Modulators of Mortality Benefit From Peri-Angioplasty Adjunctive Tirofiban in Patients With ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

BACKGROUND: Studies investigating the modulators of mortality benefit conferred by peri-angioplasty glycoprotein IIb/IIIa inhibitors in ST-elevation myocardial infarction (STEMI) are still lacking.Methods and Results:A prospective database (n=1,025) of consecutive cases undergoing primary percutaneous coronary intervention for STEMI was retrospectively analyzed. For patients in Killip class I, II or III, IV, the multivariate-adjusted hazard ratios of 30-day all-cause mortality associated with adjunctive tirofiban were 3.873 (95% CI 0.504-29.745; P=0.193), 0.550 (95% CI 0.188-1.609; P=0.275), and 0.264 (95% CI 0.099-0.704; P=0.008), respectively. The P value for a linear trend was 0.032. Patients who had a body mass index (BMI) within 22.9-25.0 kg/m2had a significant benefit from tirofiban (adjusted HR 0.344; 95% CI 0.145-0.814; P=0.015) compared to other BMI groups. The P value for a quadratic trend was 0.012. A novel Killip-BMI score (KBS = 2.5 × Killip category - | BMI - 24 |) was calculated to select the beneficial population. A KBS ≥2 was associated with significant mortality benefit, whereas a KBS <0 predicted increased 30-day mortality with tirofiban use. CONCLUSIONS: Survival benefit from peri-angioplasty tirofiban therapy for STEMI was positively correlated with the Killip class. Tirofiban should be used cautiously in either underweight or overweight patients. The novel KBS used in this study can guide peri-angioplasty use of adjunctive tirofiban in patients with STEMI undergoing primary angioplasty.

Extracellular matrix protein laminin enhances mesenchymal stem cell (MSC) paracrine function through αvß3/CD61 integrin to reduce cardiomyocyte apoptosis.

Myocardial ischaemia (MI) results in extensive cardiomyocyte death and reactive oxygen species (ROS)-induced damage in an organ with little or no regenerative capacity. Although the use of adult bone marrow mesenchymal stem cells (BMMSCs) has been proposed as a treatment option, the high cell numbers required for clinical use are difficult to achieve with this source of MSCs, and animal studies have produced inconsistent data. We recently demonstrated in small and large animal models of acute MI that the application of human term placenta-derived multipotent cells (PDMCs), a foetal-stage MSC, resulted in reversal of cardiac injury with therapeutic efficacy. However, the mechanisms involved are unclear, making it difficult to strategize for therapeutic improvements. We found that PDMCs significantly reduced cardiomyocyte apoptosis and ROS production through the paracrine factors GRO-α, HGF and IL-8. Moreover, culturing PDMCs on plates coated with laminin, an extracellular matrix (ECM) protein, resulted in significantly enhanced secretion of all three paracrine factors, which further reduced cardiomyocyte apoptosis. The enhancement of PDMC paracrine function by laminin was mediated through αvß3 integrin, with involvement of the signalling pathways of JNK, for GRO-α and IL-8 secretion, and PI3K/AKT, for HGF secretion. Our results demonstrated the utility of PDMC therapy to reduce cardiomyocyte apoptosis through modulation of ECM proteins in in vitro culture systems as a strategy to enhance the therapeutic functions of stem cells.

Epidemiology of appendicitis and appendectomy for the low-income population in Taiwan, 2003-2011.

BACKGROUND: Although numerous epidemiological studies on appendicitis have been conducted worldwide, only a few studies have paid attention to the effect of socioeconomic status on appendicitis, particularly studies focusing on the low-income population (LIP). METHODS: We analyzed the epidemiological features of appendicitis in Taiwan using data from the National Health Insurance Research Database from 2003 to 2011. All cases diagnosed as appendicitis were enrolled. RESULTS: Between 2003 and 2011, 2,916 patients from the LIP and 209,206 patients from the normal population (NP) were diagnosed with appendicitis. Our finding revealed that the ratios of comorbidities, complicated appendicitis, and readmissions in LIP patients were slightly higher than those of NP patients. LIP patients were more likely to live in suburban and rural areas, and hence a higher proportion of them were hospitalized in a district or regional hospital compared with NP patients. The crucially finding was that the overall incidence ratios of appendicitis, acute appendicitis, and perforated appendicitis in the LIP were substantially higher than those in the NP (36.25%, 35.33%, and 37.28%, respectively). The mean LOS in LIP patients was longer than that of NP patients. The overall case-fatality ratio of appendectomy in the LIP was higher when compared with the NP (0.41% versus 0.12%, p < 0.05). We also observed that appendicitis was occurred frequently in male patients, with a higher incidence for those aged 15-29 years in both the LIP and NP. The incidences of incidental appendectomy showed a decreasing trend in both the LIP and NP. Finally, a valuable discovery was that the total hospital cost was comparable between the laparoscopic appendectomy (LA) and open appendectomy (OA) (1,178 ± 13 USD versus 1,191 ± 19 USD, p < 0.05) in LIP patients because they saved more hospitalization costs than NP patients when the previous one chose the LA. CONCLUSION: This study confirmed that a lower socioeconomic status has significantly negative impact on the occurrence and treatment of appendicitis and appendectomy. In terms of hospital costs and LOS, LIP patients benefit more from the LA approach than they do from the OA approach in the treatment of appendicitis.

Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury.

Fibrosis of the peritoneal cavity remains a serious, life-threatening problem in the treatment of kidney failure with peritoneal dialysis. The mechanism of fibrosis remains unclear partly because the fibrogenic cells have not been identified with certainty. Recent studies have proposed mesothelial cells to be an important source of myofibroblasts through the epithelial-mesenchymal transition; however, confirmatory studies in vivo are lacking. Here, we show by inducible genetic fate mapping that type I collagen-producing submesothelial fibroblasts are specific progenitors of α-smooth muscle actin-positive myofibroblasts that accumulate progressively in models of peritoneal fibrosis induced by sodium hypochlorite, hyperglycemic dialysis solutions, or TGF-ß1. Similar genetic mapping of Wilms' tumor-1-positive mesothelial cells indicated that peritoneal membrane disruption is repaired and replaced by surviving mesothelial cells in peritoneal injury, and not by submesothelial fibroblasts. Although primary cultures of mesothelial cells or submesothelial fibroblasts each expressed α-smooth muscle actin under the influence of TGF-ß1, only submesothelial fibroblasts expressed α-smooth muscle actin after induction of peritoneal fibrosis in mice. Furthermore, pharmacologic inhibition of the PDGF receptor, which is expressed by submesothelial fibroblasts but not mesothelial cells, attenuated the peritoneal fibrosis but not the remesothelialization induced by hypochlorite. Thus, our data identify distinctive fates for injured mesothelial cells and submesothelial fibroblasts during peritoneal injury and fibrosis.

Detection of asymptomatic paroxysmal atrial fibrillation with the trans-telephonic electrocardiograph system.

Paroxysmal atrial fibrillation (PAF) carries an equally high annual stroke rate as chronic atrial fibrillation (AF). Furthermore, the frequency and duration of PAF are thought to be associated with stroke risk. In this pilot study, a trans-telephonic electrocardiograph (TTE) monitoring system was used to detect asymptomatic PAF and to study the relationship between ischemic stroke and the frequency of PAF. Between December 2004 and April 2006, 70 patients enrolled in the TTE monitoring program. Patients either transmitted electrocardiograms (ECGs) daily or upon experiencing cardiac symptoms. Of the 70 patients included, 25 were diagnosed with PAF. In total, 11% (855/7,768) of the recordings were diagnosed as PAF, yet less than 2% of total calls collected and less than 17% of all the calls with PAF were associated with obvious symptoms. Four patients developed five ischemic strokes resulting in a calculated annual stroke rate of 0.56%. Patients with stroke had more episodes of AF (56.5±106.3 versus 6.7±85.9, p=0.685) and symptomatic AF episodes (9.8±17.5 versus 4.9±8.1, p=0.381) than the patients who did not have a stroke, but the differences were not statistically significant because of the low numbers of patients and episodes. Most PAF episodes were asymptomatic, and the TTE system could easily detect these episodes. Furthermore, these four patients tended to have more episodes of PAF and more symptomatic attacks of PAF than patients who did not have a stroke.

Case report: Stereotactic body radiation therapy with 12 Gy for silencing refractory ventricular tachycardia.

Background: Encouraging results have been reported for the treatment of ventricular tachycardia (VT) with stereotactic body radiation therapy (SBRT) with 25 Gy. SBRT with 12 Gy for refractory VT was designed to reduce long-term cardiac toxicity. Methods: Stereotactic body radiation therapy-VT simulation, planning, and treatment were performed using standard techniques. A patient was treated with a marginal dose of 12 Gy in a single fraction to the planning target volume (PTV). The goal was for at least ≥ 95% of the PTV to be covered by at least 95% of 12 Gy radiation. Results: From April 2021 through June 2022, a patient with refractory VT underwent treatment. The volume for PTV was 65.8 cm3. The mean radiation dose administered to the heart (the heart volume excluding the PTV) was 2.2 Gy. No acute or late toxicity was observed after SBRT. Six months after SBRT, the patient experienced new monomorphic right ventricular outflow tract (RVOT) VT. Interestingly, the substrate of the left ventricular basal to middle posteroseptal wall before SBRT was turned into scar zones with a local voltage < 0.5 mV. Catheter ablation to treat RVOT VT was performed, and the situation remains stable to date. Conclusion: This study reports the first patient with refractory VT successfully treated with 12.0 Gy SBRT, suggesting that 12 Gy is a potential dose to treat refractory VT. Further investigations and enrollment of more patients are warranted to assess the long-term efficacy and side effects of this treatment.

Cardiovascular Stem Cells in Regenerative Medicine: Ready for Prime Time?

Restoration of cardiovascular function is the ultimate goal of stem cell-based therapy. In principle, cardiovascular stem cells can improve cardiac function via de novo cardiomyogenesis, enhanced myocardial neovascularization, and prevention of post-infarct remodeling. Stem cell transplantation to improve cardiac function has received mixed results in human clinical trials. These early data suggest that a critical reassessment of the scientific basis to stem cell-based therapy is needed in order to bring this highly promising treatment modality to mainstream clinical care.

Using multiple buddy wires to facilitate left ventricular lead advancement in cardiac resynchronization therapy.

Left ventricular lead positioning is always the critical step in cardiac resynchronization therapy because of the complex anatomy of coronary sinus branches. We describe the case of a 46-year-old man with dilated cardiomyopathy and complete left bundle branch block presenting with heart failure. The placing of the left ventricular lead into the posterolateral branch was hampered by an angulated portion at the proximal branch even with the assistance of anchor wire technique and one to two additional parallel wires' support. The use of three buddy wires facilitated the advancement of the left ventricular lead.

Relationship of serum uric acid and Killip class on mortality after acute ST-segment elevation myocardial infarction and primary percutaneous coronary intervention.

BACKGROUND: There is conflicting information regarding the association between hyperuricemia and survival in STEMI patients. Our study examined the interaction between hyperuricemia and Killip class on mortality of STEMI patients. METHODS: We analyzed 951 consecutive STEMI patients between February 2006 and September 2012. Hyperuricemia was defined as SUA of at least 7mg/dL in males and 6mg/dL in females. Killip class I patients were divided into hyperuricemia and normouricemia groups. RESULTS: The Killip class I hyperuricemia and normouricemia groups had similar baseline and procedural characteristics, but the hyperuricemia group had significantly greater BMI, serum creatinine, and SUA, and a lower TIMI risk score (2, IQR: 1-4 vs. 3, IQR: 2-4, p=0.019). The hyperuricemia group also had greater 30-day and 1-year mortality rates (2.9% vs. 0.3%, p=0.022; 6.5% vs. 1.1%, p=0.002, respectively). However, hyperuricemia was not associated with mortality of patients in Killip classes II-IV or in the overall study population. Hyperuricemia was associated with increased mortality in subgroups of patients who were at least 65years-old, male, had BMI of 25kg/m2 or less, were in Killip class I, without diabetes, and who did not receive intra-aortic balloon pump support. Hyperuricemia interacted with Killip class I in increasing the risk for 1-year mortality (p for interaction=0.038). CONCLUSIONS: Hyperuricemia increased the 1-year mortality of STEMI patients in Killip class I, but not of patients in Killip classes II-IV. An interaction of hyperuricemia and Killip class significantly affects the mortality of STEMI patients.

Nkx2.5+ Cardiomyoblasts Contribute to Cardiomyogenesis in the Neonatal Heart.

During normal lifespan, the mammalian heart undergoes limited renewal of cardiomyocytes. While the exact mechanism for this renewal remains unclear, two possibilities have been proposed: differentiated myocyte replication and progenitor/immature cell differentiation. This study aimed to characterize a population of cardiomyocyte precursors in the neonatal heart and to determine their requirement for cardiac development. By tracking the expression of an embryonic Nkx2.5 cardiac enhancer, we identified cardiomyoblasts capable of differentiation into striated cardiomyocytes in vitro. Genome-wide expression profile of neonatal Nkx2.5+ cardiomyoblasts showed the absence of sarcomeric gene and the presence of cardiac transcription factors. To determine the lineage contribution of the Nkx2.5+ cardiomyoblasts, we generated a doxycycline suppressible Cre transgenic mouse under the regulation of the Nkx2.5 enhancer and showed that neonatal Nkx2.5+ cardiomyoblasts mature into cardiomyocytes in vivo. Ablation of neonatal cardiomyoblasts resulted in ventricular hypertrophy and dilation, supporting a functional requirement of the Nkx2.5+ cardiomyoblasts. This study provides direct lineage tracing evidence that a cardiomyoblast population contributes to cardiogenesis in the neonatal heart. The cell population identified here may serve as a promising therapeutic for pediatric cardiac regeneration.

Rapid Early Triage by Leukocytosis and the Thrombolysis in Myocardial Infarction (TIMI) Risk Score for ST-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: An Observational Study.

The clinical utility of leukocytosis in risk assessment for ST-elevation myocardial infarction (STEMI) is still unclear. We aim to demonstrate the prognostic value of leukocyte counts independent from traditional risk factors and the TIMI risk score (TRS) for STEMI and to propose a practical model comprising leukocyte count for early triage in STEMI undergoing primary angioplasty. A prospective database (n = 796) of consecutive STEMI cases receiving primary angioplasty at a tertiary medical center was retrospectively analyzed in the period from February 1, 2007 through December 31, 2012. Primary endpoints were 30-day and 1-year mortality. Propensity score-adjusted Cox regression models and subdivision analysis were performed. Leukocytosis group (n = 306) had higher 30-day mortality (5.9% vs 3.1%, P = 0.048) and 1-year mortality (9.2% vs 5.1%, P = 0.022). After adjustment by propensity score and TRS, leukocyte count (per 10/µL) was an independent predictor of 1-year mortality (HR: 1.086, 95% CI: 1.034-1.140, P = 0.001). Subdivision analysis demonstrated the correlation between leukocytosis and higher 1-year mortality within both high and low TRS strata (divided by 4, the median of TRS). Additionally, 24% (191 out of 796) of patients were characterized by nonleukocytosis and TRS < 4, having 0% of mortality rate at 1-year follow-up. In conclusion, leukocyte count is an independent prognostic factor adding incremental value to TRS for STEMI. Nonleukocytosis in conjunction with TRS < 4 identifies a large patient group at extremely low risk and thus provides rapid early triage for STEMI patients undergoing primary PCI. This finding is worth validation in the future.

Developmental origin of postnatal cardiomyogenic progenitor cells.

AIM: To trace the cell origin of the cells involved in postnatal cardiomyogenesis. MATERIALS & METHODS: Nkx2.5 enhancer-eGFP (Nkx2.5 enh-eGFP) mice were used to test the cardiomyogenic potential of Nkx2.5 enhancer-expressing cells. By analyzing Cre excision of activated Nkx2.5-eGFP+ cells from different lineage-Cre/Nkx2.5 enh-eGFP/ROSA26 reporter mice, we traced the developmental origin of Nkx2.5 enhancer-expressing cells. RESULTS: Nkx2.5 enhancer-expressing cells could differentiate into striated cardiomyocytes both in vitro and in vivo. Nkx2.5-eGFP+ cells increased remarkably after experimental myocardial infarction (MI). The post-MI Nkx2.5-eGFP+ cells originated from the embryonic epicardial cells, not from the pre-existing cardiomyocytes, endothelial cells, cardiac neural crest cells or perinatal/postnatal epicardial cells. CONCLUSION: Postnatal Nkx2.5 enhancer-expressing cells are cardiomyogenic progenitor cells and originate from embryonic epicardium-derived cells.

Pharmacological inhibition of TGFß receptor improves Nkx2.5 cardiomyoblast-mediated regeneration.

AIMS: Our previous study found that A83-01, a small molecule type 1 TGFß receptor inhibitor, could induce proliferation of postnatal Nkx2.5(+) cardiomyoblasts in vitro and enhance their cardiomyogenic differentiation. The present study addresses whether A83-01 treatment in vivo could increase cardiomyogenesis and improve cardiac function after myocardial infarction through an Nkx2.5(+) cardiomyoblast-dependent process. METHODS AND RESULTS: To determine the effect of A83-01 on the number of Nkx2.5(+) cardiomyoblasts in the heart after myocardial injury, we treated transgenic Nkx2.5 enhancer-GFP reporter mice for 7 days with either A83-01 or DMSO and measured the number of GFP(+) cardiomyoblasts in the heart at 1 week after injury by flow cytometry. To determine the degree of new cardiomyocyte formation after myocardial injury and the effect of A83-01 in this process, we employed inducible Nkx2.5 enhancer-Cre transgenic mice to lineage label postnatal Nkx2.5(+) cardiomyoblasts and their differentiated progenies after myocardial injury. We also examined the cardiac function of each animal by intracardiac haemodynamic measurements. We found that A83-01 treatment significantly increased the number of Nkx2.5(+) cardiomyoblasts at baseline and after myocardial injury, resulting in an increase in newly formed cardiomyocytes. Finally, we showed that A83-01 treatment significantly improved ventricular elastance and stroke work, leading to improved contractility after injury. CONCLUSION: Pharmacological inhibition of TGFß signalling improved cardiac function in injured mice and promoted the expansion and cardiomyogenic differentiation of Nkx2.5(+) cardiomyoblasts. Direct modulation of resident cardiomyoblasts in vivo may be a promising strategy to enhance therapeutic cardiac regeneration.

Epidemiology and socioeconomic features of appendicitis in Taiwan: a 12-year population-based study.

INTRODUCTION: This paper presents an epidemiologic study of appendicitis in Taiwan over a twelve-year period. An analysis of the incidence in the low-income population (LIP) is included to explore the effects of lower socioeconomic status on appendicitis. METHODS: We analyzed the epidemiological features of appendicitis in Taiwan using data from the National Health Insurance Research Database (NHIRD) from 2000 to 2011. All cases diagnosed as appendicitis were enrolled. RESULTS: The overall incidences of appendicitis, primary appendectomy, and perforated appendicitis were 107.76, 101.58, and 27.20 per 100,000 per year, respectively. The highest incidence of appendicitis was found in persons aged 15 to 29 years; males had higher rates of appendicitis than females at all ages except for 70 years and older. Appendicitis rates were 11.76 % higher in the summer than in the winter months. A multilevel analysis with hierarchical linear modeling (HLM) revealed that male patients, younger patients (aged ≤14 years), and elderly patients (aged ≥60 years) had a higher risk of perforated appendicitis; among adults, the incidence increased with age. Moreover, the risk of perforation was higher in patients with one or more comorbidities. LIP patients comprised 1.25 % of the total number of patients with appendicitis from 2000 to 2011. The overall incidence of appendicitis was 34.99 % higher in the LIP than in the normal population (NP), and the incidence of perforated appendicitis was 40.40 % higher in the LIP than in the NP. After multivariate adjustment, the adjusted hospital costs and length of hospital stay (LOS) for the LIP patients were higher than those for the NP patients. CONCLUSIONS: Appendicitis and appendectomy in Taiwan had similar overall incidences, seasonality patterns, and declining trends compared to numerous previous studies. Compared to NP patients, LIP patients had a higher risk of appendicitis, longer LOS and higher hospital costs as a result of appendectomy.

Human Placenta-Derived Multipotent Cells (hPDMCs) Modulate Cardiac Injury: From Bench to Small and Large Animal Myocardial Ischemia Studies.

Cardiovascular disease is the leading cause of death globally, and stem cell therapy remains one of the most promising strategies for regeneration or repair of the damaged heart. We report that human placenta-derived multipotent cells (hPDMCs) can modulate cardiac injury in small and large animal models of myocardial ischemia (MI) and elucidate the mechanisms involved. We found that hPDMCs can undergo in vitro cardiomyogenic differentiation when cocultured with mouse neonatal cardiomyocytes. Moreover, hPDMCs exert strong proangiogenic responses in vitro toward human endothelial cells mediated by secretion of hepatocyte growth factor, growth-regulated oncogene-α, and interleukin-8. To test the in vivo relevance of these results, small and large animal models of acute MI were induced in mice and minipigs, respectively, by permanent left anterior descending (LAD) artery ligation, followed by hPDMC or culture medium-only implantation with follow-up for up to 8 weeks. Transplantation of hPDMCs into mouse heart post-acute MI induction improved left ventricular function, with significantly enhanced vascularity in the cell-treated group. Furthermore, in minipigs post-acute MI induction, hPDMC transplantation significantly improved myocardial contractility compared to the control group (p = 0.016) at 8 weeks postinjury. In addition, tissue analysis confirmed that hPDMC transplantation induced increased vascularity, cardiomyogenic differentiation, and antiapoptotic effects. Our findings offer evidence that hPDMCs can modulate cardiac injury in both small and large animal models, possibly through proangiogenesis, cardiomyogenesis, and suppression of cardiomyocyte apoptosis. Our study offers mechanistic insights and preclinical evidence on using hPDMCs as a therapeutic strategy to treat severe cardiovascular diseases.