Adipose-derived stem cells: Effectiveness and advances in delivery in diabetic wound healing.

With the increasing global prevalence of diabetes mellitus, a significant rise in the number of patients suffering from non-healing wounds is expected. However, available treatments, such as revascularization surgery and foot care education are often insufficient to ensure satisfactory wound healing. One therapeutic strategy that has been identified as particularly promising utilizes adipose-derived stem cells (ADSCs). Through a comprehensive literature search of published and ongoing studies, we aimed to provide an overview of the experimental basis, the scientific background, and advances in the delivery of ADSCs for treating non-healing diabetic wounds. ADSCs have the capacity to differentiate into multiple cell lineages and are considered an alternative to bone marrow-derived mesenchymal stem cells. They can be easily extracted from the adipose tissue and are capable of in-vitro expansion. The reviewed experimental studies showed that ADSCs can enhance diabetic wound healing through increasing epithelialization and granulation tissue formation, anti-inflammatory and anti-apoptotic effects, and release of angiogenic cytokines. Moreover, few small clinical trials showed that ADSCs treatment in patients with diabetic ulcers caused enhanced ulcer evolution, lower pain scores, and improved claudication walking distances with no reported complications. In conclusion, ADSCs have a promising potential in the regenerative therapy of chronic diabetic wounds. However, larger studies should confirm their efficacy and long-term safety in diabetic patients.

Incidental cardiac findings on computed tomography imaging of the thorax.

BACKGROUND: Investigation of pulmonary pathology with computed tomography also allows visualisation of the heart and major vessels. We sought to explore whether clinically relevant cardiac pathology could be identified on computed tomography pulmonary angiograms (CTPA) requested for the exclusion of pulmonary embolism (PE). 100 consecutive CT contrast-enhanced pulmonary angiograms carried out for exclusion of PE at a single centre were assessed retrospectively by two cardiologists. FINDINGS: Evidence of PE was reported in 5% of scans. Incidental cardiac findings included: aortic wall calcification (54%), coronary calcification (46%), cardiomegaly (41%), atrial dilatation (18%), mitral annulus calcification (15%), right ventricular dilatation (11%), aortic dilatation (8%) and right ventricular thrombus (1%). Apart from 3 (3%) reports describing cardiomegaly, no other cardiac findings were described in radiologists' reports. Other reported pulmonary abnormalities included: lung nodules (14%), lobar collapse/consolidation (8%), pleural effusion (2%), lobar collapse/consolidation (8%), emphysema (6%) and pleural calcification (4%). CONCLUSIONS: CTPAs requested for the exclusion of PE have a high yield of cardiac abnormalities. Although these abnormalities may not have implications for acute clinical management, they may, nevertheless, be important in long-term care.

Markers of thrombosis and hemostasis in acute coronary syndromes: relationship to increased heart rate and reduced heart-rate variability.

BACKGROUND: Acute coronary syndromes (ACS) are characterized by abnormal heart-rate variability (HRV) and biomarkers of endothelial damage and thrombosis. HYPOTHESIS: We hypothesized an association between these factors in patients with ACS. METHODS: We studied 99 patients with ACS measuring HRV and plasma markers of endothelial damage/dysfunction (von Willebrand factor, vWF) and thrombosis/hemostasis (soluble P-selectin (s-Psel); CD(40)-ligand (CD(40)-L); D-dimer). HRV and plasma indices were compared to age- and gender-matched controls. Measures were repeated at 4 months in a subset. vWF, s-Psel and D-Dimer levels were raised compared to control. RESULTS: HRV indices were reduced (mean RR, SDNN, SDNNi, RMSSD, Triangular index, LF and HF). There were weak correlations between mean RR and s-Psel (R = - 0.234, p = 0.023) and D-dimer (R = - 0.219, p = 0.041). At 4-month follow-up, significant correlations were between mean RR and CD(40)L (R = - 0.414, p = 0.008) and D-dimer (R = - 0.363, p = 0.012). On multivariate logistic regression analysis statin use (p = 0.046) was the only independent predictor of acute s-Psel levels. Age (p = 0.004) and mean RR interval (p = 0.01) were independent predictors of D-dimer levels at follow-up. CONCLUSIONS: Abnormal HRV is associated with markers of hemostasis and thrombosis in ACS, and present both in the acute and rehabilitation phases.

Comparative dose titration responses to the introduction of bisoprolol or carvedilol in stable chronic systolic heart failure.

INTRODUCTION: Several beta blocking drugs (BB) reduce mortality in systolic heart failure (LVSD). We have compared the initial response to introduction of carvedilol and bisoprolol during the standard dose titration protocols for each drug. METHODS: Approximately 31 unselected patients with stable LVSD were randomised to either carvedilol or bisoprolol measuring blood pressure, heart rate responses and both time and frequency domain heart rate variability (HRV). RESULTS: One subject died; five withdrew due to intolerable BB related side effects. Carvedilol (n = 13) and bisoprolol (n = 12) attained similar maximal heart rate reduction and induced comparable falls in systolic and diastolic blood pressure. Higher carvedilol doses were associated with lower blood pressure compared to baseline. Individual time domain HRV indices remained unchanged over the initial titration period. Significant increases in triangular Index (TI) were seen with both BB. Carvedilol demonstrated greater (but non-significant) rises in TI compared to Bisoprolol. CONCLUSIONS: In this study we found similar degrees and rate of onset of HR, HRV and BP response to both carvedilol and bisoprolol in treated LVSD patients. Carvedilol appears to show superior HRV rises compared to bisoprolol during initial titration. Any significant increases in HRV attributable to carvedilol compared to bisoprolol may emerge over a longer treatment interval in LVSD.

Oral omega n3-PUFA therapy (Omacor) has no impact on indices of heart rate variability in stable post myocardial infarction patients.

OBJECTIVE: To determine the effects of n3-PUFA supplementation, in the dose used in the GISSI-Prevenzione study, on indices of heart rate variability (HRV) in patients following myocardial infarction (AMI). MATERIALS AND METHODS: Open label randomised single blind controlled trial. Thirty eight patients post AMI, stable on standard secondary prevention drug therapy were single blind randomised to receive either Omacor 1 g/day (n = 21) or usual care (n = 17). HRV indices (time and frequency-domain) were measured at baseline and following 3 months of treatment. RESULTS: At baseline there were no significant differences in clinical, biochemical or HRV indices between patient groups. After 3 months therapy there were no observed changes in measured HRV indices in either the Omacor supplemented or 'usual care' groups. CONCLUSIONS: Three month supplementation of omega 3 PUFA (Omacor) 1 g/day has no effect on HRV is patients post AMI.

Sudden death is less common than might be expected in underprivileged ethnic minorities at high cardiovascular risk.

UNLABELLED: Sudden cardiac death can be the presenting feature of coronary disease. Limited epidemiological studies from the US suggest an increased prevalence of sudden death in the African-American community. There are no reports in UK minority communities. We present sudden death data from an area with a high density of underprivileged ethnic minority groups. METHODS: Ambulance data forms and accident and emergency records of all sudden unexpected deaths bought to City Hospital Birmingham in 2002 were extracted by retrospective review. The clinical characteristics and timing of the events were defined and analysed on the basis of the ethnic origins of the victims. RESULTS: The prevalence of sudden death amongst Caucasians was substantially greater than among minorities. Both Indo-Asians and Afro-Caribbean groups had a lower than expected sudden death rate. Caucasian patients more commonly demonstrated a ventricular fibrillation (VF) rhythm at presentation while Indo-Asians and Afro-Caribbean's demonstrated a non-VF rhythm (asystole and pulseless electrical activity (PEA). Collapse with syncope was more common in Afro-Caribbean subjects while Indo-Asian subjects more often arrested in transit. There were no differences in call or transfer times. CONCLUSIONS: Despite a well-described pattern of more aggressive coronary disease, particularly noted in South Asian communities in the UK, the sudden death rate are not increased and may be decreased. This implies a potentially separate mechanism or a confounding cultural influence in these events.

Short-term adjuvant atorvastatin improves frequency domain indices of heart rate variability in stable systolic heart failure.

UNLABELLED: The autonomic nervous system marks beneficial drug responses in systolic heart failure management. The impact of statin therapy in this broad disease class is unclear and patient studies are extremely limited. METHODS: We studied a group of 23 patients with stable systolic ventricular impairment and randomised them single (patient) blind to high dose Atorvastatin 40 mg daily or placebo in addition to standard therapies over a 12-week treatment interval. Impact on the autonomic nervous system was assessed by anonymised short-term (20 min) standardised supine heart rate variability analyses. RESULTS: Two subjects withdrew one due to decompensation and one due to gastric intolerance. The remaining subjects completed both monitoring events without changes in standard medicines. Frequency domain but not time domain HRV indices improved with active statin therapy suggesting beneficial effects in attenuating sympathetic tone. CONCLUSIONS: In this small study we saw short-term high potency statin treatment had a beneficial impact on frequency domain HRV measures suggestive of an impact on sympatho-activation. We found no effect on time domain HRV indices. This may suggest a lesser or no effect on parasympathetic tone.

Markers of inflammation in acute coronary syndromes: association with increased heart rate and reductions in heart rate variability.

BACKGROUND: Systemic and vascular inflammation is at the heart of the thrombotic occlusion of coronary arteries. HYPOTHESIS: The study was undertaken to determine the relationship between established inflammatory markers (interleukin-6 [IL-6] and high-sensitivity C-reactive protein [hs-CRP]), neutrophil or white cell count, and concomitant autonomic tone in patients with coronary artery disease soon after occlusive events. METHODS: We tested the linkage between autonomic tone (as defined using both time domain and frequency domain estimates of heart rate variability [HRV]) and circulating markers of inflammation (white cell counts, hs-CRP, and IL-6) in a sample of 100 patients with proven acute coronary syndrome and compared these with healthy controls (n = 49) and the relationships on repeated measures at 4 months in recovery (n = 51). RESULTS: We demonstrated predictable depressed HRV in acute patients who tended to show recovery by 4 months. The acute changes in HRV indices (e.g., triangular index) showed modest negative correlation (r = -0.2-0.3) with the acute elevation of white cell count, IL-6, and hs-CRP. These associations did not persist on multivariate analysis of data gathered at 4 months post event. CONCLUSION: These observational data, while limited, are the first to link autonomic tone and in particular sympathetic tone (as indicated by HRV), to the process of acute leukocytosis and systemic inflammation common in acute coronary syndromes.

Heart rate variability estimates of autonomic tone: relationship to mapping pathological and procedural stress responses in coronary disease.

Many lines of experimental evidence suggest the interplay of the autonomic nervous system and a variety of mediators of vascular atheroma and ultimately vascular occlusion. In vivo study in human volunteers and patients is hampered by the lack of a reliable and sensitive marker of prevailing autonomic tone able to reflect the appropriate dynamic change in nervous activity. Currently, the modern standard for definition of autonomic tone is based on a variety of analyses of R-R interval variability from the surface ECG. In this review, we consider whether heart rate variability techniques are sensitive enough to define relevant clinical interactions between neural tone and other mediators of vascular occlusion--specifically, mechanical pressure, thrombotic and hormonal factors--which are relevant to atherosclerotic vascular disease.

Clinical review: clinical management of atrial fibrillation - rate control versus rhythm control.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the critically ill and is associated with adverse outcomes. Although there are plausible benefits from conversion and maintenance of sinus rhythm (the so-called 'rhythm-control' strategy), recent randomized trials have failed to demonstrate the superiority of this approach over the rate-control strategy. Regardless of approach, continuous therapeutic anticoagulation is crucial for stroke prevention. This review addresses the findings of these studies and their implications for clinical management of patients with atrial fibrillation.

Effects of dietary fat intake in sudden death: reduction of death with omega-3 fatty acids.

Sudden death is one of the most common modes of death in those who survive a myocardial infarction. A recent study of 11,324 patients showed a marked decrease in risk of sudden cardiac death as well as a reduction in all-cause mortality in the post-myocardial infarction group taking a highly purified form of omega-3 fatty acids, added to the use of other secondary prevention drugs, including b-blockers and lipid-lowering therapy. There is now amounting evidence indicating that the clinical benefits of highly purified omega-3 fatty acids may be attributed to their anti-arrhythmogenic properties. Evidence for this mechanism of benefit is reviewed here.

The METHRO trials.

Venous thromboembolism is a common and potentially fatal complication among hospital in-patients, particularly those undergoing orthopaedic surgery. Current prophylactic strategies utilise low molecular weight heparins (LMWHs) and warfarin. However, painful subcutaneous injections for LMWHs and delays in achieving target anticoagulation for warfarin pose significant problems clinically. The Melagatran for THRombin inhibition in Orthopaedic surgery (METHRO) trial represents a landmark step in the sequential combination of subcutaneous and oral anticoagulation with melagatran and ximelagatran, respectively, for surgical venous thromboprophylaxis. These agents have proven to be as effective and safe as LMWHs. Furthermore, with no need for dosage adjustment or therapeutic drug monitoring there is emerging evidence that ximelagatran may replace warfarin as the anticoagulant of choice.

Unheralded sudden cardiac death: do autonomic tone and thrombosis interact as key factors in aetiology?

Unheralded sudden cardiac death is a personal and family tragedy that continues to elude research-based progress on aetiology or prevention. Instinctive links between autonomic imbalance, sympathetic activation and serious arrhythmia are longstanding and backed by many observational reports. However the role of the more familiar mechanisms of coronary occlusion and thrombus formation are underplayed. Sympathetic overactivity may also mediate sudden death through precipitation of vasospasm; platelet activation and inhibition of endogenous fibrinolysis as well as the propagation of arrhythmia. The integration of autonomic, thrombotic and vascular tone may be the key to better understanding of the individual process of unheralded sudden cardiac death. In this review we analyse the evidence for this hypothesis.