Complex percutaneous coronary intervention in patients unable to undergo coronary artery bypass grafting during the COVID-19 pandemic: insights from the UK-ReVasc Registry.

OBJECTIVES: Cardiac surgery for coronary artery disease was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with disease ordinarily treated with coronary artery bypass grafting (CABG) instead underwent percutaneous coronary intervention (PCI). We sought to describe 12-month outcomes following PCI in patients who would typically have undergone CABG. METHODS: Between March 1 and July 31, 2020, patients who received revascularization with PCI when CABG would have been the primary choice of revascularization were enrolled in the prospective, multicenter UK-ReVasc Registry. We evaluated the following major adverse cardiovascular events at 12 months: all-cause mortality, myocardial infarction, repeat revascularization, stroke, major bleeding, and stent thrombosis. RESULTS: A total of 215 patients were enrolled across 45 PCI centers in the United Kingdom. Twelve-month follow up data were obtained for 97% of the cases. There were 9 deaths (4.3%), 5 myocardial infarctions (2.4%), 12 repeat revascularizations (5.7%), 1 stroke (0.5%), 3 major bleeds (1.4%), and no cases of stent thrombosis. No difference in the primary endpoint was observed between patients who received complete vs incomplete revascularization (residual SYNTAX score £ 8 vs > 8) (P = .22). CONCLUSIONS: In patients with patterns of coronary disease in whom CABG would have been the primary therapeutic choice outside of the pandemic, PCI was associated with acceptable outcomes at 12 months of follow-up. Contemporary randomized trials that compare PCI to CABG in such patient cohorts may be warranted.

Transcoronary electrophysiological parameters in patients undergoing elective and acute coronary intervention.

INTRODUCTION: Percutaneous coronary intervention is performed routinely in the management of myocardial infarction with obstructive coronary disease, but intervention to arteries supplying nonviable myocardium may be harmful. It is important therefore to establish myocardial viability, and there is an unmet need in current clinical practice for real time viability assessment to aid in decision making. Transcoronary pacing to assess myocardial electrophysiological parameters may be a novel viability assessment technique which could be used in this regard. METHODS: Coronary intervention was carried out according to standard departmental procedure with standard equipment. An exchange length coronary guidewire was passed into both target and reference coronary vessels and an over-the-wire balloon or microcatheter was used to insulate the guidewire and allow electrophysiological parameters to be assessed. Readings were obtained from all major epicardial vessels and substantial branches. At each position, an intracoronary electrocardiogram was recorded, and R wave amplitude was measured. Transcoronary pacing was then performed to establish threshold and impedance for each myocardial segment. A viability cardiac MRI scan was performed for each patient. A standard segmental model was used to determine viability in each segment using an 'infarct score' based on degree of late gadolinium enhancement. Studies were reported blinded to the electrical parameters obtained from the coronary guidewire. The primary outcome was the relationship between pacing threshold and myocardial segment infarct score. Secondary outcomes included the relationship between segmental infarct score and R wave height, and between segmental infarct score and pacing impedance. Data were collected on the feasibility of studying the coronary segments as well as safety. RESULTS: Sixty-five patients presenting with stable coronary artery disease or acute coronary syndromes to Leeds General Infirmary between September 2019 and August 2021 were included in the study. Electrophysiological parameters from segments with an infarct score of zero were obtained, with wide variances seen, with no significant difference in impedance or threshold in any territory. There was a significant difference in sensitivity for segments in the right coronary artery territory for both elective and acute patients. This likely relates to reduced myocardial mass in these territories. No significant association between infarct score and sensitivity, impedance or threshold were seen. CONCLUSION: This study has established intracoronary electrophysiological parameters in both normal myocardium and areas of myocardial scar. No reliable association was seen between impedance, threshold or R wave amplitude and degree of myocardial viability, contrasting with prior findings from our group and others. More work is therefore required to fully understand the role of transcoronary pacing in this setting.

Fractional Flow Reserve versus Angiography-Guided Management of Coronary Artery Disease: A Meta-Analysis of Contemporary Randomised Controlled Trials.

Background and Aims: Randomised controlled trials (RCTs) comparing outcomes after fractional flow reserve (FFR)-guided versus angiography-guided management for obstructive coronary artery disease (CAD) have produced conflicting results. We investigated the efficacy and safety of an FFR-guided versus angiography-guided management strategy among patients with obstructive CAD. Methods: A systematic electronic search of the major databases was performed from inception to September 2022. We included studies of patients presenting with angina or myocardial infarction (MI), managed with medications, percutaneous coronary intervention, or bypass graft surgery. A meta-analysis was performed by pooling the risk ratio (RR) using a random-effects model. The endpoints of interest were all-cause mortality, MI and unplanned revascularisation. Results: Eight RCTs, with outcome data from 5077 patients, were included. The weighted mean follow up was 22 months. When FFR-guided management was compared to angiography-guided management, there was no difference in all-cause mortality [3.5% vs. 3.7%, RR: 0.99 (95% confidence interval (CI) 0.62−1.60), p = 0.98, heterogeneity (I2) 43%], MI [5.3% vs. 5.9%, RR: 0.93 (95%CI 0.66−1.32), p = 0.69, I2 42%], or unplanned revascularisation [7.4% vs. 7.9%, RR: 0.92 (95%CI 0.76−1.11), p = 0.37, I2 0%]. However, the number patients undergoing planned revascularisation by either stent or surgery was significantly lower with an FFR-guided strategy [weighted mean difference: 14 (95% CI 3 to 25)%, p =< 0.001]. Conclusion: In patients with obstructive CAD, an FFR-guided management strategy did not impact on all-cause mortality, MI and unplanned revascularisation, when compared to an angiography-guided management strategy, but led to up to a quarter less patients needing revascularisation.

Safety and efficacy of interrupting dual antiplatelet therapy one month following percutaneous coronary intervention: a meta-analysis of randomized controlled trials.

Very short duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) has recently attracted a lot of attention with the introduction of newer generations stents. This is appealing, especially in patients at high bleeding risk. However, none of the trials were powered for the individual ischemic and bleeding endpoints. All randomised controlled trials (RCTs) investigating one-month versus routine duration of DAPT in patients undergoing PCI and reporting outcomes from the time of cessation of DAPT (1 month) to 1 year were eligible for inclusion in the meta-analysis. The pooled risk ratios (RR) with their 95% confidence interval (CI) were calculated with the random-effects model using the Mantel-Haenszel method. Four RCTs involving 26,576 patients were included in this meta-analysis. Cessation of DAPT after 1 month was associated with significantly less major bleeding [RR 0.70, 95%CI (0.51-0.95), P = 0.02, heterogeneity (I2) = 42%]. There was no statistically significant difference in all-cause mortality [RR 0.84 (95%CI 0.69-1.03), P = 0.10, I2 = 0%] and stroke [RR 0.71 (95%CI 0.45-1.13), P = 0.15, I2 = 42%] when compared to routine duration of DAPT. There was also no difference in myocardial infarction (MI) [RR 1.12 (95%CI 0.91-1.39), P = 0.28, I2 = 0%], and definite or probable stent thrombosis [RR 1.49 (95%CI 0.92-2.41), P = 0.11, I2 = 0%] with cessation of DAPT after 1 month. Cessation of DAPT 1 month after PCI was associated with significantly less major bleeding, but there was no difference in the rate of all-cause mortality, stroke, MI and stent thrombosis.

Outcomes following PCI in CABG candidates during the COVID-19 pandemic: The prospective multicentre UK-ReVasc registry.

OBJECTIVES: To describe outcomes following percutaneous coronary intervention (PCI) in patients who would usually have undergone coronary artery bypass grafting (CABG). BACKGROUND: In the United Kingdom, cardiac surgery for coronary artery disease (CAD) was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with "surgical disease" instead underwent PCI. METHODS: Between 1 March 2020 and 31 July 2020, 215 patients with recognized "surgical" CAD who underwent PCI were enrolled in the prospective UK-ReVasc Registry (ReVR). 30-day major cardiovascular event outcomes were collected. Findings in ReVR patients were directly compared to reference PCI and isolated CABG pre-COVID-19 data from British Cardiovascular Intervention Society (BCIS) and National Cardiac Audit Programme (NCAP) databases. RESULTS: ReVR patients had higher incidence of diabetes (34.4% vs 26.4%, P = .008), multi-vessel disease with left main stem disease (51.4% vs 3.0%, P < .001) and left anterior descending artery involvement (94.8% vs 67.2%, P < .001) compared to BCIS data. SYNTAX Score in ReVR was high (mean 28.0). Increased use of transradial access (93.3% vs 88.6%, P = .03), intracoronary imaging (43.6% vs 14.4%, P < .001) and calcium modification (23.6% vs 3.5%, P < .001) was observed. No difference in in-hospital mortality was demonstrated compared to PCI and CABG data (ReVR 1.4% vs BCIS 0.7%, P = .19; vs NCAP 1.0%, P = .48). Inpatient stay was half compared to CABG (3.0 vs 6.0 days). Low-event rates in ReVR were maintained to 30-day follow-up. CONCLUSIONS: PCI undertaken using contemporary techniques produces excellent short-term results in patients who would be otherwise CABG candidates. Longer-term follow-up is essential to determine whether these outcomes are maintained over time.

Preoperative chronic beta-blocker prescription in elderly patients as a risk factor for postoperative mortality stratified by preoperative blood pressure: a cohort study.

BACKGROUND: Recent data suggest that beta blockers are associated with increased perioperative risk in hypertensive patients. We investigated whether beta blockers were associated with an increased risk in elderly patients with raised preoperative arterial blood pressure. METHODS: We conducted a propensity-score-matched cohort study of primary care data from the UK Clinical Practice Research Datalink (2004-13), including 84 633 patients aged 65 yr or over. Conditional logistic regression models, including factors that were significantly associated with the outcome, were constructed for 30-day mortality after elective noncardiac surgery. The effects of beta blockers (primary outcome), renin-angiotensin system (RAS) inhibitors, calcium-channel blockers, thiazides, loop diuretics, and statins were investigated at systolic and diastolic arterial pressure thresholds. RESULTS: Beta blockers were associated with increased odds of postoperative 30-day mortality in patients with systolic hypertension (defined as systolic BP >140 mm Hg; adjusted odds ratio [aOR]: 1.92; 95% confidence interval [CI]: 1.05-3.51). After excluding patients for whom prior data suggest benefit from perioperative beta blockade (patients with prior myocardial infarction or heart failure), rather than adjusting for them, the point estimate shifted slightly (aOR: 2.06; 95% CI: 1.09-3.89). Compared with no use, statins (aOR: 0.35; 95% CI: 0.17-0.75) and thiazides (aOR: 0.28; 95% CI: 0.10-0.78) were associated with lower mortality in patients with systolic hypertension. CONCLUSIONS: These data suggest that the safety of perioperative beta blockers may be influenced by preoperative blood pressure thresholds. A randomised controlled trial of beta-blocker withdrawal, in select populations, is required to identify a causal relationship.

Effects of five preoperative cardiovascular drugs on mortality after coronary artery bypass surgery: A retrospective analysis of an observational study of 16, 192 patients.

BACKGROUND: Statins reduce risk from coronary artery bypass graft (CABG) surgery, but the influence of angiotensin-converting enzyme inhibitors, alpha-2 adrenergic agonists, calcium channel blockers and beta-blockers is less clear. OBJECTIVES: We investigated the association of each of these drugs with perioperative risk, accounting for different confounders, and evaluated the class, dose-response and long-term protective effect of statins. DESIGN: A retrospective analysis of observational data. SETTING: United Kingdom. PATIENTS: Sixteen thousand one hundred and ninety-two patients who underwent CABG surgery during the period 01 January 2004 to 31 December 2013 and contributed data to Primary Care Clinical Practice Research Datalink. EXPOSURE VARIABLES: Cardiovascular drugs. OUTCOME MEASURE: Perioperative mortality within 30 days of surgery. STATISTICAL ANALYSIS: Five multivariable logistic regression models and a further Cox regression model were used to account for preexisting cardiovascular and other comorbidities along with lifestyle factors such as BMI, smoking and alcohol use. RESULTS: Exposure to statins was most prevalent (85.1% of patients), followed by beta-blockers (72.8%), angiotensin-converting enzyme inhibitors (60.5%), calcium channel blockers (42.8%) and alpha-2 adrenergic agonists (1.2%). The mortality rate was 0.8% in patients not prescribed statins and 0.4% in those on statins. Statins were associated with a statistically significant reduced perioperative mortality in all five logistic regression models with adjusted odds ratios (OR) (95% confidence interval, 95% CI) ranging from 0.26 (0.13 to 0.54) to 0.35 (0.18 to 0.67). Cox regression for perioperative mortality [adjusted hazard ratio (95% CI) 0.40 (0.20 to 0.80)] and 6-month mortality [adjusted hazard ratio (95% CI) 0.63 (0.42 to 0.92)] produced similar results. Of the statin doses tested, only simvastatin 40 mg exerted protective effects. The other cardiovascular drugs lacked consistent effects across models. CONCLUSION: Statins appear consistently protective against perioperative mortality from CABG surgery in multiple models, an effect not shared by the other cardiovascular drugs. Further data are needed on whether statins exert class and dose-response effects.

Comparison of clinical characteristics and outcomes in patients with left bundle branch block versus ST-elevation myocardial infarction referred for primary percutaneous coronary intervention.

AIMS: Recent studies have suggested that a low proportion of patients presenting with left bundle branch block (LBBB) require emergency intervention. In this study, we have compared baseline clinical characteristics, angiographic findings and subsequent outcomes in patients with LBBB versus ST-elevation myocardial infarction (STEMI) referred to our tertiary centre for primary percutaneous coronary intervention (PCI). METHODS AND RESULTS: A large retrospective observational study was performed involving 1875 consecutive patients presenting to our single tertiary cardiac centre for primary PCI over a 27-month period. Patients presenting with LBBB (n=155, 8.3%) were significantly older (P<0.0001) and were more likely to be female (P<0.0001) and have a prior history of myocardial infarction (P<0.0001) or coronary artery bypass graft surgery (P=0.005). Rates of acute occlusion (12.2 vs. 63%; P<0.0001) and PCI (26 vs. 83%; P<0.0001) were significantly lower in LBBB patients compared with STEMI patients. Although the 30-day mortality was similar, overall mortality during the 2 years of follow-up was significantly higher in the LBBB group compared with the STEMI group (27.8 vs. 13.9%; P=0.023). CONCLUSION: The incidence of an acutely occluded vessel is low in LBBB when compared with STEMI, but the long-term outcome is significantly worse. Patients with LBBB referred for primary PCI need better risk stratification, and further work is needed to identify potential diagnostic and management strategies.

Clinical feasibility study to detect angiogenesis following bone marrow stem cell transplantation in chronic ischaemic heart failure.

BACKGROUND: Bone marrow stem cell (BMSC) therapy for cardiovascular disease has shown considerable preclinical and clinical promise, but there remains a need for mechanistic studies to help bridge the transition from bench to bedside. We have designed a substudy to our REGENERATE-IHD trial (ClinicalTrial.gov Identifier: NCT00747708) to assess the feasibility of a novel imaging technique to detect angiogenesis following BMSC therapy. METHODS AND RESULTS: Nine patients who had been randomized to receive intracoronary injection of G-CSF-mobilized BMSCs or control (serum) were included in this substudy. Patients underwent SPECT imaging using a novel radiolabelled peptide (Tc-NC100692), which has a high affinity for the αvß3 integrin, an angiogenesis-related integrin. This was repeated 4 days after intracoronary injection of BMSCs/control to assess for neoangiogenesis. The imaging study was well tolerated with no adverse effects. Myocardial tracer uptake was detectable at baseline in all nine patients, with no myocardial uptake seen in two control patients used for comparison. Baseline uptake appeared to correlate with baseline ejection fraction but changes with therapy did not reach statistical significance. CONCLUSION: SPECT imaging with a Tc-NC100692 is feasible in patients with heart failure, with baseline activity suggesting persistent angiogenesis in patients with remote myocardial infarction.

Impact of a chronic total occlusion in a non-infarct related artery on clinical outcomes following primary percutaneous intervention in acute ST-elevation myocardial infarction.

AIMS: We aimed to assess the impact of a non-infarct related artery (IRA) chronic total occlusion (CTO) on clinical outcomes following primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI) in a real-world cohort of patients. METHODS AND RESULTS: This is a retrospective observational study of 1435 patients treated at a large single tertiary cardiac center providing a high-volume PPCI service. Patients with coexisting CTO (4.7%) were significantly more likely to have presented in cardiogenic shock and less likely to achieve TIMI 2/3 flow in the IRA post procedure resulting in lower ejection fraction and higher peak troponin-T levels. A concurrent CTO in a non-IRA was associated with higher in-hospital mortality (16.4% vs 3.1%; P<.001), 30-day mortality (19.4% vs 5.9%; P<.001) and long-term mortality (23.9% vs 12.2%; P=.01). Binary logistic regression analysis showed that the presence of a non-IRA CTO was independently predictive of mortality at 30 days (odds ratio, 3.2; 95% confidence interval, 1.2-8.1) but not for long-term mortality. CONCLUSION: The presence of a coexisting CTO in patients undergoing PPCI for STEMI is associated with adverse clinical outcomes; further work is required to improve prognosis in these patients, which may include early staged revascularization of the non-IRA CTO.

The utility of a guideliner™ catheter in retrograde percutaneous coronary intervention of a chronic total occlusion with reverse cart-the "capture" technique.

The hybrid approach to percutaneous treatment of chronic total occlusion (CTO) of coronary arteries requires both antegrade and retrograde skillsets. In the retrograde approach, wire externalization through the antegrade guide catheter often requires the use of a short donor guide catheter and a long (>150 cm) micro-catheter. Despite this there are occasions where the micro-catheter is unable to reach the anterograde guide catheter because of long collateral channels particularly when the retrograde limb involves a bypass graft. We report such a case where retrograde intervention was used to treat a right coronary artery (RCA) CTO in a patient with stable angina. The retrograde limb involved a saphenous vein graft to the native circumflex artery, which in turn provided collateral channels to the distal RCA. After performing reverse controlled anterograde and retrograde sub-intimal tracking (CART), the retrograde micro-catheter was only able to reach the mid RCA. To solve this, a Guideliner™ catheter was passed on the antegrade wire and successfully advanced over and "captured" the retrograde micro-catheter. Wire externalization was then completed and the RCA was subsequently stented with a good final angiographic result. This case illustrates a novel approach to completing wire externalization and provides a further indication for the role of the Guideliner™ catheter in treating CTOs.

Management of ST elevation myocardial infarction in pregnancy.

A 33-year-old lady in the second trimester of pregnancy presented to the emergency department having suffered a cardiac arrest at home. An emergency caesarean section was performed in the resuscitation area. On return of spontaneous circulation, a 12-lead ECG showed anterior ST elevation myocardial infarction. She was transferred to our tertiary centre for an emergency coronary angiography and was successfully treated, making a full recovery. This case report examines the relatively rare entity of myocardial infarction in pregnancy and looks at the mechanisms underlying this.

The effects of age, disease state, and granulocyte colony-stimulating factor on progenitor cell count and function in patients undergoing cell therapy for cardiac disease.

The potential of autologous bone marrow (BM)-derived progenitor/stem cell (BMSC) therapy for cardiac repair maybe limited by patient-related factors, such as age and the disease process itself. In this exploratory analysis, we assessed the impact of age, different disease states, and granulocyte colony-stimulating factor (G-CSF) therapy on progenitor cell concentration and function in patients recruited to our clinical trials of BMSC therapy for ischaemic heart failure (IHD), dilated cardiomyopathy (DCM), and acute myocardial infarction (AMI). The concentrations of CD34+ cells and endothelial progenitor cells (EPCs) were measured in the peripheral blood (PB) and BM of 201 patients. Additionally, cell mobilization following G-CSF and the functional capability of CD34+ cells (using a colony-forming unit assay) were assessed. We found that older age was associated with a lower PB CD34+ cell concentration in the whole study group as well as blunting the effect of G-CSF on BMSC mobilization in IHD patients. Nonischaemic heart failure (DCM) was associated with a significantly higher baseline PB CD34+ and EPC concentration compared to IHD. Following G-CSF treatment, the CD34+ cell concentration was greater in the BM compared to PB, however, the PB CD34+ cells appeared to have a greater and improved (compared to baseline) functional potential. Our results suggest treatment with G-CSF improves the functional potential of mobilized circulating progenitor cells compared to those in the BM. Further work is required to determine which source of cells is best for the purposes of cardiac repair following G-CSF therapy.

Percutaneous balloon venoplasty of pacemaker-associated superior vena cava obstruction to facilitate upgrade to a biventricular pacing system.

Superior vena cava (SVC) obstruction is an uncommon, but serious, complication of transvenous device implantation. We present a case of a 52-year-old lady admitted for upgrade to a biventricular pacemaker with significant SVC stenosis. Percutaneous balloon venoplasty of the SVC followed by insertion of biventricular pacing leads was carried out as a single procedure with no complications.

Stem cell therapy for heart diseases.

BACKGROUND: Cardiovascular disease is the leading cause of morbidity and mortality worldwide. Despite the advances in medical and catheter-based therapy for acute myocardial infarction the 1-year mortality remains as high as 13% and the 5-year prognosis for patients with heart failure remains as high as 50%. Left ventricular systolic dysfunction, a major determinant of prognosis, is associated with significant loss of cardiomyocytes which was previously thought to be irreversible as the heart was considered a post-mitotic organ. SOURCES OF DATA: Review of literature published in peer reviewed journals and ClinicalTrials.Gov website. AREAS OF AGREEMENT: There is now growing evidence that the human heart is capable of undergoing repair and in recent years there has been an increase in basic and clinical research with the aim of harnessing the regenerative properties of stem cells in order to facilitate restoration of myocardial function. AREAS OF CONTROVERSY: The mechanisms of action of cell therapy with regards to cardiac repair remain unsatisfactorily understood and the magnitude of benefit demonstrated in animal models is yet to be fully translated in humans. GROWING POINTS: The number of clinical trials continues to increase and include treating patients with acute myocardial infarction and chronic heart failure secondary to ischaemic heart disease or dilated cardiomyopathy. AREAS TIMELY FOR DEVELOPING RESEARCH: The future of this field of research will require closer collaboration between scientists and clinicians to understand how cell therapy works and to define the ideal cell type and method of delivery to be able to derive maximum benefit.

Ghrelin exerts a proliferative effect on a rat pituitary somatotroph cell line via the mitogen-activated protein kinase pathway.

OBJECTIVES: Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities and a widespread tissue distribution. Ghrelin is the endogenous ligand of the GH secretagogue receptor type 1a (GHS-R1a), and both ghrelin and the GHS-R1a are expressed in the pituitary. There are conflicting data regarding the effects of ghrelin on cell proliferation. A positive effect on proliferation and activation of the mitogen-activated protein kinase (MAPK) pathway has been found in hepatoma, adipose, cardiomyocyte and prostate cell lines. However, ghrelin has also been shown to have anti-proliferative effects on breast, lung and thyroid cell lines. We therefore examined the effect of ghrelin on the rat pituitary cell line GH3. METHODS: RT-PCR was used for the detection of GHS-R1a and pre-proghrelin mRNA expression in GH3 cells. The effect of ghrelin on cell proliferation was studied using [(3)H]thymidine incorporation; cell counting and the activation of the MAPK pathway were studied using immunoblotting and inhibitors of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinase C (PKC) and tyrosine phosphatase pathways. RESULTS: GHS-R1a and ghrelin mRNA expression were detected in GH3 cells. Ghrelin, at 10(-10) to 10(-6) M concentrations, significantly increased [(3)H]thymidine incorporation (at 10(-9) M, 183+/-13% (means+/-s.e.m.) compared with untreated controls), while 12-phorbol 13-myristate acetate (PMA) at 10(-7) M (used as a positive control) caused a 212+/-14% increase. A reproducible stimulatory effect of desoctanoyl ghrelin was also observed on [(3)H]thymidine incorporation (135+/-5%; P<0.01 at 10(-9) M compared with control), as well as on the cell count (control 6.8 x 10(4)+/-8.7 x 10(3) cells/ml vs desoctanoyl ghrelin (10(-9) M) 1.04 x 10(5)+/-7.5 x 10(3) cells/ml; P<0.01). Ghrelin caused a significant increase in phosphorylated ERK 1/2 in immunoblotting, while desoctanoyl ghrelin showed a smaller but also significant stimulatory effect. The positive effect of ghrelin and desoctanoyl ghrelin on [(3)H]thymidine incorporation was abolished by the MAPK kinase inhibitor U0126, the PKC inhibitor GF109203X and the tyrosine kinase inhibitor tyrphostin 23, suggesting that the ghrelin-induced cell proliferation of GH3 cells is mediated both via a PKC-MAPK-dependent pathway and via a tyrosine kinase-dependent pathway. This could also be clearly demonstrated by Western blot analysis, where a transient increase in ERK 1/2 phosphorylation by ghrelin was attenuated by all three inhibitors. CONCLUSION: We have shown a novel role for ghrelin in stimulating the proliferation of a somatotroph pituitary tumour cell line, suggesting that ERK activation is involved in mediating the effects of ghrelin on cell proliferation. Desoctanoyl ghrelin showed a similar effect. As ghrelin has been shown to be expressed in both normal and adenomatous pituitary tissue, locally produced ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway.