Management of Coronary Artery Disease in Older Adults: Recent Advances and Gaps in Evidence.

Coronary artery disease (CAD) is highly prevalent in older adults, yet its management remains challenging. Treatment choices are made complex by the frailty burden of older patients, a high prevalence of comorbidities and body composition abnormalities (e.g., sarcopenia), the complexity of coronary anatomy, and the frequent presence of multivessel disease, as well as the coexistence of major ischemic and bleeding risk factors. Recent randomized clinical trials and epidemiological studies have provided new data on optimal management of complex patients with CAD. However, frail older adults are still underrepresented in the literature. This narrative review aims to highlight the importance of assessing frailty as an aid to guide therapeutic decision-making and tailor CAD management to the specific needs of older adults, taking into account age-related pharmacokinetic and pharmacodynamic changes, polypharmacy, and potential drug interactions. We also discuss gaps in the evidence and offer perspectives on how best in the future to optimize the global strategy of CAD management in older adults.

Urgent transcatheter edge-to-edge repair for severe mitral regurgitation with flail leaflet in critically Ill patients.

Introduction: Degenerative mitral valve disease (DMR) is a common valvular disorder, with flail leaflets due to ruptured chordae representing an extreme variation of this pathology. Ruptured chordae can present as acute heart failure which requires urgent intervention. While mitral valve surgery is the preferred mode of intervention, many patients have significantly elevated surgical risk and are sometimes considered inoperable. We aim to characterize patients with ruptured chordae undergoing urgent transcatheter edge-to-edge repair (TEER), and to analyze their clinical and echocardiographic outcomes. Methods: We screened all patients who underwent TEER at a tertiary referral center in Israel. We included patients with DMR with flail leaflet due to ruptured chordae and categorized them into elective and critically ill groups. We evaluated the echocardiographic, hemodynamic, and clinical outcomes of these patients. Results: The cohort included 49 patients with DMR due to ruptured chordae and flail leaflet, who underwent TEER. Seventeen patients (35%) underwent urgent intervention and 32 patients (65%) underwent an elective procedure. In the urgent group, the average age of the patient was 80.3, with 41.8% being female. Fourteen patients (82%) received noninvasive ventilation, and three patients (18%) required invasive mechanical ventilation. One patient died due to tamponade, while echo evaluation of the other 16 patients demonstrated successful reduction of ≥2 in the MR grade. Left atrial V wave decreased from 41.6 mmHg to 17.9 mmHg (p < 0.001), and the pulmonic vein flow pattern changed from reversal (68.8%) to a systolic dominant flow in all patients (p = 0.001). After the procedure, 78.5% of patients improved to New York Heart Association (NYHA) class I or II (p < 0.001). There was no significant difference in the overall mortality between the urgent and elective groups, with similar 6 months survival rates for each group. Conclusion: Urgent TEER in patients with ruptured chordae and flail leaflets can be safe and feasible with favorable hemodynamic, echocardiographic, and clinical outcomes.

Prevalence, Predictors, and Outcomes of Patients With ST-Elevation Myocardial Infarction and Angiographically Significant Coronary Artery Disease of Non-Infarct-Related Artery.

Patients with ST-elevation myocardial infarction (STEMI) can present with angiographically significant coronary artery disease (CAD) of non-infarct-related artery (IRA) or with IRA-only CAD. This study aimed to evaluate the prevalence, predictors, and outcome of patients with STEMI and angiographically significant CAD of non-IRA. All consecutive patients with STEMI who underwent primary percutaneous coronary intervention between 2000 and 2020 were included. Angiographically significant CAD was defined as >50% stenosis of the left main coronary artery and/or >90% stenosis for all other coronary arteries. A total of 2,663 patients had IRA-only CAD (80.2%) and 657 had angiographically significant non-IRA CAD (19.8%). Independent predictors for non-IRA CAD were male gender (odds ratio [OR] 1.34, 95% confidence interval [CI] 1.05 to 1.70, p = 0.021), age >50 years (OR 1.45, 95% CI 1.11 to 1.91, p = 0.007), and diabetes mellitus (OR 1.56, 95% CI 1.29 to 1.9, p <0.001), whereas smoking (OR 0.83, 95% CI 0.68 to 0.99, p = 0.004) and family history of CAD (OR 0.78, 95% CI 0.62 to 0.98, p = 0.032) were found to be negatively associated with non-IRA CAD. In-hospital 30-day and 1- and 5-year all-cause mortality were higher in patients with non-IRA CAD compared with IRA-only CAD (5.8% vs 2.5%, 8.5% vs 3.3%, 18.4% vs 7.6% and 36.3% vs 20.3%, respectively; p for all <0.001). In conclusion, 20% of patients with STEMI had angiographically significant non-IRA CAD. Older age, male gender, and diabetes mellitus were independent predictors for non-IRA CAD, whereas smoking and family history of CAD predicted IRA-only CAD. The presence of non-IRA CAD was associated with higher short- and long-term all-cause mortality rates.

Global, regional, and national burden of ischaemic heart disease and its attributable risk factors, 1990-2017: results from the Global Burden of Disease Study 2017.

AIMS: The aim of this study was to estimate the burden and risk factors for ischaemic heart disease (IHD) in 195 countries and territories from 1990 to 2017. METHODS AND RESULTS: Data from the Global Burden of Disease Study 2017 were used. Prevalence, incidence, deaths, years lived with disability (YLDs), and years of life lost (YLLs) were metrics used to measure IHD burden. Population attributable fraction was used to estimate the proportion of IHD deaths attributable to potentially modifiable risk factors. Globally, in 2017, 126.5 million [95% uncertainty interval (UI) 118.6 to 134.7] people lived with IHD and 10.6 million (95% UI 9.6 to 11.8) new IHD cases occurred, resulting in 8.9 million (95% UI 8.8 to 9.1) deaths, 5.3 million (95% UI 3.7 to 7.2) YLDs, and 165.0 million (95% UI 162.2 to 168.6) YLLs. Between 1990 and 2017, despite the decrease in age-standardized rates, the global numbers of these burden metrics of IHD have significantly increased. The burden of IHD in 2017 and its temporal trends from 1990 to 2017 varied widely by geographic location. Among all potentially modifiable risk factors, age-standardized IHD deaths worldwide were primarily attributable to dietary risks, high systolic blood pressure, high LDL cholesterol, high fasting plasma glucose, tobacco use, and high body mass index in 2017. CONCLUSION: Our results suggested that IHD remains a major public health challenge worldwide. More effective and targeted strategies aimed at implementing cost-effective interventions and addressing modifiable risk factors are urgently needed, particularly in geographies with high or increasing burden.

Acute myocardial infarction in the Covid-19 era: Incidence, clinical characteristics and in-hospital outcomes-A multicenter registry.

BACKGROUND: We aimed to describe the characteristics and in-hospital outcomes of ST-segment elevation myocardial infarction (STEMI) patients during the Covid-19 era. METHODS: We conducted a prospective, multicenter study involving 13 intensive cardiac care units, to evaluate consecutive STEMI patients admitted throughout an 8-week period during the Covid-19 outbreak. These patients were compared with consecutive STEMI patients admitted during the corresponding period in 2018 who had been prospectively documented in the Israeli bi-annual National Acute Coronary Syndrome Survey. The primary end-point was defined as a composite of malignant arrhythmia, congestive heart failure, and/or in-hospital mortality. Secondary outcomes included individual components of primary outcome, cardiogenic shock, mechanical complications, electrical complications, re-infarction, stroke, and pericarditis. RESULTS: The study cohort comprised 1466 consecutive acute MI patients, of whom 774 (53%) were hospitalized during the Covid-19 outbreak. Overall, 841 patients were diagnosed with STEMI: 424 (50.4%) during the Covid-19 era and 417 (49.6%) during the parallel period in 2018. Although STEMI patients admitted during the Covid-19 period had fewer co-morbidities, they presented with a higher Killip class (p value = .03). The median time from symptom onset to reperfusion was extended from 180 minutes (IQR 122-292) in 2018 to 290 minutes (IQR 161-1080, p < .001) in 2020. Hospitalization during the Covid-19 era was independently associated with an increased risk of the combined endpoint in the multivariable regression model (OR 1.65, 95% CI 1.03-2.68, p value = .04). Furthermore, the rate of mechanical complications was four times higher during the Covid-19 era (95% CI 1.42-14.8, p-value = .02). However, in-hospital mortality remained unchanged (OR 1.73, 95% CI 0.81-3.78, p-value = .16). CONCLUSIONS: STEMI patients admitted during the first wave of Covid-19 outbreak, experienced longer total ischemic time, which was translated into a more severe disease status upon hospital admission, and a higher rate of in-hospital adverse events, compared with parallel period.

CHADS2 and CHA2DS2-VASc scores as predictors of platelet reactivity in acute coronary syndrome.

BACKGROUND: Platelet function testing (PFT) in patients treated with P2Y12 inhibitors has been widely evaluated for the prediction of stent thrombosis, myocardial infarction, and bleeding events following percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS). Thus, PFT-guided treatment could positively affect patient outcomes. Data regarding clinical parameters for predicting platelet reactivity in ACS patients are limited. Therefore, our study aims to evaluate CHADS2 and CHA2DS2-VASc scores as predictors for platelet reactivity in ACS patients. METHODS: Two hundred and ninety-one consecutive patients who underwent PCI and were treated with aspirin and clopidogrel due to ACS were tested for their CHADS2, CHA2DS2-VASc scores and platelet reactivity using adenosine diphosphate (ADP)-induced aggregation (conventional aggregometry). Patients were classified into groups according to their CHADS2 and CHA2DS2-VASc scores. Low-risk group (0-1 score) for CHADS2 and CHA2DS2-VASc scores and high-risk group (2-6, 2-9) for CHADS2 and CHA2DS2-VASc scores, respectively. Furthermore, platelet reactivity in each group were compared (low CHADS2 group vs high CHADS2 group, and low CHA2DS2-VASc vs high CHA2DS2-VASc). Platelet reactivity was defined as low platelet reactivity (<19 U), optimal platelet reactivity [(OPR); 19-46 U], and high on-treatment platelet reactivity [(HPR); >46 U]. Thereafter receiver operating characteristic curve analysis was conducted to verify whether CHADS2 and CHA2DS2-VASc scores could predict platelet reactivity. RESULTS: Low CHADS2 and CHA2DS2-VASc scores were significantly correlated with lower mean platelet ADP-induced aggregation as compared with high CHADS2 and CHA2DS2-VASc scores [45.5 U (± 16) vs. 54.8 U (±15) and 44.2 U (±16) vs. 51.0 U (±17), respectively, p = 0.01 for both]. CONCLUSION: In ACS patients treated with clopidogrel following PCI, high CHADS2 and CHA2DS2-VASc scores correlated with HPR and lower scores correlated with OPR. Further studies are needed to evaluate our findings' clinical implications.

Nature of Cardiac Rehabilitation Around the Globe.

BACKGROUND: Cardiac rehabilitation (CR) is a clinically-effective but complex model of care. The purpose of this study was to characterize the nature of CR programs around the world, in relation to guideline recommendations, and compare this by World Health Organization (WHO) region. METHODS: In this cross-sectional study, a piloted survey was administered online to CR programs globally. Cardiac associations and local champions facilitated program identification. Quality (benchmark of ≥ 75% of programs in a given country meeting each of 20 indicators) was ranked. Results were compared by WHO region using generalized linear mixed models. FINDINGS: 111/203 (54.7%) countries in the world offer CR; data were collected in 93 (83.8%; N = 1082 surveys, 32.1% program response rate). The most commonly-accepted indications were: myocardial infarction (n = 832, 97.4%), percutaneous coronary intervention (n = 820, 96.1%; 0.10), and coronary artery bypass surgery (n = 817, 95.8%). Most programs were led by physicians (n = 680; 69.1%). The most common CR providers (mean = 5.9 ±â€¯2.8/program) were: nurses (n = 816, 88.1%; low in Africa, p < 0.001), dietitians (n = 739, 80.2%), and physiotherapists (n = 733, 79.3%). The most commonly-offered core components (mean = 8.7 ±â€¯1.9 program) were: initial assessment (n = 939, 98.8%; most commonly for hypertension, tobacco, and physical inactivity), risk factor management (n = 928, 98.2%), patient education (n = 895, 96.9%), and exercise (n = 898, 94.3%; lower in Western Pacific, p < 0.01). All regions met ≥ 16/20 quality indicators, but quality was < 75% for tobacco cessation and return-to-work counseling (lower in Americas, p = < 0.05). INTERPRETATION: This first-ever survey of CR around the globe suggests CR quality is high. However, there is significant regional variation, which could impact patient outcomes.

Exercise Hemodynamics for the Diagnosis of Diastolic Dysfunction in Dyspneic Patients with Systemic Sclerosis.

OBJECTIVES: To assess the added diagnostic value of using exercise hemodynamics during RHC in assessment of patients with symptomatic SSc. METHODS: We performed 22 RHCs in 17 SSc patients with dyspnea and/or pulmonary arterial hypertension (PAH). Exercise was performed in 15 RHCs using isotonic arm exercises while holding a 1 kg weight in each hand. Measurements of pulmonary arterial pressure (PAP), pulmonary arterial wedge pressure (PAWP), and cardiac output (CO) were taken at rest and during peak exercise. RESULTS: Normal resting RHC (PAP 22  3 mmHg, PAWP 11  3 mmHg) was found in seven cases. Of these, exercise induced elevation in PAP was found in three (38  7 mmHg), and exercise induced elevation in PAWP was found in four (24  6 mmHg). Elevated resting PAP was found in 15 (41  11 mmHg) with minor changes in exercise. Of the 22 RHCs, elevation of the PAWP was found in 11 (50%), half of which were in response to exercise. CONCLUSIONS: In symptomatic SSc patients, exercise hemodynamics provides important information on diastolic dysfunction that is not available with non-invasive testing. Findings on exercise RHC can explain patient symptoms in up to 50% of cases. Earlier and more accurate diagnosis of patient symptoms can aid in tailoring the correct therapy for each.

Acute myocardial infarction occurring while on chronic clopidogrel therapy ('clopidogrel failure') is associated with high incidence of clopidogrel poor responsiveness and stent thrombosis.

OBJECTIVES: The clinical significance of the laboratory-based phenomenon of clopidogrel hypo-responsiveness and platelet reactivity associated with acute myocardial infarction, despite chronic clopidogrel therapy, is largely unknown. We aimed to determine platelet reactivity and clinical and angiographic features in 29 consecutive patients sustaining an acute myocardial infarction despite chronic (≥1 month) clopidogrel therapy. METHODS: Platelet reactivity was determined on admission using conventional aggregometry. All patients underwent coronary angiography within 24 hours of admission. Patients were matched with clopidogrel-naïve acute myocardial infarction patients. Clopidogrel-naïve patients received a 600 mg clopidogrel loading dose and 75 mg/day thereafter. RESULTS: Of the 29 study patients, 19 (66%) presented with ST-elevation myocardial infarction, and in 25% the infarction was related to angiographically-proved definite stent thrombosis. Two-thirds of these patients were poor responders to clopidogrel (adenosine diphosphate-induced platelet aggregation >50%) and dual antiplatelet poor responsiveness was found in 57% in the chronic clopidogrel therapy group. Compared with clopidogrel-naïve patients, chronic clopidogrel therapy patients were more likely to demonstrate clopidogrel poor responsiveness (66% versus 38%, p = 0.02), to be diabetic (52% versus 33%, p = 0.1) and to have multi-vessel coronary disease (79% versus 55%, p = 0.03). CONCLUSIONS: Patients sustaining acute coronary syndrome despite chronic clopidogrel therapy are more likely to exhibit inadequate platelet inhibition with clopidogrel.

Favorable Short-Term and Long-Term Outcomes Among Patients With Prior History of Malignancy Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is now the treatment of choice for high-surgical risk patients with symptomatic aortic stenosis. Little is known regarding the outcome of TAVR in patients with previous malignancy. METHODS: We investigated 477 patients who underwent TAVR in a tertiary medical center. Subjects were divided into two groups according to malignancy status: no history of malignancy (n = 386) and positive history of malignancy (n = 91). RESULTS: Mean age of the study population was 81 ± 7 years, and 52% were men. No major differences in baseline characteristics were found between groups. All-cause mortality was 24% for both malignancy and non-malignancy groups at a mean follow-up of 851 ± 629 days. Kaplan-Meier survival analysis demonstrated no difference in all-cause mortality between groups. Multivariate Cox regression analysis showed that malignancy status did not affect prognosis regarding overall mortality (hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.5-1.4; P=.46). However, cancer therapy administered within 12-months of TAVR was significantly associated with increased total mortality among patients undergoing TAVR (HR, 4.38; 95% CI, 1.14-16.77; P=.03). CONCLUSIONS: Malignancy is a common comorbidity among TAVR candidates. Mere history of malignancy among elderly patients does not adversely affect short-term or long-term outcomes after TAVR; however, history of recent (<1 year) cancer-related treatment increases the risk for long-term mortality after TAVR. Decisions regarding TAVR among oncological patients should be individualized according to their malignancy status and anticipated life expectancy.

The "Burden" of Malignancy in a Tertiary Hospital Intensive Cardiovascular Care Unit.

OBJECTIVES: During the past decade, the most common causes of mortality and morbidity were cardiovascular diseases and malignancies. The aim of the current study was to describe the incidence, course of admission, and short-term (30-day) prognosis of patients with and without malignancy, admitted to a tertiary center intensive cardiovascular care unit (ICCU). METHODS: A prospective observational study of 2,259 patients admitted to the ICCU was conducted between January 2014 and December 2015. Patients with malignancies (n = 256) were divided into 2 groups: those with solid and those with homogenous tumors. RESULTS: The time of diagnosis was categorized into 3 patient groups: recent (<6 months), 59 patients (23%); late (6-24 months), 49 patients (19%), and very late (>24 months), 148 patients (58%). Those with a history of malignancy were older (73 ± 12 vs. 64 ± 15, p < 0.001) and were more likely to be female (p = 0.002). After using a multivariate logistic regression model analysis, no differences were found in therapeutic interventions and clinical outcomes, including major bleeding and acute renal failure, between patients with and without malignancies. CONCLUSIONS: Patients with a malignancy comprised about 10% of the entire ICCU population. While mortality was independently associated with advanced age, renal failure, and a diagnosis of ST-elevation myocardial infarction, malignancy alone was not found to be independently associated with a higher mortality rate at 30 days of follow-up.

Metformin therapy reduces the risk of malignancy after heart transplantation.

BACKGROUND: Malignancy and diabetes mellitus (DM) cause significant morbidity and mortality after heart transplantation (HTx). Metformin, one of the most commonly used anti-diabetic drugs worldwide, has also been shown to exhibit anti-tumor activity. We therefore investigated the association between metformin therapy and malignancy after HTx. METHODS: The study population comprised 237 patients who underwent HTx between 1991 and 2016 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcome was any cancer recorded during 15 years of follow-up. Treatment with metformin and the development of DM after HTx were assessed as time-dependent factors in the analyses. RESULTS: Of the 237 study patients, 85 (36%) had diabetes. Of the DM patients, 48 (56%) were treated with metformin. Kaplan-Meier survival analysis showed that, at 15 years after HTx, malignancy rate was 4% for DM patients treated with metformin, 62% for those who did not receive metformin and 27% for non-DM patients (log-rank test, p < 0.0001). Consistently, multivariate analysis showed that for DM patients, metformin therapy was independently associated with a significant 90% reduction (hazard ratio = 0.10; 95% confidence interval 0.02 to 0.40; p = 0.001) in the risk of the development of a malignancy. DM patients who were treated with metformin had a markedly lower risk (65%; p = 0.001) for the development of a malignancy or death after HTx as compared with non-DM patients. CONCLUSIONS: Our findings suggest that metformin therapy is independently associated with a significant reduction in the risk of malignancy after HTx.

Chewing versus Swallowing Ticagrelor to Accelerate Platelet Inhibition in Acute Coronary Syndrome - the CHEERS study. For The PLATIS (Platelets and Thrombosis in Sheba) Study Group.

It was the study objective to evaluate whether chewing a 180 mg loading dose of ticagrelor versus an equal dose of traditional oral administration, enhances inhibition of platelet aggregation 1 hour (h) after administering a ticagrelor loading dose in non-ST elevation myocardial infarction (NSTEMI) patients. Dual anti-platelet therapy represents standard care for treating NSTEMI patients. Ticagrelor is a direct acting P2Y12 inhibitor and, unlike clopidogrel and prasugrel, does not require metabolic activation. Fifty NSTEMI patients were randomised to receive either a chewing loading dose of 180 mg ticagrelor or an equal standard oral dose of ticagrelor. Platelet reactivity was evaluated by VerifyNow at baseline, 1 and 4 h post-loading dose. Results are reported in P2Y12 reaction units. Patients then continued to receive standard 90 mg oral ticagrelor twice daily. Baseline characteristics did not differ between the two groups. P2Y12 reaction units in the chewing group compared with the standard group at 0, 1 and 4 h after ticagrelor loading dose were: 245 vs 239 (p=0.59), 45 vs 130 (p=0.001) and 39 vs 60 (p=0.12), respectively, corresponding to a relative inhibition of platelet aggregation of 83 % vs only 47 % at 1 h (p< 0.001), and 84 % vs 77 % (p=0.59) at 4 h. Major adverse cardiac and cardiovascular events at 30 days were low (2 %), occurring in only one patient in the standard group. In conclusion, chewing a 180 mg ticagrelor loading dose is feasible and facilitates both faster and improved early inhibition of platelet aggregation in NSTEMI patients, compared with a standard oral-loading dose.

Real-World Use of Novel P2Y12 Inhibitors in Patients with Acute Myocardial Infarction: A Treatment Paradox.

OBJECTIVE: To assess the real-world use, clinical outcomes, and adherence to novel P2Y12 inhibitors. METHODS: We evaluated 1,093 consecutive acute myocardial infarction patients undergoing a percutaneous intervention. Patients were derived from a prospective, multicenter, nationwide registry and were followed for 30 days; 381 patients (35%) received clopidogrel, 468 (43%) received prasugrel, and 244 (22%) received ticagrelor. Patients treated with clopidogrel were older and more likely to suffer from chronic renal failure and stroke and/or present with non-ST-elevation myocardial infarction (NSTEMI) (p < 0.01 for all). Independent predictors of undertreatment with novel P2Y12 inhibitors included: older age (OR 0.17; 95% CI 0.1-0.27, p < 0.0001), a prior stroke (OR 0.41; 95% CI 0.2-0.68, p = 0.008), and NSTEMI (OR 0.37; 95% CI 0.26-0.54, p < 0.0001). RESULTS: Novel P2Y12 inhibitors were associated with a lower incidence of cardiovascular events, major bleeding, and/or death (7.6 vs.11%, HR 0.67; 95% CI 0.43-1, p = 0.05). However, after a multivariate analysis this trend was not statistically significant. Patients discharged with ticagrelor versus thienopyridines demonstrated a higher rate of crossover to other P2Y12 inhibitors (11 vs. 5%, p = 0.03). CONCLUSIONS: In a real-world cohort, there was an underutilization of novel P2Y12 inhibitors which was more pronounced in higher-risk subsets that might benefit from novel P2Y12 inhibitors at least as much as other patients.

Immediate response to prasugrel loading in patients with ST-elevation myocardial infarction: Predictors and outcome.

INTRODUCTION: Information regarding immediate response to novel P2Y12 inhibitors in ST-elevation myocardial infarction (STEMI) is scarce and has been associated with adequate reperfusion. Recent studies have shown that the onset of anti-platelet effects of novel P2Y12 inhibitors in patients with STEMI might be slower and more variable than in stable coronary syndrome. We aimed to assess the predictors and significance of immediate platelet response to prasugrel loading in STEMI. METHODS: Platelet aggregation (PA) was prospectively evaluated in STEMI patients upon prasugrel loading and at primary percutaneous coronary intervention (PPCI). Early platelet responsiveness was defined as percent reduction of PA from baseline to PPCI, divided by the time lapse from loading to PPCI. High- and low-platelet responsiveness was defined as above and below the median value respectively. RESULTS: Fifty consecutive STEMI patients (age 58±8, 90% male) underwent PPCI with a mean door-to-balloon time of 42±15min. Mean PA upon prasugrel loading and at PPCI was 76±9% and 63±19%, respectively. Older age and prior aspirin use were predictors of low platelet responsiveness to prasugrel [ß=(-0.33), p=0.02 and ß=(-0.28), p=0.04, respectively]. Fast compared with slow responders demonstrated more frequent early ST resolution (93% vs. 72%, p=0.02) and lower peak troponin levels (76±62µg/L vs. 48±28µg/L, p=0.05). CONCLUSIONS: Immediate platelet responsiveness to prasugrel among STEMI patients is highly variable and inversely associated with older age and prior aspirin use. Fast compared with slow responders have improved reperfusion and infarct size markers.

Incidence and Clinical Features of Early Stent Thrombosis in the Era of New P2y12 Inhibitors (PLATIS-2).

Early stent thrombosis (EST) (≤ 30 days after stent implantation) is a relatively rare but deleterious complication of percutaneous coronary intervention (PCI). Administration of newer P2Y12 inhibitors (prasugrel and ticagrelor) combined with aspirin has been shown to reduce the incidence of sub-acute and late stent thrombosis, compared with clopidogrel. We investigated the "real life" incidence of EST in patients from a large acute coronary syndrome (ACS) national registry, where newer P2Y12 inhibitors are widely used. Patients were derived from the ACS Israeli Survey (ACSIS), conducted during 2006, 2008, 2010 and 2013. Major adverse cardiac events (MACE) at 30days were defined as all-cause death, recurrent ACS, EST and stroke.Of the 4717 ACS patients who underwent PCI and stenting, 83% received clopidogrel and 17% newer P2Y12 inhibitors. The rate of EST was similar in both groups (1.7% in the newer P2Y12 inhibitor group vs. 1.4% in the clopidogrel-treated patients, p = 0.42). Results were consistent after multivariate analysis (adjusted HR = 1.06 [p = 0.89]). MACE occurred in 6.4% in the newer P2Y12 inhibitor group compared with 9.2% in the clopidogrel group (P<0.01). However, multivariate logistic regression modeling showed that treatment with newer P2Y12 inhibitors was not significantly associated with the secondary endpoint of MACE when compared with clopidogrel therapy [OR = 1.26 95%CI (0.93-1.73), P = 0.136]. The incidence of "real life" EST at 1month is relatively low, and appears to be similar in patients who receive newer P2Y12 inhibitors as well as in those who receive clopidogrel.

Prior chronic clopidogrel therapy is associated with increased adverse events and early stent thrombosis.

Despite the growing use of clopidogrel, limited data exist regarding the prognostic significance of chronic clopidogrel therapy in patients sustaining acute coronary syndrome (ACS). Our aim was to determine whether patients sustaining ACS while on chronic clopidogrel therapy have a worse prognosis than clopidogrel-naïve patients. A total of 5,386 consecutive ACS patients were prospectively characterised and followed-up for 30 days. Of them, 680 (13%) were treated with clopidogrel prior to the index ACS. Major adverse cardiovascular events (MACE) were defined as death, recurrent ACS, stroke and/or stent thrombosis. Compared with clopidogrel-naïve, chronic clopidogrel-treated patients were older (66 ± 12 vs 63 ± 13, respectively; p<0.01), suffered more from diabetes mellitus, hypertension, dyslipidaemia, prior cardiovascular history, including prior myocardial infarction, revascularisation, coronary artery bypass graft and stroke (p<0.01 for all), and were less likely to present with ST-elevation myocardial infarction (21% vs 45%; respectively; p < 0.001). Prior clopidogrel therapy was associated with a two-fold increase in in-hospital (1.6% vs 0.6%, respectively; p =0.006) as well as 30-day stent thrombosis (2.2% vs 1.0%, respectively; p=0.007). MACE at 30 days was also higher among chronic clopidogrel-treated compared with clopidogrel-naïve patients [12.3% vs 9.4%, respectively; p<0.01]. In multivariate log regression analysis chronic clopidogrel treatment was an independent predictor of stent thrombosis [OR=2.6 (95%CI 1.2-5.6), p=0.001]. Patients sustaining ACS while on chronic clopidogrel treatment are at higher risk for in-hospital and 30-day adverse outcomes, including stent thrombosis.

[A snapshot: the causes of admission and complications to an acute coronary care unit in a tertiary center in Israel].

BACKGROUND: The reasons for admission to the Acute Coronary Care Unit (ACCU) have changed in the past few years. The classical cause of acute coronary syndrome sets aside the causes of acute heart failure and post-procedural complications. There is also a change in the demographic characteristics and co-morbidities of the admitted patients. OBJECTIVES: The aim of this study is to illustrate the current causes of admission and complications during hospitalization in a tertiary center. METHOD: We compiled a computerized prospective registry during the months of January to March 2014. The registry includes the cause of admission, demographic characteristics, co-morbidities, interventions and clinical outcomes. RESULTS: A total of 257 patients were admitted to the ACCU with a calculated sum of 937 hospitalization days. The average age was 67 ± 15; a third of the patients were above the age of 75 and a third were female; 100 patients have presented with other co-morbidities such as COPD, chronic renal failure, CVA or malignancy; and 46% of the patients were admitted due to acute coronary syndrome (ACS). Other causes were acute heart failure, shock and post-procedural complications. The average length of hospitalization was 2.9 ± 1.7 days for ACS patients compared to 4.3 ± 5 days due to other causes. Approximately 25% had developed acute heart failure during their hospital stay; most of them were older with higher rates of co-morbidities. The duration of hospitalization was longer in those patients, 5.5 ± 5 days, compared to 3.2 ± 4 (p < 0.005); 20% of the patients needed mechanical ventilation; 8.3% had acute renal failure; 4.7% acquired infection while hospitalized; 3.1% had major bleeding and 1.9% had arrhythmias. The total mortality rate was 2.3%. Patients who presented with ACS had a mortality rate of 1% compared to patients who were admitted due to heart failure or shock who had a mortality rate of 10.4% in this period. CONCLUSION: We have presented the current trend of admission to the ACCU with a shift from ACS to other cardiac causes such as acute heart failure, shock or peri-procedural complications. The rate of co-morbidities and hospital complications is increasing as the patients' age increases. This shift of patients' characteristics requires a re-examination of the role of the medical staff in this new era. There is a need to increase funding for acquiring new technology, staff education and reinforcing current staff.

The origin of human mesenchymal stromal cells dictates their reparative properties.

BACKGROUND: Human mesenchymal stromal cells (hMSCs) from adipose cardiac tissue have attracted considerable interest in regard to cell-based therapies. We aimed to test the hypothesis that hMSCs from the heart and epicardial fat would be better cells for infarct repair. METHODS AND RESULTS: We isolated and grew hMSCs from patients with ischemic heart disease from 4 locations: epicardial fat, pericardial fat, subcutaneous fat, and the right atrium. Significantly, hMSCs from the right atrium and epicardial fat secreted the highest amounts of trophic and inflammatory cytokines, while hMSCs from pericardial and subcutaneous fat secreted the lowest. Relative expression of inflammation- and fibrosis-related genes was considerably higher in hMSCs from the right atrium and epicardial fat than in subcutaneous fat hMSCs. To determine the functional effects of hMSCs, we allocated rats to hMSC transplantation 7 days after myocardial infarction. Atrial hMSCs induced greatest infarct vascularization as well as highest inflammation score 27 days after transplantation. Surprisingly, cardiac dysfunction was worst after transplantation of hMSCs from atrium and epicardial fat and minimal after transplantation of hMSCs from subcutaneous fat. These findings were confirmed by using hMSC transplantation in immunocompromised mice after myocardial infarction. Notably, there was a correlation between tumor necrosis factor-α secretion from hMSCs and posttransplantation left ventricular remodeling and dysfunction. CONCLUSIONS: Because of their proinflammatory properties, hMSCs from the right atrium and epicardial fat of cardiac patients could impair heart function after myocardial infarction. Our findings might be relevant to autologous mesenchymal stromal cell therapy and development and progression of ischemic heart disease.

Human macrophage regulation via interaction with cardiac adipose tissue-derived mesenchymal stromal cells.

BACKGROUND: Mesenchymal stromal cells (MSCs) improve tissue repair but their mechanism of action is not fully understood. We aimed to test the hypothesis that MSCs may act via macrophages, and that specifically, human cardiac adipose tissue-derived mesenchymal stromal cells (AT-MSCs) can polarize human macrophages into a reparative, anti-inflammatory (M2) phenotype. Methods and RESULTS: We isolated and grew AT-MSCs from human cardiac adipose tissue obtained during cardiac surgery. Macrophages were grown from CD14(+) monocytes from healthy donor blood and then cocultured with AT-MSCs, with and without transwell membrane, for 1 to 14 days. In response to AT-MSCs, macrophages acquired a star-shaped morphology, typical of alternatively activated phenotype (M2), and increased the expression of M2 markers CD206(+), CD163(+), and CD16(+) by 1.5- and 9-fold. Significantly, AT-MSCs modified macrophage cytokine secretion and increased the secretion of anti-inflammatory and angiogenic cytokines: interleukin (IL)-10 (9-fold) and vascular endothelial growth factors (3-fold). Moreover, AT-MSCs decreased macrophage secretion of inflammatory cytokines such as IL-1α (2-fold), tumor necrosis factor α (1.5-fold), IL-17 (3-fold), and interferon gamma (2-fold). Remarkably, the interaction between AT-MSCs and macrophages was bidirectional and macrophages enhanced AT-MSC secretion of typical M2 inducers IL-4 and IL-13. Notably, AT-MSCs decreased macrophage phagocytic capacity. Finally, IL-6 mediates the M2 polarization effect of AT-MSCs on macrophages, by increasing M2-associated cytokines, IL-10 and IL-13. CONCLUSIONS: Human cardiac AT-MSCs can polarize human macrophages into anti-inflammatory phenotype. Our findings suggest a new mechanism of action of AT-MSCs that could be relevant to the pathogenesis and treatment of myocardial infarction, atherosclerosis, and various cardiovascular diseases.