Epigenetic processes associated with neonatal spinal transection.

In early development, the spinal cord in healthy or disease states displays remarkable activity-dependent changes in plasticity, which may be in part due to the increased activity of brain derived neurotrophic factor (BDNF). Indeed, BDNF delivery has been efficacious in partially ameliorating many of the neurobiological and behavioral consequences of spinal cord injury (SCI), making elucidating the role of BDNF in the normative developing and injured spinal cord a critical research focus. Recent work in our laboratory provided evidence for aberrant global and locus-specific epigenetic changes in methylation of the Bdnf gene as a consequence of SCI. In the present study, animals underwent thoracic lesions on P1, with cervical and lumbar tissue being later collected on P7, P14, and P21. Levels of Bdnf expression and methylation (exon IX and exon IV), in addition to global methylation levels were quantified at each timepoint. Results indicated locus-specific reductions of Bdnf expression that was accompanied by a parallel increase in methylation caudal to the injury site, with animals displaying increased Bdnf expression at the P14 timepoint. Together, these findings suggest that epigenetic activity of the Bdnf gene may act as biomarker in the etiology and intervention effort efficacy following SCI.

Developmental administration of valproic acid alters DNA methylation and maternal behavior.

Exposure to adversity in early development has powerful and potentially lasting consequences on behavior. Previous work in our laboratory using female Long-Evans rats has demonstrated that exposure to early-life maltreatment manifests into alterations in dam behavior, including a perpetuation of the maltreatment phenotype. These observed behavioral changes coincide with changes in epigenetic activity in the prefrontal cortex (PFC). Further, treating dams with a chromatin modifying agent (Zebularine) normalizes methylation and maltreatment phenotypes, suggesting a link between epigenetic programming and phenotypic outcomes. Here, we sought to investigate if administration of a chromatin modifying agent concurrent with the experience of maltreatment normalizes epigenetic activity associated with maltreatment and alters behavioral trajectories. Administration of valproic acid (VPA) transiently lowered levels of global DNA methylation in the PFC, regardless of exposure to nurturing care or maltreatment. When VPA-exposed animals reached adulthood, they engaged in more adverse behaviors toward their offspring. These data provide further evidence linking epigenetic changes in the developing brain with effects on behavior.

Natural history and prognostic implications of left ventricular end-diastolic pressure in reperfused ST-segment elevation myocardial infarction: an analysis of the thrombolysis in myocardial infarction (TIMI) II randomized controlled trial.

BACKGROUND: The aim of the current study is to assess the natural history and prognostic value of elevated left ventricular end-diastolic pressure (LVEDP) in patients with ST-segment elevation myocardial infarction (STEMI) after reperfusion with thrombolysis; we utilize data from the Thrombolysis in Myocardial Infarction (TIMI) II study. METHODS: A total of 3339 patients were randomized to either an invasive (n = 1681) or a conservative (n = 1658) strategy in the TIMI II study following thrombolysis. To make the current cohort as relevant as possible to modern pharmaco-invasively managed cohorts, patients in the invasive arm with TIMI flow grade ≥ 2 (N = 1201) at initial catheterization are included in the analysis. Of these, 259 patients had a second catheterization prior to hospital discharge, and these were used to define the natural history of LVEDP in reperfused STEMI. RESULTS: The median LVEDP for the whole cohort was 18 mmHg (IQR: 12-23). Patients were divided into quartiles by LVEDP measured during the first cardiac catheterization. During a median follow up of 3 (IQR: 2.1-3.2) years, quartile 4 (highest LVEDP) had the highest incidence of mortality and heart failure admissions. In the cohort with paired catheterization data, the LVEDP dropped slightly from 18 mmHg (1QR: 12-22) to 15 mmHg (IQR: 10-20) (p = 0.01) from the first to the pre-hospital discharge catheterization. CONCLUSIONS: LVEDP remains largely stable during hospitalisation post-STEMI. Elevated LVEDP is a predictor of death and heart failure hospitalization in STEMI patients undergoing successful thrombolysis.

Pre-hospital thrombolysis for ST-segment elevation myocardial infarction in regional Australia: long-term follow up.

BACKGROUND: Delivering reperfusion therapy to patients with ST-segment elevation myocardial infarction (STEMI) in regional areas without access to tertiary cardiology care remains challenging. The systems of care in Hunter New England Health, New South Wales, Australia (area covered = 130 000 km2 ) to provide reperfusion to patients with STEMI involve a 12-lead electrocardiogram in the ambulance, discussion between cardiologist and paramedic, followed by pre-hospital thrombolysis (PHT) delivered in ambulance to appropriate patients >60 min from the cardiac catheterisation laboratories. Patients who can access the cardiac catheterisation laboratories within 60 min are treated with primary percutaneous coronary intervention (PCI). AIMS: We have previously reported excellent 12-month outcomes for patients receiving PHT and the aim of the current analysis is to look at the long term outcomes. METHODS: We assessed long-term all-cause mortality and major adverse cardiovascular events of STEMI patients undergoing PHT in our health district from August 2008 to August 2013 and compared with the primary PCI group. RESULTS: One hundred and fifty (mean age: 62 ± 13 years, males: 76%, n = 114) patients were administered PHT and 334 patients (mean age: 65 ± 13 years, males: 75%, n = 251) underwent primary PCI during the study period. During a median follow up of 6.2 years (interquartile range: 4.8-7.4 years) all-cause mortality was 16% and 19% in the PHT and primary PCI groups respectively (P = 0.4). CONCLUSION: Our real-world experience shows that PHT followed by early transfer to a primary PCI-capable centre is an effective reperfusion strategy, with comparable results to primary PCI, and mortality benefits are sustained to more than 6 years.

Sedation and Analgesia for Cardiac Catheterisation and Coronary Intervention.

BACKGROUND: While cardiac catheterisation is typically well tolerated, discomfort and anxiety are commonplace. Sedation using anxiolytic and analgesic medications has the potential to ameliorate such symptoms, however, is variably employed, with lack of standardised regimens and limited evidence. METHODS: We performed a review of the role of sedation for cardiac catheterisation, including current practices and summarising available evidence relevant to diagnostic and interventional coronary procedures in the cardiac catheterisation laboratory. RESULTS: Use of sedation and the medication regimens employed are highly variable. Available relevant studies are limited in number and mostly small. Sedation appears to modestly reduce anxiety and pain in most studies. The incidence of radial spasm and the consequent need to alter access site is reduced with procedural sedation. The majority of existing evidence applies to benzodiazepines and opioid use, which appear acceptably efficacious and safe when used with appropriate training and staffing; noting opioid medications reduce the absorption of loading doses of oral anti-platelet drugs. CONCLUSIONS: In conclusion, benzodiazepines and opioids result a modest reduction in pain, improved patient tolerability and reduced risk of radial artery spasm. The decision on whether to use sedation, and which agent(s) and dose, should be individualised based on patient factors, including need for oral antiplatelet therapy administration. Appropriate staffing and monitoring is essential.

Incidence, time of occurrence and response to heart failure therapy in patients with anthracycline cardiotoxicity.

BACKGROUND: Anthracyclines are commonly used chemotherapeutic medications. AIM: In the current analysis, we evaluated all-cause mortality and incidence, timing and response to medical therapy of anthracycline cardiotoxicity. METHODS: Left ventricular ejection fraction (LVEF) was serially assessed using gated heart pool scan/echocardiography in patients receiving anthracycline-based chemotherapy from January 2009 to December 2014. RESULTS: A total of 1204 patients was administered anthracyclines during the study period. During a median follow up of 32 (interquartile range: 15-58) months, all-cause mortality was 38% (n = 463), with the incidence of cardiotoxicity 10.2% (n = 123). Only 15.4% (n = 19) patients required heart failure hospitalisation, with 48% (n = 59) of patients commenced on beta blockade therapy and/or angiotensin-converting enzyme inhibitors. The majority of patients (73.2%, n = 90) experienced cardiotoxicity within 1 year of anthracycline initiation. The proportion of patients with complete, partial and no LVEF recovery were 16.3% (n = 20), 29.3% (n = 36) and 54.4% (n = 67) respectively. Mortality was higher in the cardiotoxicity group (49% vs 37%, P < 0.01). History of coronary artery disease, leukaemia, idarubicin use and high cumulative anthracycline dose were predictors of cardiotoxicity. CONCLUSIONS: Cardiotoxicity after anthracycline use predictably occurs within the first year of therapy and is dose-related, with variable degrees of recovery. While the need for hospitalisation for heart failure was uncommon, medical therapy appears underutilised, suggesting there may be a role for improved surveillance and early initiation of treatment.

Elevated Soluble Suppressor of Tumorigenicity 2 Predict Hospital Admissions Due to Major Adverse Cardiovascular Events (MACE).

The role of soluble suppression of tumorigenicity (sST2) as a biomarker in predicting clinical outcomes in patients with cardiovascular diseases (CVD) has not been fully elucidated. In this study, we sought to determine the relationship between sST2 levels and any unplanned hospital readmissions due to a major adverse cardiovascular event (MACE) within 1 year of first admission. Patients (n = 250) admitted to the cardiology unit at John Hunter Hospital were recruited. Occurrences of MACE, defined as the composite of total death, myocardial infarction (MI), stroke, readmissions for heart failure (HF), or coronary revascularization, were recorded after 30, 90, 180, and 365 days of first admission. On univariate analysis, patients with atrial fibrillation (AF) and HF had significantly higher sST2 levels vs. those who did not. Increasing levels of sST2 by quartiles were significantly associated with AF, HF, older age, low hemoglobin, low eGFR, and high CRP levels. On multivariate analysis: high sST2 levels and diabetes remained as risk predictors of any MACE occurrence; an sST2 level in the highest quartile (Q4: >28.4 ng/mL) was independently associated with older age, use of beta-blockers, and number of MACE events within a 1 year period. In this patient cohort, elevated sST2 levels are associated with unplanned hospital admission due to MACE within 1 year, independent of the nature of the index cardiovascular admission.

Absorbable Suture Embolization in Distal Coronary Perforation.

Coronary artery perforation is a rare but serious complication during percutaneous coronary intervention. Distal or small vessel perforation is usually treated by coil, fat, or microsphere embolization. We describe 5 cases of distal coronary perforation that were managed successfully by a novel technique that uses absorbable sutures. (Level of Difficulty: Advanced.).

Pulmonary Hypertension Due to Left Heart Disease: Diagnosis, Pathophysiology, and Therapy.

Pulmonary hypertension (PH) due to left heart disease (LHD) is the most common type of PH and is defined as mean pulmonary artery systolic pressure of >20 mm Hg and pulmonary capillary wedge pressure >15 mm Hg during right heart catheterization. LHD may lead to elevated left atrial pressure alone, which in the absence of intrinsic pulmonary vascular disease will result in PH without changes in pulmonary vascular resistance. Persistent elevation in left atrial pressure may, however, also be associated with subsequent pulmonary vascular remodeling, vasoconstriction, and an increase in pulmonary vascular resistance. Hence, there are 2 subgroups of PH due to LHD, isolated postcapillary PH and combined post- and precapillary PH, with these groups have differing clinical implications. Differentiation of pulmonary arterial hypertension and PH due to LHD is critical to guide management planning; however, this may be challenging. Older patients, patients with metabolic syndrome, and patients with imaging and clinical features consistent with left ventricular dysfunction are suggestive of LHD etiology rather than pulmonary arterial hypertension. Hemodynamic measures such as diastolic pressure gradient, transpulmonary gradient, and pulmonary vascular resistance may assist to differentiate pre- from postcapillary PH and offer prognostic insights. However, these are influenced by fluid status and heart failure treatment. Pulmonary arterial hypertension therapies have been trialed in the treatment with concerning results reflecting disease heterogeneity, variation in inclusion criteria, and mixed end point criteria. The aim of this review is to provide an updated definition, discuss possible pathophysiology, clinical aspects, and the available treatment options for PH due to LHD.

Targeting elevated left ventricular end-diastolic pressure following primary percutaneous coronary intervention for ST-segment elevation myocardial infarction - a phase one safety and feasibility study.

INTRODUCTION: Elevated left ventricular end diastolic pressure (LVEDP) is an independent predictor of mortality and heart failure in patients with ST-segment elevation myocardial infarction (STEMI). Whether lowering elevated LVEDP improves outcomes remains unknown. METHODS: This non-randomized, single blinded study with prospective enrolment and sequential group allocation recruited patients undergoing primary percutaneous coronary intervention for STEMI with LVEDP ⩾ 20 mmHg measured immediately after primary percutaneous coronary intervention. The intervention arm (n=10) received furosemide 40 mg intravenous bolus plus escalating doses of glyceryl trinitrate (100 µg per min to a maximum of 1000 µg) during simultaneous measurement of LVEDP. The control group (n=10) received corresponding normal saline boluses with simultaneous measurement of LVEDP (10 readings over 10 min). Efficacy endpoints were final LVEDP achieved, and the dose of glyceryl trinitrate needed to reduce LVEDP by ⩾ 20%. Safety endpoint was symptomatic hypotension (systolic blood pressure < 90 mmHg). RESULTS: From 1 April 2017 to 23 August 2017 we enrolled 20 patients (age: 64±9 years, males: 60%, n=12, anterior STEMI: 65%, n=13). The mean LVEDP for the whole cohort (n=20) was 29±4 mmHg (intervention group: 28±3 mmHg vs. control group: 31±5 mmHg; p=0.1). The LVEDP dropped from 28±3 to 16±2 mmHg in the glyceryl trinitrate + furosemide group (p <0.01) but remained unchanged in the control group. The median dose of glyceryl trinitrate required to produce ⩾ 20% reduction in LVEDP in the intervention group was 200 µg (range: 100-800). One patient experienced asymptomatic decline in systolic blood pressure to below 90 mmHg. There was no correlation between LVEDP and left ventricular ejection fraction. CONCLUSION: The administration of glyceryl trinitrate plus furosemide in patients with elevated LVEDP following primary percutaneous coronary intervention for STEMI safely reduces LVEDP.

Ibrutinib-related atrial fibrillation: A single center Australian experience.

BACKGROUND: Ibrutinib increases the risk of atrial fibrillation (AF) and is associated with bleeding tendencies. Reported rates of arrhythmia are variable in different studies. The aim of the current analysis was to evaluate the incidence of AF in a single-center cohort of patients. METHODS: This analysis was conducted at Hunter New England Local Health District, Australia between April 1, 2015 and June 30, 2017. We included all consecutive patients commenced on ibrutinib for hematological malignancies. Patients with a history of paroxysmal AF were excluded. The primary end point was incidence of AF. Time to diagnosis and management were secondary outcomes of interest. RESULTS: A total of 24 patients (age 73 ± 9 years, males n = 16 [67%]) were commenced on ibrutinib treatment during the study period with chronic lymphocytic leukemia (n = 21, 88%) as the main indication. During a median follow-up of 12 months, four (17%) patients were diagnosed with AF with increasing age, duration of ibrutinib treatment as associations. The median time to AF diagnosis was 9 (interquartile range [IQR]: 7-18) months. All patients were managed with a rate control strategy with beta blockers as the preferred agents. Three (75%) patients were commenced on anticoagulation for stroke prevention. During a follow-up of 18 (IQR: 17-23) months following AF onset, one patient required hospitalization for AF. There were no bleeding complications reported. CONCLUSIONS: In conclusion, this series noted a higher incidence of AF than previously reported. Oncologists and cardiologists need to be aware of the increased risk of AF in patients receiving ibrutinib.

Common themes in patients requiring urgent cardiothoracic surgery after percutaneous coronary interventions: Case series and review of the literature.

Urgent cardiothoracic surgical intervention for the management of complications of percutaneous coronary intervention is uncommon in the stent era. Nonetheless, given increasing procedural complexity, in part reflecting an aging population, an ongoing hazard for urgent surgery remains. We sought to review the incidence and outcome of urgent cardiothoracic surgery in patients undergoing PCI in a contemporary cohort at a tertiary referral centre. The incidence of cardiothoracic intervention for PCI related complications was low at 0.1% over a ten-year period, with iatrogenic coronary artery and aortic root dissection unable to successfully managed percutaneously recurrent precipitants for surgical involvement. Procedural features associated with the need for urgent surgery are noted and methods to overcome such complications discussed.

ST elevation myocardial infarction in patients with anomalous left main coronary artery: Case series and review of the literature.

Anomalous left main coronary artery is rare. We present four cases where anomalous left main coronary artery was diagnosed during emergent cardiac catheterization for ST elevation myocardial infarction. Procedural characteristics, technical challenges, and relevant literature are discussed.

Echocardiographic assessment of pulmonary artery systolic pressure following treadmill stress testing.

AIMS: The use of treadmill stress echocardiography (SE) for the diagnosis of nascent pulmonary hypertension (PH) has been hampered by a lack of well-defined, post-exercise pulmonary artery systolic pressure (PASP) values across representative age groups in a normal cohort. METHODS AND RESULTS: Five hundred and eleven subjects (mean age: 53 ±14, 68% female) with normal resting PASP were included in the study. All participants performed treadmill exercise using the Bruce protocol to a high level of perceived exertion. PASP was calculated before and immediately after exercise using Doppler assessment of tricuspid regurgitation. For the cohort, post-exercise PASP was 39 ± 7 mmHg (range: 23-64 mmHg) representing an increase of 11 ± 6 mmHg (44%) from resting values (P < 0.001). The 95th centile values for post-exercise PASP were calculated for the following age cohorts: <30 years; 46 mmHg, 31-50 years; 50 mmHg, 51-70 years; 52 mmHg, >70 years; 53 mmHg. There was a modest independent correlation between post-exercise PASP and (i) increasing age and (ii) resting PASP (r2 = 0.35 and 0.49, respectively, P = 0.01). CONCLUSION: An increase of post-exercise PASP was seen in all patients undergoing SE in this study. Age was directly correlated with post-exercise PASP. Using normative data from healthy controls, treadmill SE-derived post-exercise PASP may be a useful adjunct in the diagnosis of PH.

Clozapine and incidence of myocarditis and sudden death - Long term Australian experience.

BACKGROUND: Clozapine is the cornerstone of therapy for refractory schizophrenia; however, the potential for cardiotoxicity is an important limitation in its use. In the current analysis we sought to evaluate the long term cardiac outcomes of clozapine therapy. METHODS: All-cause mortality, incidence of sudden death and time to myocarditis were assessed in a cohort of patients maintained on clozapine between January 2009 and December 2015. All patients had regular electrocardiograms, complete blood count, clozapine levels and echocardiography as part of a formal protocol. RESULTS: A total of 503 patients with treatment-resistant schizophrenia were maintained on clozapine during the study period of which 93 patients (18%) discontinued therapy with 29 (6%) deaths. The incidence of sudden death and myocarditis were 2% (n=10) and 3% (n=14) respectively. Amongst patients with sudden death, 7 out of 10 (70%) were documented to have used illicit drugs prior to death, with a tendency to weight gain also noted. The mean time to myocarditis post clozapine commencement was 15±7days. The reduction in left ventricular ejection fraction in those with myocarditis was 11±2%. CONCLUSION: Myocarditis and sudden cardiac death are uncommon but clinically important complications in a cohort of patients followed while maintained on clozapine undergoing regular cardiac assessment. Further studies are required to document the role of preventive measures for left ventricular dysfunction and sudden cardiac death in this population.

Late complete heart block in an adult patient undergoing percutaneous ventricular septal defect closure.

With advances in transcatheter treatment options, percutaneous device closure of ventricular septal defects has become a safe and practical alternative to surgical repair. While outcomes have been excellent, late complete heart bock has been documented during follow up of pediatric patients. We report a case of late complete heart block complicating percutaneous device closure of a ventricular septal defect in a 37-year-old female requiring permanent pacemaker insertion. The patient underwent transcatheter closure of an atrial and ventricular septal defect in the context of treated pulmonary hypertension and significant intracardiac shunting. Seven months after the procedure, the patient was admitted with presyncope, with electrocardiographic monitoring confirming complete heart block. While previously only reported in the pediatric literature, awareness of the possibility of complete heart block should be considered during the late follow up of adult patients.

Complex right subclavian artery dissection during diagnostic cardiac catheterization.

Vascular complications are important and unfortunate sequelae of cardiac catheterization. We report a case of complex right subclavian artery dissection following attempted diagnostic cardiac catheterization of a right internal mammary artery (RIMA) coronary bypass graft. Subsequent dissection of the right subclavian artery involved the origin of the right vertebral and internal mammary arteries, as well as producing critical right upper limb ischemia. The anatomy dictated that therapy consist of conservative management of the proximal dissection involving the vertebral artery and the RIMA graft origins, with endovascular stent deployment at the distal site of the vessel occlusion. This example reinforces the need for prompt diagnosis and management of vascular complications, and emphasizes the need for available, appropriate skills relevant to the peripheral vascular interventions.