6,273 of patients with ED without a prior diagnosis of AF were enrolled from January 1, 2001 through December 31, 2009, and a propensity-score matching method was used to identify 3,516 patients in the ED and control groups. MAIN OUTCOME MEASURES: Newly incident AF at follow-up was recorded as the end point. RESULTS: The mean age of the study population was 40.0 ± 17.1 years, and the follow-up period was 8.0 ± 0.5 years. Compared with the control group, patients with ED were older and had more of the following comorbidities: D'Hoore Charlson Comorbidity Index, hypertension, congestive heart failure, diabetes mellitus, dyslipidemia, chronic kidney disease, coronary artery disease, stroke, chronic lung disease, major depression disorder, obstructive sleep apnea, and hyperthyroidism. After adjusting for confounders, the ED group was not associated with more incident AF compared with the control group (hazard ratio = 1.031, 95% confidence interval = 0.674-1.578, P =.888). In these patients, ED of an organic origin was associated with a trend of having AF more often compared with ED of a psychosexual type (P =.272 by log-rank test). CONCLUSION: Although ED is known as a predictor of atherosclerotic cardiovascular diseases, it is not independently associated with incident AF in men.

Comparative Molecular Characteristics of Community-Associated and Healthcare-Associated Methicillin-Resistant Staphylococcus aureus Isolates From Adult Patients in Northern Taiwan.

Methicillin-resistant Staphylococcus aureus (MRSA) is an important nosocomial pathogen in hospitals, and increases rapidly in the community, named as community-associated MRSA (CA-MRSA). We conducted a prospective/retrospective study to understand the epidemiology, antimicrobial susceptibility, and molecular characteristics of MRSA infections in adult patients in Taiwan.From March to June, 2012, all clinical MRSA isolates were prospectively collected from adult patients in a tertiary hospital in northern Taiwan. Selective isolates were further characterized. We reviewed the detailed medical record of each case retrospectively.A total of 857 clinical isolates were collected from 555 patients. A total of 749 isolates from 453 patients were classified as healthcare-associated (HA)-MRSA and 108 isolates from 102 patients as CA-MRSA by the epidemiologic criteria. Compared to HA-MRSA, CA-MRSA isolates were significantly more frequently identified from pus (78% vs 28%, P < 0.001) and less frequently from sputum (4.6% vs 43.8%, P < 0.001) and blood (3.7% vs 15%, P = 0.002). CA-MRSA isolates were more susceptible to all antibiotics tested. A total of 102 CA-MRSA and 101 HA-MRSA isolates were characterized, showing significantly different molecular characteristics between CA and HA isolates (P < 0.001). The clone of sequence type (ST) 59/t437 complex, with 2 pulsotypes, accounted for 70% of CA isolates. Three major clones were identified from HA-MRSA isolates, namely clonal complex (CC) 59 (32.7%), CC239 (29.7%), and CC5 (24.8%). Among HA isolates, a significant difference was also seen between community-onset and hospital-onset MRSA isolates in terms of the source of specimens, antibiotic susceptibility patterns, and molecular characteristics.CA-MRSA isolates from adults in northern Taiwan were genetically significantly different from HA isolates. The community clones, CC59, spread into hospitals.

Plasma angiopoietin-1 level, left ventricular ejection fraction, and multivessel disease predict development of 1-year major adverse cardiovascular events in patients with acute ST elevation myocardial infarction - a pilot study.

OBJECTIVES: Patients with acute myocardial infarction (AMI) are frequently complicated with major cardiovascular events (MACEs). Endothelial dysfunction has been found to be involved in pathogenesis of AMI, but its role in development of MACEs after AMI is not clearly investigated. This study aimed to determine whether the plasma markers of endothelial dysfunction could serve as independent predictors for MACEs in patients with AMI. METHODS: This prospective study was conducted from March 2010 to July 2012 and enrolled consecutive 132 patients with acute ST elevation myocardial infarction (STEMI) receiving primary percutaneous coronary intervention (PCI). Plasma levels of thrombomodulin (TM), von Willebrand factor (vWF), angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) were measured on day 1 of AMI. The development of MACEs at 1-year follow-up was recorded. RESULT: Patients with STEMI who developed MACEs had increased heart rate on admission (86±24 vs. 74±20bpm, p=0.006), lower left ventricular ejection fraction (LVEF) (49.0±12.4 vs. 57.2±12.4%, p=0.002), and higher incidence of multivessel disease (66.7% vs. 42.2%, p=0.018) comparing with those without MACEs. Plasma level of Ang-1 was lower in patients with MACEs than in those without (21,165±16,281 vs. 31,411±21,593pg/mL, p=0.018). In multivariate analysis, Ang-1 level

Elevated plasma thrombomodulin and angiopoietin-2 predict the development of acute kidney injury in patients with acute myocardial infarction.

INTRODUCTION: Acute kidney injury (AKI) following acute myocardial infarction (AMI) is associated with unfavorable prognosis. Endothelial activation and injury were found to play a critical role in the development of both AKI and AMI. This pilot study aimed to determine whether the plasma markers of endothelial injury and activation could serve as independent predictors for AKI in patients with AMI. METHODS: This prospective study was conducted from March 2010 to July 2012 and enrolled consecutive 132 patients with AMI receiving percutaneous coronary intervention (PCI). Plasma levels of thrombomodulin (TM), von Willebrand factor (vWF), angiopoietin (Ang)-1, Ang-2, Tie-2, and vascular endothelial growth factor (VEGF) were measured on day 1 of AMI. AKI was defined as elevation of serum creatinine of more than 0.3 mg/dL within 48 hours. RESULTS: In total, 13 out of 132 (9.8%) patients with AMI developed AKI within 48 hours. Compared with patients without AKI, patients with AKI had increased plasma levels of Ang-2 (6338.28 ± 5862.77 versus 2412.03 ± 1256.58 pg/mL, P = 0.033) and sTM (7.6 ± 2.26 versus 5.34 ± 2.0 ng/mL, P < 0.001), and lower estimated glomerular filtration rate (eGFR) (46.5 ± 20.2 versus 92.5 ± 25.5 mL/min/1.73 m2, P < 0.001). Furthermore, the areas under the receiver operating curves demonstrated that plasma thrombomodulin (TM) and Ang-2 levels on day 1 of AMI had modest discriminative powers for predicting AKI development following AMI (0.796, P <0.001; 0.833, P <0.001; respectively). CONCLUSIONS: Endothelial activation, quantified by plasma levels of TM and Ang-2 may play an important role in development of AKI in patients with AMI.