[Show abstract][Hide abstract] ABSTRACT: Raised blood pressure is the leading attributable risk factor for global morbidity and mortality. Real world data demonstrates that half of treated patients are at elevated cardiovascular risk because of inadequately controlled BP. In addition to pharmacotherapy, certain interventional strategies to reduce blood pressure and cardiovascular risk in hypertension can be considered according to international guidelines. One of the newer technologies entering this field is a proprietary arteriovenous coupler device that forms a fixed flow arteriovenous conduit in the central vasculature. In this review, we examine the development of and rationale for the creation of a central arteriovenous anastomosis in patients with hypertension and review the proposed mechanisms by which it may ameliorate hypertension. We critically review the clinical trial evidence base to date and postulate on future therapeutic directions.
Current Hypertension Reports 09/2015; 17(9):585. DOI:10.1007/s11906-015-0585-6 · 3.44 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction Mean platelet volume is increased in the setting of acute myocardial infarction (AMI) and is a poor prognostic marker despite antiplatelet use. The megakaryocyte (platelet precursor) that resides in the bone marrow has a mean physiological ploidy of 16n. Megakaryocyte size and DNA content are also shown to be increased in AMI. To investigate if megakaryocytes of higher ploidy are transcriptionally different and therefore have the ability to produce larger and more active platelets we performed RNA sequencing in megakaryocytes cultured with or without dimethylfasudil (diMF), an exogenous peptide that drives megakaryocyte ploidy further than previously documented by non-selective aurora kinase inhibition.
Methods Human adult blood CD34+ derived megakaryocytes from 4 individuals underwent 3 days of culture with or without 5 µM diMF. RNA from untreated and treated cells was sequenced and used for differential gene and transcript expression analysis.
Results Mean ploidy in the untreated megakaryocytes was 2n while diMF treatment drove mean ploidy to approximately 8n. This was associated with a morphological increase in size and nuclear multilobulation. Differential gene expression analysis revealed that in megakaryocytes that had been driven to high ploidy levels, 33 genes were downregulated while 65 genes underwent significant upregulation when compared with untreated megakaryocytes. Gene ontology analysis demonstrated that the downregulated genes were significantly enriched for transcripts involved in the cell cycle including CDC45, chromatin assembly factor 1β, and MCMs. In contrast, genes that were upregulated in higher ploidy megakaryocytes were significantly enriched for transcripts involved in haemostatic and coagulation pathways including VWF, coagulation factor XIII, thrombin receptor-like 2, PDGFβ, angiopoietin 1, thrombospondin 1 and plasminogen activator inhibitor type 1. Furthermore, glycoprotein IIIa (part of the fibrinogen/VWF receptor) and tubulin β1 (involved in microtubule changes in platelet release) were both significantly upregulated in higher ploidy megakaryocytes. Both of these genes are specific to megakaryocytes and platelets.
Conclusion This is the first analysis of megakaryocytes driven to high ploidy level in vitro using RNA sequencing. Our results demonstrate that along with the anticipated modulation of cell cycle genes with increasing ploidy, higher ploidy megakaryocytes significantly overexpress genes that are involved in megakaryocyte function, platelet activation and thrombosis. These results therefore support a role for platelet production from megakaryocytes of higher ploidy in thrombotic disease.
[Show abstract][Hide abstract] ABSTRACT: Intolerance of antihypertensive medications is a major cause of non-adherence to pharmacotherapy leading to poor blood pressure control in the hypertensive population. We investigated the role of a central iliac arteriovenous (AV) anastomosis in a woman with uncontrolled hypertension due to multidrug intolerances.
A sixty-one year old Caucasian female with long-standing poorly-controlled hypertension was referred with multiple drug intolerances. She was unable to take Amlodipine, Nifedipine, Lercanidipine, Lisinopril, Candesartan, Bendroflumethiazide, Indapamide, Spironolactone, Amiloride, Doxazosin, Bisoprolol due to unacceptable side effects. After multiple pharmacotherapeutic attempts over a one year period, she could only tolerate Nebivolol 2.5 mg daily, liquid Nifedipine solution 16 mg twice daily and one quarter Glyceryl trinitrate (GTN) 5 mg transdermal patch daily. Despite this BP control remained suboptimal and she was offered treatment with the ROX coupler device having declined renal denervation for personal reasons.
At baseline the office BP (OBP) was 165/92 mmHg and 24 hour ambulatory BP (ABP) confirmed suboptimal control with an average daytime mean of 158/83 mmHg, nocturnal mean 126/65 mmHg. At 6 months after creation of a right-sided iliac AV anastomosis, OBP was reduced by 24/21 mmHg), and 24 hour ABP daytime average by 14/12 mmHg. At this point her BP was sufficiently well controlled to allow discontinuation of the nebivolol and GTN patch with no further change in BP at 1 year follow up. Baseline and 6 month echocardiograms both showed mild LVH with no change in ventricular wall thickness or ejection fraction. There was no significant change in renal function post-AV anastomosis. Right heart catheterisation at 6 months showed normal pressure in the right heart and pulmonary system.
This is the first report of a patient with multiple drug intolerances and uncontrolled hypertension undergoing treatment with a central iliac AV anastomosis resulting in early and sustained OBP lowering to target levels and reduction in daytime mean ABP. This novel therapy appears to target mechanical properties of the circulation and may be of benefit in the management of patients with uncontrolled hypertension including those with multiple medication intolerances.
[Show abstract][Hide abstract] ABSTRACT: Tβ4 is an integral factor in repair of myocardium in animal models. To investigate whether Tβ4 is important in human cardiac disease and has a role in mediating the beneficial cardiac effects of bone-marrow-derived stem cell (BMSC) therapy, we measured serial plasma Tβ4 levels in patients enrolled on the REGENERATE-IHD cell therapy trial.
Plasma Tβ4 concentrations were measured in 13 patients who received BMSCs and 14 controls.
There was a significant increase in plasma Tβ4 in the BMSC group 24 h after intracardiac injection. Increases in Tβ4 levels were associated with improvement in New York Heart Association symptom class.
This exploratory study highlights the need for further study of Tβ4 in human cardiovascular disease.
Regenerative Medicine 05/2015; 10(4):403-10. DOI:10.2217/rme.15.9 · 2.79 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The field of percutaneous intervention for chronic total occlusion (CTO) has enjoyed significant innovations in the recent years. Novel techniques and technologies have revolutionized the field and have resulted in considerably higher success rates even in patients with high anatomical complexity. Successful CTO recanalization is associated with significant clinical benefits, such as the improvement of angina and quality of life, reduced rates of surgical revascularization, improvement of left ventricular function and decreased mortality rates. However, complex CTO procedures often require prolonged x-ray exposure which have been associated with adverse long term outcomes.
[Show abstract][Hide abstract] ABSTRACT: The relation between socio-economic status (SES) and outcomes after percutaneous coronary intervention (PCI) has not been established. We sought to determine whether or not socio-economic status impacts on prognosis after PCI.
This was an observational cohort study of 13,770 consecutive patients who underwent PCI at a single centre between 2005 and 2011. Patient socio-economic status was defined by the English Index of Multiple Deprivation (IMD) score, according to residential postcode. Patients were analysed by quintile of IMD score (Q1, least deprived; Q5, most deprived). Median follow-up was 3.7 (IQR: 2.0-5.1) years and the primary outcome was all-cause mortality. Patients in Q5 (most deprived) were younger, more commonly South Asian, and had higher rates of smoking, diabetes mellitus, renal impairment, previous MI, and previous PCI than patients in Q1. Rates of long-term mortality increased progressively across the five quintiles of IMD score in a linear fashion (p=0.0004), as did rates of recurrent MI, target vessel revascularisation, and CABG. The difference in mortality rates persisted after adjustment for other potential confounding factors after multivariate analysis (Q5 vs. Q1: HR 1.93, 95% CI: 1.38-2.69).
In this large contemporary cohort of patients receiving PCI, socio-economic status was associated with prognosis in a linear fashion.
EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 02/2015; 10(11):e1-8. DOI:10.4244/EIJV10I10A196 · 3.77 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction:
Several studies have examined the relationship between age and clinical outcomes in patients with ST-elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PPCI). The majority of studies have concentrated on describing elderly patients and there has been less focus on the profile and outcome of young patients suffering from STEMI. The aim of this study was to describe the clinical profile and outcomes of young patients compared with an older cohort and to establish what risk factors were associated with young patients having PPCI for STEMI.
This was an observational cohort study of 3618 patients with STEMI treated by PPCI at a regional heart attack centre in London between January 2004 and September 2012. Clinical characteristics and outcomes in (young) patients aged ≤45 years were compared with those in (older) patients aged >45 years. The primary and main secondary outcomes were all-cause mortality and major adverse cardiovascular event rates, respectively, at a median follow-up of 3.0 (interquartile range 1.2-4.6) years.
Of the 3618 patients, 367 (10.1%) were aged ≤45 years and 3251 (89.9%) were aged >45 years. The proportion of patients aged ≤45 years increased from 8.5% to 11.5% (p=0.04) during the study period. Compared with older patients, those aged ≤45 years were more likely to be male, smokers, of South Asian ethnicity and to have a family history of premature coronary artery disease. Young patients were less likely to have a history of hypertension, hypercholesterolaemia, diabetes mellitus, previous myocardial infarction, myocardial revascularisation, or to have left ventricular systolic impairment or renal impairment. Over the follow-up period, mortality (2.7% vs. 7.6%; p<0.0001) and major adverse cardiovascular event rates (7.0% vs. 13.5%; p<0.0001) were significantly lower in patients aged ≤45 years compared with older patients. After adjustment for potential confounding factors, young age remained a predictor of reduced all cause mortality when compared with older patients (hazard ratio 0.12 (95% confidence interval 0.04-0.38)), including after incorporation of a propensity score (hazard ratio: 0.14 (95% confidence interval 0.04-0.36)).
In this cohort of patients with STEMI treated by PPCI there was an increasing incidence of young patients aged ≤45 years throughout the study period. These patients were more often male, smokers and of South Asian ethnicity. Outcomes in younger patients was good. Focusing preventative strategies on smokers and high risk ethnic groups may help reduce the incidence of premature coronary artery disease.
European Heart Journal: Acute Cardiovascular Care 01/2015; DOI:10.1177/2048872614567453
[Show abstract][Hide abstract] ABSTRACT: Rationale: Pre-clinical evidence demonstrates that inorganic nitrite, following its in situ conversion to nitric oxide, attenuates consequent myocardial reperfusion injury. Objective: We investigated whether intra-coronary injection of nitrite during primary percutaneous coronary intervention (PCI) might improve infarct size in ST-elevated myocardial infarction (STEMI). Methods and Results: Patients undergoing primary PCI (n=80) were randomised to receive intracoronary (10mL) sodium nitrite (1.8μmol) or NaCl (placebo) before balloon inflation. The primary endpoint was infarct size assessed by measuring creatine kinase (CK) release. Secondary outcomes included infarct size assessed by troponin T release and by cardiac magnetic resonance imaging (CMR) on day 2. Baseline characteristics were similar between the groups. No evidence of differences in CK release (p=0.92), troponin T (p=0.85) or CMR-assessed infarct size (p=0.254) were evident. In contrast there was a reduction in myocardial salvage index (p=0.05) and MACE at 1 year (2.6% vs 15.8%, p=0.04) in the nitrite group. In a 66-patient sub-group with TIMI≤1 flow there was reduced serum CK (p=0.030) and a 19% reduction in CMR-determined infarct size (p=0.034) with nitrite. No adverse effects of nitrite were detected. Conclusions: In this phase II study intra-coronary nitrite infusion did not alter infarct size although a trend to improved myocardial salvage index and a significant reduction in MACE was evident. In a sub-group of patients with TIMI flow≤1 nitrite reduced infarct size and MACE and improved myocardial salvage index indicating that a phase III clinical trial assessing intra-coronary nitrite administration as an adjunct to PCI in STEMI patients is warranted. Clinical Trial Registration: http://clinicaltrials.gov - NCT01584453.
Circulation Research 12/2014; 116(3). DOI:10.1161/CIRCRESAHA.116.305082 · 11.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
It is estimated that up to two thirds of patients presenting with ST-segment-elevation myocardial infarction have multivessel disease. The optimal strategy for treating nonculprit disease is currently under debate. This study provides a real-world analysis comparing a strategy of culprit-vessel intervention (CVI) versus multivessel intervention at the time of primary percutaneous coronary intervention in patients with ST-segment-elevation myocardial infarction.
Methods and results:
We compared CVI versus multivessel intervention in 3984 patients with multivessel disease undergoing primary percutaneous coronary intervention between 2004 and 2011 at all 8 tertiary cardiac centers in London. Multivariable-adjusted models were built to determine independent predictors for in-hospital major adverse cardiovascular events (MACEs) and all-cause mortality at 1 year. To reduce confounding and bias, propensity score methods were used. CVI was associated with reduced in-hospital MACE (4.6% versus 7.2%; P=0.010) and mortality at 1 year (7.4% versus 10.1%; P=0.031). CVI was an independent predictor for reduced in-hospital MACE (odds ratio, 0.49; 95% confidence interval [CI], 0.32-0.75; P<0.001) and survival at 1 year (hazard ratio, 0.65; 95% CI, 0.47-0.91; P=0.011) in the complete cohort; and in 2821 patients in propensity-matched cohort (in-hospital MACE: odds ratio, 0.49; 95% CI, 0.32-0.76; P=0.002; and 1-year survival: hazard ratio, 0.64; 95% CI, 0.45-0.90; P=0.010). Inverse probability treatment weighted analyses also confirmed CVI as an independent predictor for reduced in-hospital MACE (odds ratio, 0.38; 95% CI, 0.15-0.96; P=0.040) and survival at 1 year (hazard ratio, 0.44; 95% CI, 0.21-0.93; P=0.033).
In this observational analysis of patients with ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention, CVI was associated with increased survival at 1 year. Acknowledging the limitations with observational analyses, our findings support current recommended practice guidelines.
[Show abstract][Hide abstract] ABSTRACT: Background:
Current recommendations are for primary percutaneous coronary intervention (pPCI) in ST-elevation myocardial infarction (STEMI) complicated by out of hospital cardiac arrest (OHCA). However, information about longer-term outcomes is sparse, particularly among high-risk patients who do not regain consciousness promptly after resuscitation.
Methods and results:
Of 1836 consecutive patients admitted with STEMI for pPCI between April 2008-October 2011, 132 (7.2%) who had suffered OHCA with recovery of spontaneous circulation (ROSC) form the study population. 101 patients survived to hospital discharge (76.5%) with only one further death in the first year. Prognosis was worse for the 62 patients who were unconscious on arrival and required admission to the intensive therapy unit (ITU), only 54% of whom survived. Every additional minute in the time to ROSC increased the hazard of death by 1.7% while alertness upon ROSC and successful reperfusion in response to pPCI reduced the hazard of death by 90% and 65% respectively. Full neurological recovery was recorded in 85.1% of those who survived to be discharged but in only 30.6% of the 34 survivors who were admitted unconscious and received ITU treatment. Every additional minute in the time to ROSC increased the odds of neurological deficit by 7.0%.
In patients with STEMI who are conscious after OHCA, high rates of survival can be achieved with pPCI, depending in part on the time it takes for ROSC. Prognosis is less good in the subgroup brought to hospital unconscious but even in this high risk group neurologically intact survival can be achieved in about one-third of cases, suggesting the benefit of immediate pPCI in STEMI patients successfully resuscitated after OHCA.
European Heart Journal: Acute Cardiovascular Care 10/2014; 4(4). DOI:10.1177/2048872614555990
[Show abstract][Hide abstract] ABSTRACT: Percutaneous coronary intervention is currently the most commonly used revascularization procedure. This success is a direct consequence of the improved medium- and long-term target vessel patency achieved with drug-eluting stents (DES). However, DES are associated with stent thrombosis (ST), a rare but potentially catastrophic complication. Early interruption of dual anti-platelet therapy (DAPT) is a major risk factor for ST and guidelines recommend a minimum duration of DAPT of 6 to 12 months post implantation. Recently published observational data suggest that premature DAPT interruption is not associated with ST in patients treated with the second-generation Resolute zotarolimus-eluting stent. This article reviews the background to the development of Resolute DES and reviews recently published data on ST and DAPT interruption.
[Show abstract][Hide abstract] ABSTRACT: Objective
National guidelines recommend ‘early’ coronary angiography within 96 h of presentation for patients with non-ST elevation acute coronary syndromes (NSTE-ACS). Most patients with NSTE-ACS present to their district general hospital (DGH), and await transfer to the regional cardiac centre for angiography. This care model has inherent time delays, and delivery of timely angiography is problematic. The objective of this study was to assess a novel clinical care pathway for the management of NSTE-ACS, known locally as the Heart Attack Centre-Extension or HAC-X, designed to rapidly identify patients with NSTE-ACS while in DGH emergency departments (ED) and facilitate transfer to the regional interventional centre for ‘early’ coronary angiography.
This was an observational study of 702 patients divided into two groups; 391 patients treated before the instigation of the HAC-X pathway (Pre-HAC-X), and 311 patients treated via the novel pathway (Post-HAC-X). Our primary study end point was time from ED admission to coronary angiography. We also assessed the length of hospital stay.
Median time from ED admission to coronary angiography was 7.2 (IQR 5.1–10.2) days pre-HAC-X compared to 1.0 (IQR 0.7–2.0) day post-HAC-X (p<0.001). Median length of hospital stay was 3.0 (IQR 2.0–6.0) days post-HAC-X v 9.0 (IQR 6.0–14.0) days pre-HAC-X (p<0.0005). This equates to a reduction of six hospital bed days per NSTE-ACS admission.
The introduction of this novel care pathway was associated with significant reductions in time to angiography and in total hospital bed occupancy for patients with NSTE-ACS.
BMJ Open 09/2014; 4(9):e005525. DOI:10.1136/bmjopen-2014-005525 · 2.27 Impact Factor