Strategies to improve the therapeutic effect of pluripotent stem cell-derived cardiomyocytes on myocardial infarction.

Myocardial infarction (MI) is a common cardiovascular disease caused by permanent loss of cardiomyocytes and the formation of scar tissue due to myocardial ischemia. Mammalian cardiomyocytes lose their ability to proliferate almost completely in adulthood and are unable to repair the damage caused by MI. Therefore, transplantation of exogenous cells into the injured area for treatment becomes a promising strategy. Pluripotent stem cells (PSCs) have the ability to proliferate and differentiate into various cellular populations indefinitely, and pluripotent stem cell-derived cardiomyocytes (PSC-CMs) transplanted into areas of injury can compensate for part of the injuries and are considered to be one of the most promising sources for cell replacement therapy. However, the low transplantation rate and survival rate of currently transplanted PSC-CMs limit their ability to treat MI. This article focuses on the strategies of current research for improving the therapeutic efficacy of PSC-CMs, aiming to provide some inspiration and ideas for subsequent researchers to further enhance the transplantation rate and survival rate of PSC-CMs and ultimately improve cardiac function.

A Novel Biomarker Scoring System Alone or in Combination with the GRACE Score for the Prognostic Assessment in Non-ST-Elevation Myocardial Infarction.

Purpose: The Global Registry of Acute Coronary Events (GRACE) score has proven value in predicting short-term prognosis in non-ST-elevation myocardial infarction (NSTEMI), but it has only moderate discrimination for long-term outcomes. The purpose of this study is to develop and test a multi-biomarker score for better risk stratification and indication of 2-year risk in patients with NSTEMI. Patients and Methods: A total of 6076 consecutive patients with NSTEMI (66 [59-73] years, 73.1% males) admitted at Zhongshan Hospital, Fudan University were collected in this observational, prospective study between 2012 and 2018 with a 24-month follow-up. The primary endpoint was all-cause death and non-fatal major adverse cardiac events (MACE). A biomarker score ranged from 0 to 12 was constructed. The predictive power of the biomarker score was evaluated alone or combined with the GRACE score by C-statistic, net reclassification index (NRI) and integrated discrimination index (IDI). Results: During a 2-year follow-up, all-cause death occurred in 159 patients (2.6%), and non-fatal MACEs were presented in 709 patients (11.7%). When added to the GRACE score, the biomarker score demonstrated better prognostic accuracy, patient reclassification and risk discrimination for both mortality and non-fatal MACEs at 2 years by improving the C-statistic from 0.714 (0.671-0.756) and 0.623 (0.600-0.646) to 0.851 (0.820-0.882) and 0.721 (0.702-0.741) with NRI >25% (P<0.001) and IDI >0.30 (P<0.001). Conclusion: The single use of biomarker score could markedly enhance the prognostic value of concurrent risk stratification tools for 2-year mortality and non-fatal MACEs in NSTEMI. The GRACE score with incorporation of the biomarker score led to more accurate risk reclassification and warrants more consideration in further NSTEMI management.

Intermittent Starvation Promotes Maturation of Human Embryonic Stem Cell-Derived Cardiomyocytes.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) represent an infinite cell source for cardiovascular disease modeling, drug screening and cell therapy. Despite extensive efforts, current approaches have failed to generate hPSC-CMs with fully adult-like phenotypes in vitro, and the immature properties of hPSC-CMs in structure, metabolism and electrophysiology have long been impeding their basic and clinical applications. The prenatal-to-postnatal transition, accompanied by severe nutrient starvation and autophagosome formation in the heart, is believed to be a critical window for cardiomyocyte maturation. In this study, we developed a new strategy, mimicking the in vivo starvation event by Earle's balanced salt solution (EBSS) treatment, to promote hPSC-CM maturation in vitro. We found that EBSS-induced starvation obviously activated autophagy and mitophagy in human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Intermittent starvation, via 2-h EBSS treatment per day for 10 days, significantly promoted the structural, metabolic and electrophysiological maturation of hESC-CMs. Structurally, the EBSS-treated hESC-CMs showed a larger cell size, more organized contractile cytoskeleton, higher ratio of multinucleation, and significantly increased expression of structure makers of cardiomyocytes. Metabolically, EBSS-induced starvation increased the mitochondrial content in hESC-CMs and promoted their capability of oxidative phosphorylation. Functionally, EBSS-induced starvation strengthened electrophysiological maturation, as indicated by the increased action potential duration at 90% and 50% repolarization and the calcium handling capacity. In conclusion, our data indicate that EBSS intermittent starvation is a simple and efficient approach to promote hESC-CM maturation in structure, metabolism and electrophysiology at an affordable time and cost.

Laparoscopic based renal denervation in a canine neurogenic hypertension model.

BACKGROUND: Previous renal denervation (RDN) studies showed controversial results in reducing blood pressure. The aim of this study was to provide evidence supporting the effectiveness of laparoscopic-based renal denervation (L-RDN) in treating hypertension. METHODS: Sixteen Beagle dogs were randomly divided into RDN group (n = 12) and sham group (n = 4). Neurogenic hypertension was generated in all dogs via carotid artery route. L-RDN was performed in the RDN group, with sham operation performed as a control. Blood pressure (BP) changes were recorded at 2, 4, 6, and 8 weeks after the procedure. Changes in serum creatinine (sCr), blood urea nitrogen (BUN) and level of norepinephrine (NE) were analyzed. Histological changes of kidney and renal arteries were also evaluated. RESULTS: BP and NE levels were significantly elevated after hypertension induction (p < 0.01). Systolic and diastolic BP of RDN group were decreased by 15.5 mmHg and 7.3 mmHg (p < 0.0001 and p = 0.0021, respectively) at the eighth week after L-RDN. Invasive systolic and diastolic BP of RDN group were significantly decreased by 14.5 mmHg and 15.3 mmHg (p < 0.0001). In contrast, there was no significant decrease in blood pressure in the sham group. In addition, RDN group but not the sham group showed a significant decrease in NE levels (p < 0.001), while no significant changes in sCr and BUN were observed in both groups. Pathological examinations showed no discernible damage, tear, or dissection to the renal arteries in RND group. CONCLUSIONS: L-RDN lowered BP and NE levels in hypertensive dogs without affecting renal artery morphology and kidney function.

Independent prognostic value of left atrial function by two-dimensional speckle tracking imaging in patients with non -ST-segment-elevation acute myocardial infarction.

BACKGROUND: The objective of this study is to evaluate left atrial(LA) function and its prognostic value by two-dimensional speckle tracking echocardiography (STE) in patients with non-ST-segment-elevation acute myocardial infarction (NSTEAMI). METHODS: Global longitudinal LA S/SR data obtained by 2D speckle imaging with automated software (Echo PAC, GE Medical). RESULTS: Clinical variables and angiographic, echocardiographic, and STE parameters were studied in 65 patients with NSTEAMI (51 males and 14 females; mean age of 60.7 ± 9.8 years) who underwent elective PCI. The final study population consisted of 51 individuals (43 males and 8 females; mean age of 62.9 ± 11.1 years) and a 12 ± 3 months follow-up was performed. A total of 22 combined cardiovascular events(20 patients) occurred. With the use of Univariable Cox regression, all parameters were evaluated in the prediction of cardiac events, ischemic events, and/or cardiac death. According to ROC analysis, baseline mean global left atrial SRs (ROC area 0.82, p = 0.001) and baseline mean global left atrial SRe (ROC area 0.68, p = 0.036) were the only predictive variables. CONCLUSIONS: In patients with NSTEAMI, we found that the novel global strain parameter of left atrial function is a valuable predictor of combined cardiovascular events over conventional echocardiography and may therefore be an important clinical tool for risk stratification in the acute phase of NSTEAMI.

Influence of insulin resistance on in-stent restenosis in patients undergoing coronary drug-eluting stent implantation after long-term angiographic follow-up.

OBJECTIVE: Previous studies have reported that insulin resistance is related to early in-stent restenosis (ISR) after coronary stenting. This study aimed to evaluate the influence of insulin resistance on the long-term angiographic outcome in patients undergoing coronary drug-eluting stent (DES) implantation. MATERIALS AND METHODS: Within a single hospital-based cohort of patients (n=529) who underwent coronary DES implantation, angiographic follow-up was performed successfully for 417 study patients at 12-48 months after coronary stenting. ISR was defined as stenosis of at least 50% of the luminal diameter. Fasting plasma glucose and fasting plasma insulin were measured. Insulin resistance was expressed by the homeostasis model assessment index (HOMA-IRI). RESULTS: Among the 417 patients who completed angiographic follow-up (mean 17.5±10.2 months), 58 patients (13.9%) had ISR whereas the remaining 359 patients (86.1%) did not have ISR. Patients with ISR had higher insulin resistance index (IRI) than nonrestenosis patients (P=0.004). Multiple logistic regression analysis (logit) showed that IRI was associated significantly with ISR (adjusted odds ratio 1.476, 95% confidence interval 1.227-1.776; P<0.001). In the nondiabetes subgroup of 309 patients, IRI was higher in patients with ISR than in nonrestenosis patients, as confirmed in a separate logit analysis (adjusted odds ratio 1.456, 95% confidence interval 1.152-1.839; P=0.002). Multiple linear regression analysis showed that IRI was associated significantly with in-stent diameter stenosis degree (P=0.043). CONCLUSION: Insulin resistance was associated with ISR in patients undergoing coronary DES implantation at long-term angiographic follow-up.

Complex made easy: left anterior descending artery trifurcation lesion completely treated with a single device.

Coronary trifurcation lesions are a complex subset of lesions. We present a case of a percutaneous intervention of a trifurcation lesion involving the left anterior descending artery and 2 diagonal branches completely treated with one single device, the novel stent-on-a-wire (SOAW) (Svelte Medical Systems), for the whole procedure. The SOAW is an all-in-one device with a bare cobalt-chrome stent mounted on a balloon directly connected to a wire. The stent of the SOAW was deployed in the left anterior descending artery over the ostia of the 2 diagonal branches. Using the same wire plus balloon device of the SOAW, further recrossing in direction of the 2 side branches and balloon dilation of both ostia through the stent struts was possible. Conclusive post-dilatation of the stent was then performed once again with the same SOAW device. The final angiographic result was successful, and patency of the stented segment was confirmed also at 5-month angiographic follow-up.

First results of the DEB-AMI (drug eluting balloon in acute ST-segment elevation myocardial infarction) trial: a multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in primary percutaneous coronary intervention with 6-month angiographic, intravascular, functional, and clinical outcomes.

OBJECTIVES: The goal of this study was to compare angiographic, intravascular imaging, and functional parameters, as well as the clinical outcomes of patients treated with drug-eluting balloon (DEB) plus bare-metal stent (BMS) versus BMS versus drug-eluting stent (DES) for ST-segment elevated acute myocardial infarction (STEMI). BACKGROUND: Concerns remain regarding the long-term safety of DES in STEMI. DEB could provide an attractive alternative in order to achieve potentially similar effectiveness but limiting the long-term hazards related to late-acquired stent malapposition and thus stent thrombosis. METHODS: In this randomized, international, 2-center, single-blinded, 3-arm study, STEMI patients were randomly assigned to group A: BMS; group B: DEB plus BMS; or group C: DES after successful thrombus aspiration. The primary endpoint was 6-month angiographic in-stent late-luminal loss. Secondary endpoints were in-stent binary restenosis, major adverse cardiac events (MACE: cardiac death, myocardial infarction, target vessel revascularization). In a subgroup of patients, stent (mal)apposition (by optical coherence tomography) and endothelial function (by acetylcholine infusion) was assessed. RESULTS: Overall, 150 patients were randomized. Procedural success was achieved in 96.7%. In groups A, B, and C, respectively, late-luminal loss was 0.74 ± 0.57 mm, 0.64 ± 0.56 mm, and 0.21 ± 0.32 mm (p < 0.01); binary restenosis was 26.2%, 28.6%, and 4.7% (p = 0.01); and MACE rates were 23.5%, 20.0%, and 4.1% (p = 0.02), respectively. The median percentage [25th to 75th interquartile range] of uncovered and malapposed stent struts per lesion was 0 [0 to 0.35], 2.84 [0 to 6.63], and 5.21 [3.25 to 14.5] (p < 0.01). Significant paradoxical vasoconstriction was seen in groups B and C. CONCLUSIONS: In STEMI patients, DEB followed by BMS implantation failed to show angiographic superiority to BMS only. Angiographic results of DES were superior to both BMS and DEB. Moreover, DEB before implantation induced more uncovered and malapposed stent struts than BMS, but less than after DES. (Drug-Eluting Balloon in Acute Myocardial Infarction [DEB-AMI]; NCT00856765).