Randomized placebo controlled trial evaluating the safety and efficacy of single low-dose intracoronary insulin-like growth factor following percutaneous coronary intervention in acute myocardial infarction (RESUS-AMI).

BACKGROUND: Residual and significant postinfarction left ventricular (LV) dysfunction, despite technically successful percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI), remains an important clinical issue. In preclinical models, low-dose insulin-like growth factor 1 (IGF1) has potent cytoprotective and positive cardiac remodeling effects. We studied the safety and efficacy of immediate post-PCI low-dose intracoronary IGF1 infusion in STEMI patients. METHODS: Using a double-blind, placebo-controlled, multidose study design, we randomized 47 STEMI patients with significantly reduced (≤40%) LV ejection fraction (LVEF) after successful PCI to single intracoronary infusion of placebo (n = 15), 1.5 ng IGF1 (n = 16), or 15 ng IGF1 (n = 16). All received optimal medical therapy. Safety end points were freedom from hypoglycemia, hypotension, or significant arrhythmias within 1 hour of therapy. The primary efficacy end point was LVEF, and secondary end points were LV volumes, mass, stroke volume, and infarct size at 2-month follow-up, all assessed by magnetic resonance imaging. Treatment effects were estimated by analysis of covariance adjusted for baseline (24 hours) outcome. RESULTS: No significant differences in safety end points occurred between treatment groups out to 30 days (χ2 test, P value = .77). There were no statistically significant differences in baseline (24 hours post STEMI) clinical characteristics or LVEF among groups. LVEF at 2 months, compared to baseline, increased in all groups, with no statistically significant differences related to treatment assignment. However, compared with placebo or 1.5 ng IGF1, treatment with 15 ng IGF1 was associated with a significant improvement in indexed LV end-diastolic volume (P = .018), LV mass (P = .004), and stroke volume (P = .016). Late gadolinium enhancement (±SD) at 2 months was lower in 15 ng IGF1 (34.5 ± 29.6 g) compared to placebo (49.1 ± 19.3 g) or 1.5 ng IGF1 (47.4 ± 22.4 g) treated patients, although the result was not statistically significant (P = .095). CONCLUSIONS: In this pilot trial, low-dose IGF1, given after optimal mechanical reperfusion in STEMI, is safe but does not improve LVEF. However, there is a signal for a dose-dependent benefit on post-MI remodeling that may warrant further study.

Heart failure symptom burden in outpatient cardiology: observational cohort study.

OBJECTIVES: To assess the self-reported symptom burden in patients with a diagnosis of heart failure attending an outpatient cardiology clinic through the utilisation of validated patient-reported outcome measures. METHODS: Eligible patients were invited to partake in this observational cohort study. Participant demographics and comorbidities were recorded, followed by participants recording their symptoms using the Integrated Palliative care Outcome Scale (IPOS) and Brief Pain Inventory (BPI) outcome measure tools. RESULTS: A total of 22 patients were included in the study. The majority were male (n=15). The median age was 74.5 (range 55-94) years. Atrial fibrillation and hypertension were the most common comorbidities (n=10). Dyspnoea, weakness and poor mobility were the most prevalent symptoms, affecting 15 (68%) of the 22 patients. Dyspnoea was reported as being the most troublesome symptom. The BPI was completed by 68% (n=15) of the study participants. Median average pain score was 5/10; median worst pain score in the preceding 24 hours was 6/10 and median pain score at time of BPI completion was 3/10. The impact of pain on daily living during the preceding 24 hours ranged from impacting on all activities (n=7) to not impacting on activities (n=1). CONCLUSIONS: Patients with heart failure experience a range of symptoms that vary in severity. Introduction of a symptom assessment tool in the cardiology outpatient setting could help identify patients with a high symptom burden and prompt timely referral to specialist palliative care services.

Phenotypic and genetic analyses of two Campylobacter fetus isolates from a patient with relapsed prosthetic valve endocarditis.

Campylobacter fetus can cause intestinal and systemic disease in humans and are well-established veterinary and economic pathogens. We report the complete genomic sequences of two C. fetus subsp. fetus (Cff) isolates recovered in 2017 (CITCf01) and 2018 (CITCf02) from a case of recurrent prosthetic valve endocarditis. Both were capable of growth aerobically. Their genomes were found to be highly conserved and syntenic with 99.97% average nucleotide identity (ANI) while differences in their respective sap loci defined the temporal separation of their genomes. Based on core genome phylogeny and ANI of 83 Cff genomes belonging to the previously described human-associated Cff lineage, CITCf01 and CITCf02 grouped in a clade of 11 sequence type (ST)3 Cff (including the Cff type strain NCTC 10842T). CITCf01 and CITCf02 were marked for their lack of unique genomic features when compared to isolates within the subspecies and the type strain in particular. We identified point mutations in oxidative stress response genes, among others, that may contribute to aerobiosis. We report a case of Cff causing relapsed prosthetic valve endocarditis and we highlight the sap island as a polymorphic site within the genetically stable ST3 lineage, central to pathogenicity.

COVID-19-induced postural orthostatic tachycardia syndrome treated with ivabradine.

A 22-year-old woman was referred with exertional dyspnoea and chest tightness 3 weeks following a diagnosis of COVID-19. Evaluation revealed a resting sinus tachycardia and criteria for postural orthostatic tachycardia syndrome were met. After non-pharmacological interventions failed to yield symptomatic improvement, ivabradine was commenced. This intervention was followed by a substantial improvement in the patient's exercise tolerance and energy levels and an objective reduction in supine and standing heart rate.

Guideline-led prescribing to ambulatory heart failure patients in a cardiology outpatient service.

Background Guidelines recommend heart failure (HF) patients be treated with multiple medications at doses proven to improve clinical outcomes. Objective To study guideline-led prescribing in an Irish outpatient HF population. Setting Cardiology Outpatient Clinic, Mercy University Hospital, Cork, Ireland. Methods Guideline-led prescribing was assessed using the Guideline Adherence Index (GAI-3), that considered the prescribing of ACE inhibitors and angiotensin receptor blockers; beta-blockers and mineralocorticoid receptor antagonists. The GAI-based target dose was calculated based on the prescription of ≥ 50% of the guideline-recommended target dose of each of the three GAI medications to HF patients with ejection fraction ≤ 40%. High-GAI was achieved by prescription of ≥ 2 GAI medicines. Potentially inappropriate prescribing was assessed using a HF-specific tool. Main outcome measure Heart failure guideline-led prescribing assessed using the GAI-3. Results A total of 127 HF patients, mean age 71.7 ± 13.1 years, were identified in the study. Seventy-one patients had ejection fraction ≤ 40%. Population mean GAI-3 was 65.8%. When contraindications to therapy are considered, the adjusted GAI-3 increased to 72.9%. The target dose GAI was 18.5%. High-GAI management was prescribed to 54 patients (76.1%). A potentially inappropriate medicine in HF was prescribed to 14 (19.7%) patients. Conclusion Most HF patients with ejection fraction ≤ 40% in this setting received optimal guideline-led prescribing however the proportion of patients achieving the target doses of these agents was suboptimal.

Inferolateral T wave inversion in athletes: phenotype-genotype correlation.

AIMS: Significant T wave inversion in young asymptomatic athletes is rare but poses a significant clinical challenge. Pre-participation sports screening programs identify such subjects. Clinical concern that such ECG changes represent an occult cardiomyopathy or forme fruste hypertrophic cardiomyopathy leads to diagnostic and therapeutic dilemma. We sought to genotype a cohort of such subjects with a normal cardiac phenotype identified in our unit over a 3-year period. METHODS: Ten athletes were referred from external screening. All exhibited deep T wave inversion inferolaterally. All had negative family history for sudden death and had a normal phenotype. A panel of 133 cardiac genes were screened. RESULTS: Ten male subjects with mean age of 39 years were screened. Seven had no evidence of mutations. Three subjects demonstrated variants of uncertain significance in 5 different genes: alpha-2-actinin (ACTN2), myopalladin (MYPN), the calcium channel genes CACNA1C and TRPM4 and potassium channel gene KCNQ1. The variants found have not been described in cardiomyopathies or channelopathies. At 3-year follow-up, one patient had undergone detraining, and his ECG showed complete resolution of all T wave changes. He did not have any demonstrated variants. CONCLUSIONS: The absence of mutations in target genes and heterogeneous sequence variations identified in this study suggest that inferolateral T wave inversion in athletes without a phenotype may potentially represent a benign repolarization syndrome related to athletic adaptation. This was the first study to assess a phenotype-genotype correlation in this population. Further genetic studies need to be undertaken in this area.

First reported detection of biofilm formation by Campylobacter fetus during investigation of a case of prosthetic valve endocarditis.

AIMS: Campylobacter fetus subsp fetus (CFF) can cause intestinal illness, particularly in immunocompromised humans, with the potential to cause severe systemic infections. CFF is a zoonotic pathogen with a broad host range among farm animals and humans, inducing abortion in sheep and cows. The current paper describes a strain of CFF isolated from a patient with prosthetic valve endocarditis in Mercy University Hospital, Cork, Ireland, during 2017. Only five cases of C. fetus as a cause of prosthetic valve endocarditis have been reported in the literature, with no reports of biofilm formation within the species. METHODS: The aetiological strain was speciated and subspeciated by the VITEK 2 NH card and matrix-assisted laser desorption ionisation time-of-flight mass spectrometry. CFF biofilm formation was analysed using a crystal violet staining method. C. jejuni National Collection of Type Cultures (NCTC) 11168 was used as a positive control organism. Strains were incubated statically in Mueller-Hinton broth and Mueller-Hinton broth supplemented with 0.025% sodium deoxycholate for 3 and 7 days at 37°C, microaerobically. RESULTS: The CFF strain formed stronger attached biofilms on polystyrene plates on day 3 (72 hours) than the C. jejuni NCTC 11168 control strain, but were weaker than the control strain on day 7 in Mueller-Hinton broth. Monoculture of this C. fetus isolate was found to exist in three defined forms of biofilms (attached, air-liquid interface and floccules). CONCLUSIONS: This clinically significant C. fetus isolate showed considerable biofilm-forming capability, which we suggest conferred a survivalist advantage, contributing to the genesis of infective prosthetic valve endocarditis.

Draft Genome Sequence of Campylobacter fetus subsp. fetus CITCf01, Isolated from a Patient with Subacute Bacterial Endocarditis.

Campylobacter fetus is a Gram-negative, zoonotic pathogen and a member of the class Epsilonproteobacteria We report the draft genome sequence of C. fetus subsp. fetus CITCf01, isolated from a patient with subacute bacterial endocarditis. CITCf01 grew under aerobic, microaerobic, and anaerobic conditions, and at 42°C, an unusual combination of growth conditions.

Massive thrombus in the aortic arch: a 59-year-old lady with an unknown familial predisposition to vascular thrombosis.

The following is an account of a 58-year-old lady who presented to our institution with two episodes of acute limb ischemia: one upper, which required embolectomy; and one lower, which required a below knee amputation. We subsequently performed transesophageal echocardiography (TOE), which revealed very large mobile echogenic masses adherent to the wall of her aortic arch, described below.

Eosinophilic myocarditis as a first presentation of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

We present the case of a 28-year-old man who presented with chest pain and elevated cardiac biomarkers, with no evidence of acute ischaemia. He had a pronounced eosinophilia, abnormal echocardiographic, cardiac MRI and CT findings. He underwent transbronchial biopsy of carinal lymph nodes and of lung parenchyma. Endomyocardial biopsy yielded an eosinophilic infiltrate. He was treated with high dose glucocorticoids and made a rapid recovery. Testing for FIP1L1-PDGFRA and other BCR-ABL1 mutations was negative. Ultimately, he was diagnosed with eosinophilic granulomatosis with polyangiitis, also known as Churg-Strauss syndrome.

A case of autosomal recessive hypercholesterolemia responsive to proprotein convertase subtilisin/kexin 9 inhibition.

We report the first case of hypercholesterolemia due to autosomal recessive hyperlipidemia caused by LDLRAP1 mutation responding favorably to PCSK9 inhibition.

Seizure versus syncope.

One of the most common but difficult management problems in medicine is that of patients who present with a paroxysmal loss of consciousness. All too often the underlying diagnosis remains elusive. This has a cost both in terms of mortality and ongoing morbidity and in terms of the financial burden associated with hospitalisation and repeated investigations. We describe a practical approach to this clinical dilemma, which is rooted in adherence to basic principles of history taking and examination, formulation of a reasonable differential diagnosis, followed by an intelligent use of specific investigations and selection of an appropriate treatment. We also discuss the effect of sudden unexpected death in epilepsy and sudden cardiac death. Despite a careful and thorough approach to the patient with a "seizure versus syncope" problem, many will require repeated assessment before a diagnosis is made.

The role of statins in preventing stroke.

Epidemiological studies have not demonstrated a clear relationship between stroke risk and hypercholesterolemia. Clinical trials using statins have demonstrated a reduction in stroke, in particular, in patients with established coronary artery disease. The disparity between epidemiological and clinical studies suggests hypercholesterolemia is a true risk factor for stroke that evaded detection in epidemiological studies, or that statins possess other properties that render them useful in stroke prevention. These effects have been loosely termed "pleiotropic" in the lipid literature and revolve around putative effects of statins on endothelial function, inflammation, thrombosis, plaque stability, and immune regulation. Questions remain as to the mechanisms of benefit of statin therapy in stroke prevention, the role of statins in the primary prevention of stroke, and the role of statins in modulating the immune system in the brain.

A novel CX3CR1 antagonist eluting stent reduces stenosis by targeting inflammation.

We evaluated the therapeutic efficacy of a novel drug eluting stent (DES) inhibiting inflammation and smooth muscle cell (SMC) proliferation. We identified CX3CR1 as a targetable receptor for prevention of monocyte adhesion and inflammation and in-stent neointimal hyperplasia without interfering with stent re-endothelization. Efficacy of AZ12201182 (AZ1220), a CX3CR1 antagonist was evaluated in inhibition of monocyte attachment in vitro. A prototype AZ1220 eluting PLGA-based polymer coated stent developed with an optimal elution profile and dose of 1 µM/stent was tested over 4 weeks in a porcine model of coronary artery stenting. Polymer coated stents without AZ1220 and bare metal stents were used as controls. AZ1220 inhibited monocyte attachment to CX3CL1 in a dose dependent manner. AZ1220 eluted from polymer coated stents in an ex vivo flow system retained bioactivity in inhibiting monocyte attachment to CX3CL1. At 4 weeks following deployment, AZ1220 eluting stents significantly reduced (∼60%) in-stent stenosis compared to both bare metal and polymer only coated stents and markedly reduced peri-stent inflammation and monocyte/macrophage accumulation without affecting re-endothelization. Anti-CX3CR1 drug eluting stents potently inhibited in-stent stenosis and may offer an alternative to mTOR targeting by current DES, specifically inhibiting polymer-induced inflammatory response and SMC proliferation, while retaining an equivalent re-endothelization response to bare metal stents.

Prevention of stroke and dementia with statins: Effects beyond lipid lowering.

Stroke is a major cause of mortality and morbidity. The epidemiologic association between elevated serum cholesterol and stroke risk is controversial. However, recent secondary prevention studies with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have demonstrated a significant reduction in ischemic stroke without an increase in hemorrhagic stroke. Statins probably reduce stroke by a variety of mechanisms, including modulation of precerebral atherothrombosis in the aorta and the carotid artery, thus preventing plaque disruption and artery-to-artery thromboembolism. Statins also improve endothelial homeostasis by increasing the bioavailability of nitric oxide, which orchestrates the paracrine antiatherosclerotic functions of the endothelium. Studies in experimental models of ischemic stroke show that statin therapy reduces brain infarct size and improves neurologic outcome by directly upregulating brain endothelial nitric oxide synthase. Putative anti-inflammatory actions of statins may also contribute to neuroprotection and stroke prevention. Although the clinical benefit of statins largely depends on lowering low-density lipoprotein cholesterol, accumulating data indicate that many of the pleiotropic effects of statins are attributable to the cellular consequences of depletion of intermediates in the cholesterol biosynthetic pathway (isoprenoids). These molecules play fundamental roles in cell growth, signal transduction, and mitogenesis. In addition to reducing stroke risk, emerging data suggest that statins may reduce dementia. Further studies are needed to fully address the role of statins in the prevention of stroke in patients without established vascular disease and the role of cholesterol modulation in the treatment of dementia.

Coronary artery anomalies: a practical approach to diagnosis and management.

The authors deal with common coronary anomalies, discuss their anatomy and some diagnostic and clinical aspects, and describe some of the principles of management.