Plasma soluble fms-like tyrosine kinase-1, placental growth factor, and vascular endothelial growth factor system gene variants as predictors of survival in heart failure.

AIMS: Soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt-1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF. METHODS AND RESULTS: ELISA assays for sFlt-1, PlGF and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt-1 or PlGF levels were genotyped. sFlt-1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All-cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt-1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt-1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt-1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57-16.1; p < 0.001) in PEOPLE, independent of age, NT-proBNP, ischaemic aetiology, diabetic status and beta-blocker therapy. CONCLUSIONS: Plasma sFlt-1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF.

CT Angiography Followed by Invasive Angiography in Patients With Moderate or Severe Ischemia-Insights From the ISCHEMIA Trial.

OBJECTIVES: This study aimed to examine the concordance of coronary computed tomographic angiography (CCTA) assessment of coronary anatomy and invasive coronary angiography (ICA) as the reference standard in patients enrolled in the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches). BACKGROUND: Performance of CCTA compared with ICA has not been assessed in patients with very high burdens of stress-induced ischemia and a high likelihood of anatomically significant coronary artery disease (CAD). A blinded CCTA was performed after enrollment to exclude patients with left main (LM) disease or no obstructive CAD before randomization to an initial conservative or invasive strategy, the latter guided by ICA and optimal revascularization. METHODS: Rates of concordance were calculated on a per-patient basis in patients randomized to the invasive strategy. Anatomic significance was defined as ≥50% diameter stenosis (DS) for both modalities. Sensitivity analyses using a threshold of ≥70% DS for CCTA or considering only CCTA images of good-to-excellent quality were performed. RESULTS: In 1,728 patients identified by CCTA as having no LM disease ≥50% and at least single-vessel CAD, ICA confirmed 97.1% without LM disease ≥50%, 92.2% with at least single-vessel CAD and no LM disease ≥50%, and only 4.9% without anatomically significant CAD. Results using a ≥70% DS threshold or only CCTA of good-to-excellent quality showed similar overall performance. CONCLUSIONS: CCTA before randomization in ISCHEMIA demonstrated high concordance with subsequent ICA for identification of patients with angiographically significant disease without LM disease.

Rural and Remote Cardiology During the COVID-19 Pandemic: Cardiac Society of Australia and New Zealand (CSANZ) Consensus Statement.

THE CHALLENGES: Rural and remote Australians and New Zealanders have a higher rate of adverse outcomes due to acute myocardial infarction, driven by many factors. The prevalence of cardiovascular disease (CVD) is also higher in regional and remote populations, and people with known CVD have increased morbidity and mortality from coronavirus disease 2019 (COVID-19). In addition, COVID-19 is associated with serious cardiac manifestations, potentially placing additional demand on limited regional services at a time of diminished visiting metropolitan support with restricted travel. Inter-hospital transfer is currently challenging as receiving centres enact pandemic protocols, creating potential delays, and cardiovascular resources are diverted to increasing intensive care unit (ICU) and emergency department (ED) capacity. Regional and rural centres have limited staff resources, placing cardiac services at risk in the event of staff infection or quarantine during the pandemic. MAIN RECOMMENDATIONS: Health districts, cardiologists and government agencies need to minimise impacts on the already vulnerable cardiovascular health of regional and remote Australians and New Zealanders throughout the COVID-19 pandemic. Changes in management should include.

Absence of Myostatin Improves Cardiac Function Following Myocardial Infarction.

BACKGROUND: Myostatin inhibits the development of skeletal muscle and regulates the proliferation of skeletal muscle fibroblasts. However, the role of myostatin in regulating cardiac muscle or myofibroblasts, specifically in acute myocardial infarction (MI), is less clear. This study sought to determine whether absence of myostatin altered left ventricular function post-MI. METHODS: Myostatin-null mice (Mstn-/-) and wild-type (WT) mice underwent ligation of the left anterior descending artery to induce MI. Left ventricular function was measured at baseline, days 1 and 28 post-MI. Immunohistochemistry and immunofluorescence were obtained at day 28 for cellular proliferation, collagen deposition, and myofibroblastic activity. RESULTS: Whilst left ventricular function at baseline and size of infarct were similar, significant differences in favour of Mstn-/- compared to WT mice post-MI include a greater recovery of ejection fraction (61.8±1.1% vs 57.1±2.3%, p<0.01), less collagen deposition (41.9±2.8% vs 54.7±3.4%, p<0.05), and lower mortality (0 vs. 20%, p<0.05). There was no difference in the number of BrdU positive cells, percentage of apoptotic cardiomyocytes, or size of cardiomyocytes post-MI between WT and Mstn-/- mice. CONCLUSIONS: Absence of myostatin potentially protects the function of the heart post-MI with improved survival, possibly by limiting extent of fibrosis.

ICare-ACS (Improving Care Processes for Patients With Suspected Acute Coronary Syndrome): A Study of Cross-System Implementation of a National Clinical Pathway.

BACKGROUND: Efforts to safely reduce length of stay for emergency department patients with symptoms suggestive of acute coronary syndrome (ACS) have had mixed success. Few system-wide efforts affecting multiple hospital emergency departments have ever been evaluated. We evaluated the effectiveness of a nationwide implementation of clinical pathways for potential ACS in disparate hospitals. METHODS: This was a multicenter pragmatic stepped-wedge before-and-after trial in 7 New Zealand acute care hospitals with 31 332 patients investigated for suspected ACS with serial troponin measurements. The implementation was a clinical pathway for the assessment of patients with suspected ACS that included a clinical pathway document in paper or electronic format, structured risk stratification, specified time points for electrocardiographic and serial troponin testing within 3 hours of arrival, and directions for combining risk stratification and electrocardiographic and troponin testing in an accelerated diagnostic protocol. Implementation was monitored for >4 months and compared with usual care over the preceding 6 months. The main outcome measure was the odds of discharge within 6 hours of presentation RESULTS: There were 11 529 participants in the preimplementation phase (range, 284-3465) and 19 803 in the postimplementation phase (range, 395-5039). Overall, the mean 6-hour discharge rate increased from 8.3% (range, 2.7%-37.7%) to 18.4% (6.8%-43.8%). The odds of being discharged within 6 hours increased after clinical pathway implementation. The odds ratio was 2.4 (95% confidence interval, 2.3-2.6). In patients without ACS, the median length of hospital stays decreased by 2.9 hours (95% confidence interval, 2.4-3.4). For patients discharged within 6 hours, there was no change in 30-day major adverse cardiac event rates (0.52% versus 0.44%; P=0.96). In these patients, no adverse event occurred when clinical pathways were correctly followed. CONCLUSIONS: Implementation of clinical pathways for suspected ACS reduced the length of stay and increased the proportions of patients safely discharged within 6 hours. CLINICAL TRIAL REGISTRATION: URL: https://www.anzctr.org.au/ (Australian and New Zealand Clinical Trials Registry). Unique identifier: ACTRN12617000381381.

Incidence and type of bleeding complications early and late after acute coronary syndrome admission in a New Zealand cohort (ANZACS-QI-7).

AIMS: Use of anti-thrombotic agents has reduced ischaemic events in acute coronary syndromes (ACS), but can increase the risk of bleeding. Identifying bleeding events using a consistent methodology from routinely collected national datasets would be useful. Our aims were to describe the incidence and types of bleeding in-hospital and post-discharge in the All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) cohort. METHODS: 3,666 consecutive patients admitted with ACS (2007-2010) were identified within the ANZACS-QI registry. A set of International Classification of Disease 10 (ICD-10) codes that identified bleeding events was developed. Anonymised linkage to national mortality and hospitalisation datasets was used to identify these bleeding events at the index admission and post-discharge. RESULTS: Three hundred and ninety-nine (10.8%) out of 3,666 patients had at least one bleeding event during a mean follow-up of 1.94 years. One hundred and sixty-one (4.4%) had a bleeding event during their index admission, and 271 (7.4%) patients were re-hospitalised with bleeding during follow-up. Sixty-one patients (37.9%) were transfused for bleeding in the index admission cohort, and 59 patients (21.8%) at a subsequent admission. Procedural bleeding was the most common event during the index admission, whereas gastrointestinal bleeding was the most common delayed bleeding presentation. CONCLUSION: One in ten ACS patients experienced a significant bleeding event within 2 years. The use of this ICD-10 bleeding definition in national ACS cohorts will facilitate the study of bleeding event incidence and type over time and between geographical regions, both nationally and internationally, and the impact of changes in anti-thrombotic therapy and interventional practice.

Seasonal Variations in Hospital Admissions for ST-Elevation Myocardial Infarction in New Zealand.

BACKGROUND: Increased numbers of ST Elevation Myocardial Infarction (STEMI) admissions have been observed during winter in many countries. Our aim was to assess if seasonal variation of STEMI was present in the Waikato region of New Zealand. METHODS: Case notes of patients admitted to Waikato hospital with STEMI between July 1998 and December 2007 were analysed. The incidence of STEMI during summer (December to February), autumn (March to May), winter (June to August) and spring (September to November) were calculated. The individuals were divided into 2 age groups of ≤ 70 and > 70 years of age. RESULTS: A total of 3,569 patients (mean age 66.9 ± 14.1 years, 64% men) were included. STEMI presentation during winter was significantly higher compared with summer (35 ± 13 versus 27.3 ± 11.3 cases per month, P < 0.02) with 3 additional STEMI admissions per fortnight during winter months. The increase in STEMI in winter was more apparent in patients > 70 years of age, with an 8.5% increase in winter admissions compared to summer (P < 0.01). There was no significant difference in the incidence of STEMI between other seasons. CONCLUSION: There is a higher incidence of STEMI during winter in the Waikato region compared with summer. This increased incidence is particularly pronounced in patients over 70 years of age. Further investigations are necessary to elicit potential causes.

Quality of life after late invasive therapy for occluded arteries.

BACKGROUND: The open-artery hypothesis postulates that late opening of an infarct-related artery after myocardial infarction will improve clinical outcomes. We evaluated the quality-of-life and economic outcomes associated with the use of this strategy. METHODS: We compared percutaneous coronary intervention (PCI) plus stenting with medical therapy alone in high-risk patients in stable condition who had a totally occluded infarct-related artery 3 to 28 days after myocardial infarction. In 951 patients (44% of those eligible), we assessed quality of life by means of a battery of tests that included two principal outcome measures, the Duke Activity Status Index (DASI) (which measures cardiac physical function on a scale from 0 to 58, with higher scores indicating better function) and the Medical Outcomes Study 36-Item Short-Form Mental Health Inventory 5 (which measures psychological well-being). Structured quality-of-life interviews were performed at baseline and at 4, 12, and 24 months. Costs of treatment were assessed for 458 of 469 patients in the United States (98%), and 2-year cost-effectiveness was estimated. RESULTS: At 4 months, the medical-therapy group, as compared with the PCI group, had a clinically marginal decrease of 3.4 points in the DASI score (P=0.007). At 1 and 2 years, the differences were smaller. No significant differences in psychological well-being were observed. For the 469 patients in the United States, cumulative 2-year costs were approximately $7,000 higher in the PCI group (P<0.001), and the quality-adjusted survival was marginally longer in the medical-therapy group. CONCLUSIONS: PCI was associated with a marginal advantage in cardiac physical function at 4 months but not thereafter. At 2 years, medical therapy remained significantly less expensive than routine PCI and was associated with marginally longer quality-adjusted survival. (ClinicalTrials.gov number, NCT00004562.)

Intrapericardial IGF-I improves cardiac function in an ovine model of chronic heart failure.

BACKGROUND: Following myocardial infarction, progressive deterioration of left ventricular function often follows, leading eventually to overt heart failure. In the myocardium, there is increased expression of insulin-like growth factor I (IGF-I) mRNA, protein and receptor levels, particularly in the peri-infarct zone, suggesting that IGF-I has a role to play in post-infarct cardiac structure and function. In this study, we examine the effects of exogenous IGF-I on cardiac function. METHODS: Intrapericardial IGF-I (15 microg/kg/d, n=3) or vehicle (sterile saline, n=3) was administered to sheep in chronic heart failure and the results of intrapericardial delivery compared with those of subcutaneous delivery. Left ventricular ejection fraction (EF) was measured to assess cardiac performance. Concentrations of plasma IGF-I were quantified by radioimmunoassay. RESULTS: Intrapericardial delivery of IGF-I resulted in a rapid and sustained increase (P<0.001) in EF, which remained elevated 14 days after cessation of treatment. Subcutaneous IGF-I treatment did not affect EF. Both subcutaneous and intrapericardial IGF-I administration increased concentrations of plasma IGF-I, although concentrations declined prior to the cessation of treatment. CONCLUSIONS: We conclude that the higher concentration of IGF-I in the myocardium, which results from intrapericardial delivery significantly increases EF in chronic heart failure but that subcutaneous delivery of IGF-I does not.

Spatially and temporally distinct expression of fibroblast connexins after sheep ventricular infarction.

OBJECTIVES: Myocardial infarction leads to extensive changes in the organization of cardiac myocytes and fibroblasts, and changes in gap junction protein expression. In the immediate period following ischemia, reperfusion causes hypercontraction, spreading the necrotic lesion. Further progressive infarction continues over several weeks. In reperfusion injury, the nonspecific gap junction channel uncoupler heptanol limits necrosis. We hypothesize that gap junction coupling and fibroblast invasion provide a substrate for progressive infarction via a gap junction mediated bystander effect. METHODS: A sheep coronary occlusion infarct model was used with samples collected at 12, 24 and 48 h, and 6, 12 and 30 d (days) post-infarction. Immunohistochemical labelling of gap junction connexins Cx40, Cx43, and Cx45 was combined with cell-specific markers for fibroblasts (anti-vimentin) and myocytes (anti-myomesin). Double and triple immunolabelling and confocal microscopy were used to follow changes in cardiac myocyte morphology, fibroblast content and gap junction expression after myocardial infarction. Gap junction protein levels and fibroblast numbers were quantified. RESULTS: Within 12 h of ischemia, myocyte viability is impaired within small islands in the ischemic region. These islands spread and fuse into larger infarct zones until 12 d post-infarction. Thereafter, surviving myocytes within the infarct and in the border-zone appear to become stabilized. Distant from the infarct, continuing myocyte disruption is regularly observed, even after 30 d. Cx43 becomes redistributed from intercalated discs to the lateral surface of structurally compromised myocytes within 12 d. Cx45 expressing fibroblasts infiltrate the damaged region within 24 h, becoming most numerous at 6-12 d post-infarction, with peak Cx45 levels at 6 d. Later, Cx43 expressing fibroblasts are observed, and the related Cx43 label increases over the 30 d observation period, even though fibroblast numbers decline after 12 d. Cx40 was only seen in vascular endothelium. CONCLUSIONS: Progressive infarction, identified by myocyte sarcomere disruption and subsequent cell loss, occurs in parallel with fibroblast invasion and gap junction remodeling. Two fibroblast phenotypes occur within infarcts, expressing either Cx43 or Cx45. Coupled fibroblasts may play a number of roles in tissue remodeling following myocardial infarction, including provision of a possible substrate for progressive infarction via a gap junction mediated bystander effect.

Six-month angiographic and 12-month clinical follow-up of MultiLink long (25 to 35 mm) stents for long coronary narrowings in patients with angina pectoris.

There are limited prospective angiographic data on stent deployment for long coronary lesions. This multicenter prospective study enrolled 120 patients with a single de novo stenosis >20 mm in length, in a native vessel > or =3 mm diameter, suitable for a MultiLink stent 25 to 35 mm in length with additional stent deployment if required. Quantitative angiography before and immediately after stenting and at 6-month follow-up assessed restenosis for the complete lesion and for 5-mm segments of the stented and adjacent nonstented vessel. By 1 year, myocardial infarction had occurred in 3% and target vessel repeat revascularization in 12% of patients. The mean stented length (35.8 +/- 14.6 mm) closely matched mean lesion length (30.1 +/- 13.5 mm). Restenosis to > or =50% diameter loss occurred in 32% of patients, but to > or =70% in only 8%. Of the 147 segments (5 mm in length) with baseline stenosis <25%, only 3 patients (2%) developed restenosis of > or =50%, and only in 1 of these was it > or =70%. Stenting of long narrowings is associated with good clinical outcome and a low rate of severe restenosis. Mildly diseased segments of long lesions covered by a stent rarely became severely narrowed and had negligible influence on the overall restenosis rate. These data support a strategy of full lesion coverage by stent deployment.

Percutaneous coronary intervention with bivalirudin anticoagulation, immediate sheath removal, and early ambulation: a feasibility study with implications for day-stay procedures.

We assessed the feasibility and safety of a strategy of transfemoral percutaneous coronary intervention (PCI) with bivalirudin anticoagulation, immediate sheath removal, early ambulation, and, where possible, same-day discharge in 100 consecutive patients. Ambulation was achieved by 2 hr 30 min in 85% of patients and same-day discharge in 26%. PCI was angiographically successful in 97%. In hospital, there were no deaths or Q-wave myocardial infarctions. One patient suffered a non-Q-wave infarction, another in-hospital surgical revascularization and one required blood transfusion for rectal bleeding. Femoral access site hematoma > 5 cm diameter occurred in two patients. In addition, by 1 month there had been one death (at 10 days) and one pseudoaneurysm treated nonsurgically. In this preliminary study, the strategy of bivalirudin bolus anticoagulation, immediate sheath removal, and 2-hr ambulation after PCI appeared safe, with same-day discharge possible in 26% of unselected patients with stable or unstable angina.