Sex-based outcomes on unguided de-escalation from ticagrelor to clopidogrel in stabilized patients with acute myocardial infarction undergoing percutaneous coronary intervention: a post-hoc analysis of the TALOS-AMI.

Background: The TALOS-AMI study highlighted the effectiveness of a de-escalation strategy shifting from ticagrelor to clopidogrel 1 month after percutaneous coronary intervention (PCI), resulting in significant reduction in clinical events, primarily attributed to a substantial decrease in bleeding events. Nevertheless, the impact of this strategy on outcomes based on sex remains unclear. Methods: This was a post-hoc analysis of the TALOS-AMI study. At 1 month after PCI, patients who remained adherent to aspirin and ticagrelor without experiencing major adverse events were randomized into either the de-escalation group (clopidogrel plus aspirin) or the active control group (ticagrelor plus aspirin) for an additional 12 months. The primary endpoint encompassed a composite of cardiovascular death, myocardial infarction, stroke, and Bleeding Academic Research Consortium bleeding type 2 or greater at 12 months after randomization. Results: Among the 2,697 patients included in this study, 454 (16.8%) were women. Women, characterized by older age and a higher prevalence of hypertension, diabetes, impaired renal function, and non-ST-segment myocardial infarction, exhibited a lower primary endpoint at 12 months compared to men [adjusted hazards ratio (HR), 0.60; 95% confidence interval (CI), 0.37-0.95; P = 0.03]. Compare to the active control group, the de-escalation group demonstrated a reduced risk of the primary endpoint in both women (adjusted HR, 0.38; 95% CI, 0.15-0.95; P = 0.039) and men (adjusted HR, 0.56; 95% CI, 0.40-0.79; P = 0.001) (interaction P = 0.46). Conclusions: In stabilized patients post-PCI with drug-eluting stents for acute myocardial infarction, the primary endpoint was lower among women compared to men. In this cohort, the benefits of an unguided de-escalation strategy from ticagrelor to clopidogrel were comparable in women and men.

Timing of fractional flow reserve-guided complete revascularization in patients with ST-segment elevation myocardial infarction with multivessel disease: Rationale and design of the OPTION-STEMI trial.

BACKGROUND: Current guidelines recommend complete revascularization (CR) in hemodynamically stable patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease (MVD). With regard to the timing of percutaneous coronary intervention (PCI) for non-infarct-related artery (non-IRA), recent randomized clinical trials have revealed that immediate CR was non-inferior to staged CR. However, the optimal timing of CR remains uncertain. The OPTION-STEMI trial compared immediate CR and in-hospital staged CR guided by fractional flow reserve (FFR) for intermediate stenosis of the non-IRA. METHODS: The OPTION-STEMI is a multicenter, investigator-initiated, prospective, open-label, non-inferiority randomized clinical trial. The study included patients with at least 1 non-IRA lesion with ≥50% stenosis by visual estimation. Patients fulfilling the inclusion criteria were randomized into 2 groups at a 1:1 ratio: immediate CR (i.e., PCI for the non-IRA performed during primary angioplasty) or in-hospital staged CR. In the in-hospital staged CR group, PCI for non-IRA lesions was performed on another day during the index hospitalization. Non-IRA lesions with 50%-69% stenosis by visual estimation were evaluated by FFR, whereas those with ≥70% stenosis was revascularized without FFR. The primary endpoint was the composite of all-cause death, non-fatal myocardial infarction, and all unplanned revascularization at 1 year after randomization. Enrolment began in December 2019 and was completed in January 2024. The follow-up for the primary endpoint will be completed in January 2025, and primary results will be available in the middle of 2025. CONCLUSIONS: The OPTION-STEMI is a multicenter, non-inferiority, randomized trial that evaluated the timing of in-hospital CR with the aid of FFR in patients with STEMI and MVD. TRIAL REGISTRATION: URL: https://www. CLINICALTRIALS: gov. Unique identifier: NCT04626882; and URL: https://cris.nih.go.kr. Unique identifier: KCT0004457.

Balloon-Expandable Versus Self-Expandable Valve in Transcatheter Aortic Valve Replacement: A Nation-Wide Study.

A few studies have reported comparative analysis of clinical outcomes between balloon-expandable valve (BEV) and self-expandable valve (SEV) after transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis using newer-generation devices. However, those reports were mostly limited to short-term outcomes and Western populations. In the present study, data of patients with severe aortic stenosis who underwent TAVR between March 2016 and December 2018 were obtained from the National Health Insurance Service in Korea. The primary end point, defined as all-cause mortality, was compared in BEV (SAPIEN 3, Edwards Lifesciences, Irvine, California) and SEV (Evolut R, Medtronic, Minneapolis, MN) groups using a propensity-score matching analysis. Cumulative event rates of ischemic stroke, repeat procedures, and permanent pacemaker insertion (PPI) were evaluated as secondary outcomes. All events were followed up to a maximum of 3 years. A total of 1,172 patients underwent transfemoral TAVR, of whom 707 (60.3%) were treated with BEV and 452 (38.6%) with SEV. After 1:1 propensity-score matching, the BEV group showed lower all-cause mortality after a median follow-up of 12.0 months (mean: 13.1 ± 9.3 months) based on Cox proportional hazard model analysis (hazard ratio [HR] 0.67, 95% confidence interval [CI] 0.45 to 0.99, p = 0.04). Cumulative incidence of ischemic stroke was not statistically different between the 2 groups (HR 0.68, 95% CI 0.29 to 1.59, p = 0.37). PPI occurred less frequently in the BEV group (HR 0.4, 95% CI 0.25 to 0.64, p < 0.01). Repeat procedures were rare (1 patient in BEV and 2 patients in SEV group). In conclusion, Korean nation-wide data analysis showed that BEV was associated with less all-cause death and incidence of PPI after TAVR than was SEV using a newer-generation device.

Clinical benefit of long-term use of dual antiplatelet therapy for acute myocardial infarction patients with the PEGASUS-TIMI 54 criteria.

Background: We evaluated the effectiveness of extended dual antiplatelet therapy (DAPT) usage after 2nd-generation drug elution stent implantation in acute myocardial infarction (AMI) survivors with high ischemic risk characteristics who had no major bleeding for 24 months under at least 1 year of DAPT maintenance. Materials and methods: The primary ischemic and bleeding endpoints were the risk of mortality and the risk of BARC 3 or 5 (major) bleeding. We investigated the event rates for 2-5 years after the index procedure. Results: Of 3382 post-AMI survivors who met the PEGASUS-TIMI 54 (PEGASUS) criteria and without major bleeding until 2 years, 2281 (67.4%) maintained DAPT over 24 months, and 1101 (32.5%) switched DAPT to a single antiplatelet agent. The >24 M DAPT group showed a lower risk of mortality than the 12-24 M DAPT group (7.2 vs. 9.2%; adjusted hazard ratio: 0.648; 95% confidence interval: 0.595-0.976; p < 0.001). The mortality risk was significantly greater as the number of PEGASUS criteria increased (p < 0.001). DAPT > 24 months was not significantly associated with a decreased risk for major bleeding in the population meeting the PEGASUS criteria (2.0 vs. 1.1%; p = 0.093). The results were consistent after propensity-score matching and inverse probability weighting to adjust for baseline differences. Conclusion: Extended DAPT over 24 months was associated with a lower risk of mortality without increasing the risk of major bleeding among 2 years survivors after AMI who met the PEGASUS criteria and had no major bleeding events before 24 months.

High Uric Acid Levels in Acute Myocardial Infarction Provide Better Long-Term Prognosis Predictive Power When Combined with Traditional Risk Factors.

The current study aimed to investigate the association between serum UA levels and the mortality rate of AMI patients. We analyzed 5888 patients with successfully revascularized AMI (mean age: 64.0 ± 12.7 years). The subjects were divided into the high UA group (uric acid >6.5 mg/dL for males, >5.8 mg/dL for females) or the normal UA group based on initial serum UA level measured at admission. The primary outcome was all-cause mortality. A total of 4141 (70.3%) and 1747 (29.7%) patients were classified into the normal UA group and high UA groups, respectively. Over a median follow-up of 5.02 (3.07, 7.55) years, 929 (21.5%) and 532 (34.1%) patients died in each group. Cox regression analysis identified high UA levels as an independent predictor of all-cause mortality (unadjusted hazard ratio (HR) 1.69 [95% CI 1.52−1.88]; p < 0.001, adjusted HR 1.18 [95% CI: 1.05−1.32]; p = 0.005). The results were consistent after propensity-score matching and inverse probability weighting to adjust for baseline differences. The predictive accuracies of conventional clinical factor discrimination and reclassification were significantly improved upon the addition of hyperuricemia (C-index 0.788 [95% CI 0.775−0.801]; p = 0.005, IDI 0.004 [95% CI 0.002−0.006]; p < 0.001, NRI 0.263 [95% CI 0.208−0.318]; p < 0.001).

Independent Clinical Impacts of Procedural Complexity on Ischemic and Bleeding Events in Patients with Acute Myocardial Infarction: Long-Term Clinical Study.

This study aimed to investigate the relationship between a complex percutaneous coronary intervention (C-PCI) and long-term clinical outcomes in the AMI cohort. A total of 10,329 patients were categorized into the C-PCI and non-C-PCI groups. The primary ischemic endpoint was a composite of major adverse cardiac events (MACEs, cardiac death, myocardial infarction, stent thrombosis and revascularization). The primary bleeding endpoint was the risk of overt bleeding (BARC 2, 3 or 5). The median follow-up duration was 4.9 (2.97, 7.16) years. The risks of MACEs and bleeding were significantly higher in the C-PCI group (hazard ratio (HR): 1.72; 95% confidence interval (CI): 1.60 to 1.85; p < 0.001; and HR: 1.32; 95% CI: 1.17 to 1.50; p < 0.001, respectively). After propensity score matching, compared to the non-C-PCI group, the adjusted MACE rate in C-PCI remained significantly higher (p < 0.001), but no significant interaction (p = 0.273) was observed for bleeding. Significant differences in overt bleeding were observed only within the first three months (p = 0.024). The MACEs were consistently higher in the C-PCI group with or without severe comorbid conditions (p < 0.001 for both). Patients with AMI who undergo C-PCI experience worse long-term ischemic outcomes after successful PCI, regardless of the presence of severe comorbidities.

Spatiotemporal dynamics of macrophage heterogeneity and a potential function of Trem2hi macrophages in infarcted hearts.

Heart failure (HF) is a frequent consequence of myocardial infarction (MI). Identification of the precise, time-dependent composition of inflammatory cells may provide clues for the establishment of new biomarkers and therapeutic approaches targeting post-MI HF. Here, we investigate the spatiotemporal dynamics of MI-associated immune cells in a mouse model of MI using spatial transcriptomics and single-cell RNA-sequencing (scRNA-seq). We identify twelve major immune cell populations; their proportions dynamically change after MI. Macrophages are the most abundant population at all-time points (>60%), except for day 1 post-MI. Trajectory inference analysis shows upregulation of Trem2 expression in macrophages during the late phase post-MI. In vivo injection of soluble Trem2 leads to significant functional and structural improvements in infarcted hearts. Our data contribute to a better understanding of MI-driven immune responses and further investigation to determine the regulatory factors of the Trem2 signaling pathway will aid the development of novel therapeutic strategies for post-MI HF.

Prognostic Impact of the HFA-PEFF Score in Patients with Acute Myocardial Infarction and an Intermediate to High HFA-PEFF Score.

This study aimed to investigate the efficacy of the HFA-PEFF score in predicting the long-term risks in patients with acute myocardial infarction (AMI) and an HFA-PEFF score ≥ 2. The subjects were divided according to their HFA-PEFF score into intermediate (2−3 points) and high (4−6 points) score groups. The primary outcome was all-cause mortality. Of 1018 patients with AMI and an HFA-PEFF score of ≥2, 712 (69.9%) and 306 (30.1%) were classified into the intermediate and high score groups, respectively. Over a median follow-up of 4.8 (3.2, 6.5) years, 114 (16.0%) and 87 (28.4%) patients died in each group. Multivariate Cox regression identified a high HFA-PEFF score as an independent predictor of all-cause mortality [hazard ratio (HR): 1.53, 95% CI: 1.15−2.04, p = 0.004]. The predictive accuracies for the discrimination and reclassification were significantly improved (C-index 0.750 [95% CI 0.712−0.789]; p = 0.049 and NRI 0.330 [95% CI 0.180−0.479]; p < 0.001) upon the addition of a high HFA-PEFF score to clinical risk factors. The model was better at predicting combined events of all-cause mortality and heart failure readmission (C-index 0.754 [95% CI 0.716−0.791]; p = 0.033, NRI 0.372 [95% CI 0.227−0.518]; p < 0.001). In the AMI cohort, the HFA-PEFF score can effectively predict the prognosis of patients with an HFA-PEFF score of ≥2.

Long-Term Maintenance of Sinus Rhythm Is Associated with Favorable Echocardiographic Remodeling and Improved Clinical Outcomes after Transcatheter Aortic Valve Replacement.

Periprocedural atrial fibrillation (AF) is associated with poor prognosis after transcatheter aortic valve replacement (TAVR). We evaluated the impact of long-term sinus rhythm (SR) maintenance on post-TAVR outcomes. We enrolled 278 patients treated with TAVR including 87 patients with periprocedural AF. Patients with periprocedural AF were classified into the AF-sinus rhythm maintained (AF-SRM) group or the sustained AF group according to long-term cardiac rhythm status after discharge. Patients without AF before or after TAVR were classified into the SR group. The primary clinical outcome was a composite of all-cause death, stroke, or heart failure rehospitalization. The AF-SRM and the SR groups showed significant improvements in left ventricular ejection fraction and left atrial volume index at one year after TAVR, while the sustained AF group did not. During 24.5 (±16.1) months of follow-up, the sustained AF group had a higher risk of the adverse clinical event compared with the AF-SRM group (hazard ratio (HR) 4.449, 95% confidence interval (CI) 1.614-12.270), while the AF-SRM group had a similar risk of the adverse clinical event compared with the SR group (HR 0.737, 95% CI 0.285-1.903). In conclusion, SR maintenance after TAVR was associated with enhanced echocardiographic improvement and favorable clinical outcomes.

Gender Differences in the Impact of New-Onset Atrial Fibrillation on Long-Term Risk of Ischemic Stroke after Acute Myocardial Infarction.

BACKGROUND: Atrial fibrillation (AF) has been identified as a major risk factor for mortality after acute coronary syndrome (ACS). However, the long-term risk of ischemic stroke associated with new-onset atrial fibrillation (NOAF) in ACS remains controversial, and its gender-specific association is unknown. METHODS: We analyzed the data of 10,137 ACS survivors included in a multicenter, prospective registry for Korean patients with acute myocardial infarction (AMI) between January 2004 and August 2014. Subjects were categorized into three groups (non-AF vs. NOAF vs. previous AF) based on medical history and electrocardiographic evidence of AF, either at admission or during hospitalization. RESULTS: Among the total study population (72.3% men), 370 patients (3.6%) had NOAF and 130 (1.3%) had previous AF. During a median follow-up of 61 months (interquartile range, 38.8 to 89.3 months), 245 (2.4%) patients (218 (2.3%) non-AF vs. 15 (4.1%) NOAF vs. 12 (9.2%) previous AF, p < 0.001) experienced ischemic stroke. After adjustment for confounding variables, both NOAF (adjusted hazard ratio (HR) 1.87, 95% confidence interval (CI) 1.09-3.24, p = 0.024) and previous AF (adjusted HR 4.00, 95% CI 2.03-7.87, p < 0.001), along with older age, diabetes, current smoker, and previous stroke were independent risk factors of ischemic stroke. In the gender-stratified analysis, men with previous AF but not NOAF had a significantly higher risk of ischemic stroke (adjusted HR 4.14, 95% CI 1.79-9.55, p = 0.001) than those without AF. In women, NOAF (adjusted HR 2.54, 95% CI 1.21-5.35, p = 0.014) as well as previous AF (adjusted HR 3.72, 95% CI 1.16-11.96, p = 0.028) was a strong predictor of ischemic stroke, and the predictive value was comparable to that of previous AF among patients with a CHA2DS2-VASc score ≥ 2. CONCLUSIONS: Both NOAF and previous AF were associated with ischemic stroke after AMI, but the impact of NOAF as a risk factor of ischemic stroke was significant only in women.

Unguided de-escalation from ticagrelor to clopidogrel in stabilised patients with acute myocardial infarction undergoing percutaneous coronary intervention (TALOS-AMI): an investigator-initiated, open-label, multicentre, non-inferiority, randomised trial.

BACKGROUND: In patients with acute myocardial infarction receiving potent antiplatelet therapy, the bleeding risk remains high during the maintenance phase. We sought data on a uniform unguided de-escalation strategy of dual antiplatelet therapy (DAPT) from ticagrelor to clopidogrel after acute myocardial infarction. METHODS: In this open-label, assessor-masked, multicentre, non-inferiority, randomised trial (TALOS-AMI), patients at 32 institutes in South Korea with acute myocardial infarction receiving aspirin and ticagrelor without major ischaemic or bleeding events during the first month after index percutaneous coronary intervention (PCI) were randomly assigned in a 1:1 ratio to a de-escalation (clopidogrel plus aspirin) or active control (ticagrelor plus aspirin) group. Unguided de-escalation without a loading dose of clopidogrel was adopted when switching from ticagrelor to clopidogrel. The primary endpoint was a composite of cardiovascular death, myocardial infarction, stroke, or bleeding type 2, 3, or 5 according to Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months. A non-inferiority test was done to assess the safety and efficacy of de-escalation DAPT compared with standard treatment. The hazard ratio (HR) for de-escalation versus active control group in a stratified Cox proportional hazards model was assessed for non-inferiority by means of an HR margin of 1·34, which equates to an absolute difference of 3·0% in the intention-to-treat population and, if significant, a superiority test was done subsequently. To ensure statistical robustness, additional analyses were also done in the per-protocol population. This trial is registered at ClinicalTrials.gov, NCT02018055. FINDINGS: From Feb 26, 2014, to Dec 31, 2018, from 2901 patients screened, 2697 patients were randomly assigned: 1349 patients to de-escalation and 1348 to active control groups. At 12 months, the primary endpoints occurred in 59 (4·6%) in the de-escalation group and 104 (8·2%) patients in the active control group (pnon-inferiority<0·001; HR 0·55 [95% CI 0·40-0·76], psuperiority=0·0001). There was no significant difference in composite of cardiovascular death, myocardial infarction, or stroke between de-escalation (2·1%) and the active control group (3·1%; HR 0·69; 95% CI 0·42-1·14, p=0·15). Composite of BARC 2, 3, or 5 bleeding occurred less frequently in the de-escalation group (3·0% vs 5·6%, HR 0·52; 95% CI 0·35-0·77, p=0·0012). INTERPRETATION: In stabilised patients with acute myocardial infarction after index PCI, a uniform unguided de-escalation strategy significantly reduced the risk of net clinical events up to 12 months, mainly by reducing the bleeding events. FUNDING: ChongKunDang Pharm, Medtronic, Abbott, and Boston Scientific.

Nanoparticle-Mediated Blocking of Excessive Inflammation for Prevention of Heart Failure Following Myocardial Infarction.

Severe cardiac damage following myocardial infarction (MI) causes excessive inflammation, which sustains tissue damage and often induces adverse cardiac remodeling toward cardiac function impairment and heart failure. Timely resolution of post-MI inflammation may prevent cardiac remodeling and development of heart failure. Cell therapy approaches for MI are time-consuming and costly, and have shown marginal efficacy in clinical trials. Here, nanoparticles targeting the immune system to attenuate excessive inflammation in infarcted myocardium are presented. Liposomal nanoparticles loaded with MI antigens and rapamycin (L-Ag/R) enable effective induction of tolerogenic dendritic cells presenting the antigens and subsequent induction of antigen-specific regulatory T cells (Tregs). Impressively, intradermal injection of L-Ag/R into acute MI mice attenuates inflammation in the myocardium by inducing Tregs and an inflammatory-to-reparative macrophage polarization, inhibits adverse cardiac remodeling, and improves cardiac function. Nanoparticle-mediated blocking of excessive inflammation in infarcted myocardium may be an effective intervention to prevent the development of post-MI heart failure.

Five-year clinical outcomes of the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer.

ABSTRACT: This study evaluated the 5-year clinical outcomes of the Genoss DES, the first Korean-made sirolimus-eluting coronary stent with abluminal biodegradable polymer.We previously conducted the first-in-patient prospective, multicenter, randomized trial with a 1:1 ratio of patients using the Genoss DES and Promus Element stents; the angiographic and clinical outcomes of the Genoss DES stent were comparable to those of the Promus Element stent. The primary endpoint was major adverse cardiac events (MACE), which was a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR) at 5 years.We enrolled 38 patients in the Genoss DES group and 39 in the Promus Element group. Thirty-eight patients (100%) from the Genoss DES group and 38 (97.4%) from the Promus Element group were followed up at 5 years. The rates of MACE (5.3% vs 12.8%, P = .431), death (5.3% vs 10.3%, P = .675), TLR (2.6% vs 2.6%, P = 1.000), and target vessel revascularization (TVR) (7.9% vs 2.6%, P = .358) at 5 years did not differ significantly between the groups. No TLR or target vessel revascularization was reported from years 1 to 5 after the index procedure, and no MI or stent thrombosis occurred in either group during 5 years.The biodegradable polymer Genoss DES and durable polymer Promus Element stents showed comparable low rates of MACE at the 5-year clinical follow-up.

Influence of lesion and disease subsets on the diagnostic performance of the quantitative flow ratio in real-world patients.

The quantitative flow ratio (QFR) is a novel angiography-based computational method assessing functional ischemia caused by coronary stenosis. This study aimed to evaluate the diagnostic performance of quantitative flow ratio (QFR) in patients with angina and acute myocardial infarction (AMI) and to identify the conditions with low diagnostic performance. We assessed the QFR for 1077 vessels under fractional flow ratio (FFR) evaluation in 915 patients with angina and AMI. The diagnostic accuracies of the QFR for identifying an FFR ≤ 0.8 were 95.98% (95% confidence interval [CI] 94.52 to 97.14%) for the angina group and 92.42% (95% CI 86.51 to 96.31%) for the AMI group. The diagnostic accuracy of the QFR in the borderline FFR zones (> 0.75, ≤ 0.85) (91.23% [95% CI 88.25 to 93.66%]) was significantly lower than that in others (difference: 4.32; p = 0.001). The condition accompanying both AMI and the borderline FFR zone showed the lowest QFR diagnostic accuracy in our data (83.93% [95% CI 71.67 to 92.38]). The diagnostic accuracy was reduced for tandem lesions (p = 0.04, not correcting for multiple testing). Our study found that the QFR method yielded a high overall diagnostic performance in real-world patients. However, low diagnostic accuracy has been observed in borderline FFR zones with AMI, and the hybrid FFR approach needs to be considered.

A prospective, multicentre, randomised, open-label trial to compare the efficacy and safety of clopidogrel versus ticagrelor in stabilised patients with acute myocardial infarction after percutaneous coronary intervention: rationale and design of the TALOS-AMI trial.

AIMS: In patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI), the risk of ischaemic complications is highest in the early phase (during the first 30 days), while most bleeding events occur predominantly during the maintenance phase of treatment (after the first 30 days). Data on the de-escalation of dual antiplatelet therapy by switching from ticagrelor to clopidogrel in stabilised AMI patients are limited. The aim of this study is to investigate the efficacy and safety of switching from ticagrelor to clopidogrel in AMI patients with no adverse event during the first month after the index PCI with newer-generation DES. METHODS AND RESULTS: TALOS-AMI is a multicentre, randomised, open-label study enrolling 2,590 AMI patients with no adverse events during the first month after the index PCI. One month after the index PCI, eligible patients are randomly assigned either to 1) aspirin 100 mg plus clopidogrel 75 mg daily, or to 2) aspirin 100 mg plus ticagrelor 90 mg twice daily, in a 1:1 ratio. The primary endpoint is a composite of cardiovascular death, MI, stroke, and bleeding type 2, 3 or 5 according to the Bleeding Academic Research Consortium (BARC) criteria from 1 to 12 months after the index PCI. CONCLUSIONS: The TALOS-AMI trial is the first large-scale, multicentre, randomised study exploring the efficacy and safety of the de-escalation of antiplatelet therapy by switching from ticagrelor to clopidogrel in stabilised AMI patients undergoing PCI.

MSC-Encapsulating in Situ Cross-Linkable Gelatin Hydrogels To Promote Myocardial Repair.

Current stem cell-based therapy for cardiac repair and regeneration after myocardial infarction (MI) is not readily translatable into clinical scenarios due to the low retention and survival of the transplanted cells. Here, we evaluated a simple and feasible design of gelatin-hydroxyphenyl propionic acid (GH) hydrogel as an in situ cross-linkable and injectable cell delivery platform for cardiac tissue regeneration. The GH hydrogel exhibited improved cell retention and survival in vitro and in vivo when encapsulating mouse bone marrow-derived mesenchymal stem cells (MSCs) that were used as promising therapeutic candidates for stem cell therapy. Moreover, we demonstrated that MSC-encapsulating GH hydrogels led to a significant improvement in cardiac functional metrics, such as the fractional shortening (FS), ejection fraction (EF), and end-systolic volume (ESV). Similarly, MSC-encapsulating GH hydrogels induced favorable effects in the cardiac structures of the infarcted heart, producing less fibrosis and thicker infarcted walls. These results suggest that GH hydrogels can be used as an instructive cell delivery platform to provide a suitable microenvironment for transplanted cells; therefore, their in vivo applications combined with MSCs may provide great potential for repair and regeneration of injured cardiac tissues after MI.

Anti-inflammatory effect of statin is continuously working throughout use: a prospective three time point 18F-FDG PET/CT imaging study.

No data exist whether statins have robust anti-inflammatory effects of atherosclerotic plaques primarily during the early treatment period or continuously throughout use. This prospective three time point 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) study of the carotid artery assessed anti-inflammatory effects of statin during the early treatment period (initiation to 3 months) and late treatment period (3 months to 1 year) and their correlation with lipid and inflammatory profile changes during a year of therapy. Nine statin-naïve stable angina patients with inflammatory carotid plaques received 20 mg/day atorvastatin after undergoing initial 18F-FDG PET/CT scanning of carotid arteries and ascending thoracic aorta, and then completed serial 18F-FDG PET/CT imaging at 3 and 12 months whose data were analyzed. The primary outcome was the inter-scan percent change in target-to-background ratio (ΔTBR) within the index vessel. At 3 months of atorvastatin treatment, mean serum low-density lipoprotein cholesterol (LDL-C) level decreased by 36.4% to < 70 mg/dL (p = 0.001) and mean serum high-density lipoprotein cholesterol level increased to > 40 mg/dL (p = 0.041), with both maintained with no further reduction up to 1 year (p = 0.516 and 0.715, respectively) while mean serum high sensitivity C-reactive protein level only numerically decreased (p = 0.093). The index vessel ΔTBR showed continuous plaque inflammation reduction over 1 year, by 4.4% (p = 0.015) from the initiation to 3rd months and 6.2% (p = 0.009) from 3rd months to 1 year, respectively, without correlation with lipid profile changes. The ΔTBR of the bilateral carotid arteries and ascending aorta also continuously decreased from 3 months to 1 year. Three time point 18F-FDG PET/CT imaging demonstrates that statin's anti-inflammatory effect continues throughout its use up to 1 year, even though yielding stable below-target plasma LDL-C levels at 3 months.

Differential Impact of Chronic Kidney Disease on Coronary Calcification and Atherosclerosis in Asymptomatic Individuals with or without Diabetes: Analysis from a Coronary Computed Tomographic Angiography Registry.

AIM: The aim of this study was to assess the combined effects of chronic kidney disease (CKD) and diabetes on the extent and developmental pattern of coronary artery disease (CAD). METHODS: A total of 3,017 self-referred asymptomatic individuals without known CAD who underwent 64-channel dual-source coronary computed tomography angiography between 2006 and 2010 were enrolled. The patients were divided into six groups based on their diabetes status (nondiabetic or diabetic) and estimated glomerular filtration rate (eGFR) (eGFR > 90 mL/min/1.73 m2, normal renal function; eGFR 60-89, mild CKD; or eGFR 30-59, moderate CKD). We compared the coronary artery calcium score (CACS), segment stenosis score (SSS), and ≥50% obstructive CAD among the groups. RESULTS: In nondiabetics, whereas SSS and ≥50% obstructive CAD were not different as renal function deteriorated, after adjusting for cardiovascular risk factors, CACS showed a unique developmental pattern: no CACS increase until mild CKD, but abrupt increase from the stage of moderate CKD (moderate vs. normal renal function, adjusted OR 5.118, 95% CI 1.293-20.262, p = 0.020). In diabetics, patients from the stage of mild CKD were more likely to have ≥50% obstructive CAD (p = 0.004), higher CACS (p = 0.020), and SSS (p = 0.001) in multivariable analysis. CONCLUSIONS: The presence of CKD did not have a significant impact on the development of coronary atherosclerosis, but affected the progression of coronary calcification more markedly from the stage of moderate CKD in nondiabetics. However, in diabetics, the deterioration of renal function was significantly associated with the development of coronary atherosclerosis and calcification from the stage of mild CKD.

Dipeptidyl peptidase 4 inhibitor attenuates obesity-induced myocardial fibrosis by inhibiting transforming growth factor-ßl and Smad2/3 pathways in high-fat diet-induced obesity rat model.

Obesity-induced myocardial fibrosis may lead to diastolic dysfunction and ultimately heart failure. Activation of the transforming growth factor (TGF)-ßl and its downstream Smad2/3 pathways may play a pivotal role in the pathogenesis of obesity-induced myocardial fibrosis, and the antidiabetic dipeptidyl peptidase 4 inhibitors (DPP4i) might affect these pathways. We investigated whether DPP4i reduces myocardial fibrosis by inhibiting the TGF-ß1 and Smad2/3 pathways in the myocardium of a diet-induced obesity (DIO) rat model. Eight-week-old male spontaneously hypertensive rats (SHRs) were fed either a normal fat diet (chow) or a high-fat diet (HFD) and then the HFD-fed SHRs were randomized to either the DPP4i (MK-0626) or control (distilled water) groups for 12weeks. At 20weeks old, all the rats underwent hemodynamic and metabolic studies and Doppler echocardiography. Compared with the normal fat diet (chow)-fed SHRs, the HFD-fed SHRs developed a more intense degree of hyperglycemia and dyslipidemia and showed a constellation of left ventricular (LV) diastolic dysfunction, and exacerbated myocardial fibrosis, as well as activation of the TGF-ß1 and Smad2/3 pathways. DPP4i significantly improved the metabolic and hemodynamic parameters. The echocardiogram showed that DPP4i improved the LV diastolic dysfunction (early to late ventricular filling velocity [E/A] ratio, 1.49±0.21 vs. 1.77±0.09, p<0.05). Furthermore, DPP4i significantly reduced myocardial fibrosis and collagen production by the myocardium and suppressed TGF-ß1 and phosphorylation of Smad2/3 in the heart. In addition, DPP4i decreased TGF-ß1-induced collagen production and TGF-ß1-mediated phosphorylation and nuclear translocation of Smad2/3 in rat cardiac fibroblasts. In conclusion, DPP4 inhibition attenuated myocardial fibrosis and improved LV diastolic dysfunction in a DIO rat model by modulating the TGF-ß1 and Smad2/3 pathways.