Although regenerative medicine is searching for pluripotent stem cells that could be employed for therapy, various types of more differentiated adult stem and progenitor cells are in meantime being ...employed in clinical trials to regenerate damaged organs (for example, heart, kidney or neural tissues). It is striking that, for a variety of these cells, the currently observed final outcomes of cellular therapies are often similar. This fact and the lack of convincing documentation for donor-recipient chimerism in treated tissues in most of the studies indicates that a mechanism other than transdifferentiation of cells infused systemically into peripheral blood or injected directly into damaged organs may have an important role. In this review, we will discuss the role of (i) growth factors, cytokines, chemokines and bioactive lipids and (ii) microvesicles (MVs) released from cells employed as cellular therapeutics in regenerative medicine. In particular, stem cells are a rich source of these soluble factors and MVs released from their surface may deliver RNA and microRNA into damaged organs. Based on these phenomena, we suggest that paracrine effects make major contributions in most of the currently reported positive results in clinical trials employing adult stem cells. We will also present possibilities for how these paracrine mechanisms could be exploited in regenerative medicine to achieve better therapeutic outcomes. This approach may yield critical improvements in current cell therapies before true pluripotent stem cells isolated in sufficient quantities from adult tissues and successfully expanded ex vivo will be employed in the clinic.
Circulating bone marrow (BM)-derived stem and progenitor cells (SPCs) participate in turnover of vascular endothelium and myocardial repair after acute coronary syndromes. Acute myocardial infarction ...(MI) produces a generalized inflammatory reaction, including mobilization of SPCs, increased local production of chemoattractants in the ischemic myocardium, as well as neural and humoral signals activating the SPC egress from the BM. Several types of circulating BM cells were identified in the peripheral blood, including hematopoietic stem cells, endothelial progenitor cells, mesenchymal stromal cells, circulating angiogenic cells and pluripotent very small embryonic-like cells; however, the contribution of circulating cells to the myocardial and endothelial repair is still unknown. The number and function of these cells is impaired in patients with diabetes and other cardiovascular risk factors, but can be improved by physical exercise and use of statins. The mobilization of SPCs in acute coronary syndromes and stable coronary artery disease seems to predict the clinical outcomes in selected groups of patients. Interpretation of the findings has to incorporate other factors that modulate the process of mobilization, such as coexisting diseases, age and medications. This review discusses the mobilization of SPCs in acute ischemia (MI, stroke), as well as in stable cardiovascular disease, and highlights the possibility of using the SPC as a marker of cardiovascular risk.
As compared with placebo, carvedilol reduced the risk of death by 35 percent and the combined risk of death or hospitalization by 24 percent.
Beta-blocking agents have been shown to reduce the risk ...of hospitalization and death in patients with mild-to-moderate heart failure,
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but little is known about the efficacy or safety of these agents in severe heart failure. Earlier large-scale studies with bisoprolol, carvedilol, and metoprolol enrolled primarily patients with New York Heart Association class II or III symptoms, and thus they did not provide meaningful information about the effects of these drugs in patients who have symptoms at rest or on minimal exertion. Only one large-scale study of beta-blockade (with bucindolol) focused on patients with severe heart failure; it did not . . .
Abstract Aims Occlusive coronary artery disease (CAD) is associated with left ventricular (LV) remodeling, LV systolic dysfunction, and heart failure. The BEAUTIFUL Echo substudy aimed to evaluate ...the effects of heart rate reduction with ivabradine on LV size (primary end-point: change in LV end-systolic volume index LVESVI) and function and the cardiac biomarker N-terminal pro-brain natriuretic peptide (NT-proBNP). Methods and results The substudy was carried out in 86 centers participating in the BEAUTIFUL study. 2D echocardiography was performed at baseline, and after 3 and 12 months in patients with stable CAD and LV systolic dysfunction receiving ivabradine or placebo at the same time-points. All data were read and analyzed centrally. Of 525 patients completing the study, 426 had adequate echocardiographic readings ( n = 220 ivabradine; n = 206 placebo). Treatment with ivabradine was associated with a decrease in the primary end-point LVESVI (change from baseline to last value, − 1.48 ± 13.00 mL/m2 ) versus an increase with placebo (1.85 ± 10.54 mL/m2 ) ( P = 0.018). There was an increase in LV ejection fraction with ivabradine (2.00 ± 7.02%) versus no change with placebo (0.01 ± 6.20%) ( P = 0.009). Reduction in LVESVI was related to the degree of heart rate reduction with ivabradine. There were no differences in any other echocardiographic parameters or NT-proBNP. Change in LVESVI was related to the log change in NT-proBNP in the ivabradine group only ( r = 0.18, P = 0.006). Conclusions Our observations suggest that ivabradine may reverse detrimental LV remodeling in patients with CAD and LV systolic dysfunction.
Bone marrow-derived cells which may be involved in cardiac repair/regeneration after ischaemic injury must undergo mobilisation into peripheral blood with subsequent homing and engraftment into the ...target organ. Mobilisation of the heterogeneous population of stem/progenitor cells in endothelial injury or myocardial ischaemia has been described recently. The number of circulating stem/progenitor cells reflects the endothelial damage, and turnover may be a surrogate marker reflecting the burden of cardiovascular risk factors and prognostic markers in stable coronary heart disease and acute coronary syndromes. Acute coronary syndromes are associated with increased levels of inflammatory and haematopoietic cytokines which, in turn, can mobilise progenitor cells from the bone marrow. Myocardial infarction increases the number of endothelial progenitor cells and other less well-defined subpopulations, such as CD34/c-kit(+) and CD34/CXCR4(+) cells, which may take part in cardiac repair after ischaemic injury. Data on mobilisation of stem/progenitor cells in acute coronary syndromes are summarised here. Cell types, mechanisms of mobilisation, homing and engraftment are discussed and their relevance to clinical outcomes.
OBJECTIVE:The 2017ACC/AHA high blood pressure (BP) guideline lowered the threshold defining hypertension and BP target in high-risk patients to 130/80 mmHg, Patients with coronary artery disease ...(CAD) and systolic BP 130–139 mmHg or diastolic BP 80–89 mmHg should now receive medication to achieve this target. We aimed to investigate the relationship between BP and cardiovascular events in “real-life” CAD patients considered as normotensive until the recent guideline.
DESIGN AND METHOD:Data from patients with stable CAD, with no history of hypertension and baseline BP < 140/90 mmHg, receiving > = 1 BP-lowering medication prescribed for angina, enrolled in the international CLARIFY registry from November 2009 to June 2010, were analyzed. Patients with heart failure were excluded. A Cox proportional hazards model was used to evaluate the relationship between average BP during follow-up and cardiovascular outcomes. SBP subgroups were defined as < 120 mmHg, 120–129 mmHg (reference), 130–139 mmHg, and > = 140 mmHg. DBP subgroups were defined as < 60, 60–69 mmHg, 70–79 mmHg (reference), 80–89 mmHg, and > = 90 mmHg. The primary endpoint was the composite of cardiovascular death, myocardial infarction and stroke, and secondary endpoints were each component of the primary endpoint.
RESULTS:In 5826 patients (median follow-up 5.0 years), diastolic BP 80–89 mmHg, but not systolic BP 130–139 mmHg, was associated with an increased risk of the primary endpoint (adjusted HRs 1.81, 95% CI 1.09–2.99, and 0.80, 95%CI 0.46–1.40, versus 70–79 mmHg and 120–129 mmHg, respectively). Similar results were observed for cardiovascular death and stroke. No significantly increased risk was observed for systolic BP < 120 mmHg for either endpoint (HR 1.26, 95% CI 0.76 - 2.07, for the primary endpoint). Diastolic BP < 70 mmHg was associated with an increased risk of the primary outcome, but the same was observed for stroke, suggesting a degree of reverse causality.
CONCLUSIONS:In this population of stable CAD patients defined as normotensive according to the 140/90 mmHg threshold, and receiving antianginal BP-lowering medication, achieved diastolic BP 80–89 mmHg was associated with increased cardiovascular risk while achieved systolic BP 130–139 mmHg was not, supporting the lower diastolic but the not the lower systolic BP hypertension-defining threshold and treatment target.
Abstract We intended to estimate how the zero coronary artery calcium (CAC) score in symptomatic patients with intermediate probability of coronary artery disease predicts the absence of obstructive ...non-calcified coronary plaques (NCAPs). CAC scoring and coronary arteries were evaluated by means of 64-multislice CT coronary angiography (CCTA). In 166 subject with CAC = 0, Non-obstructive NCAPs (less than 50%) were found in 17 patients (10.2%), while significant stenosis were diagnosed in 3 (2%). In the female insignificant stenoses were more frequent (12%) than in men (6%), however, all 3 cases with significant stenosis were male. In our study, where CCTA has been used as diagnostic method for CAD diagnosing, the prevalence of non-calcified plaques in CAC = 0 subjects is relatively high. Our study confirms a relatively low incidence of significant coronary stenosis in this subset of CAD-suspected subjects.
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