Sex Differences in the Inflammatory Response: Pharmacological Opportunities for Therapeutics for Coronary Artery Disease.

Coordinated molecular responses are key to effective initiation and resolution of both acute and chronic inflammation. Vascular inflammation plays an important role in initiating and perpetuating atherosclerotic disease, specifically at the site of plaque and subsequent fibrous cap rupture. Both men and women succumb to this disease process, and although management strategies have focused on revascularization and pharmacological therapies in the acute situation to reverse vessel closure and prevent thrombogenesis, data now suggest that regulation of host inflammation may improve both morbidity and mortality, thus supporting the notion that prevention is better than cure. There is a clear sex difference in the incidence of vascular disease, and data confirm biological differences in inflammatory initiation and resolution between men and women. This article reviews contemporary opinions describing the sex difference in the initiation and resolution of inflammatory responses, with a view to explore potential targets for pharmacological intervention.

An Observational Study Assessing Immediate Complete Versus Delayed Complete Revascularisation in Patients with Multi-Vessel Disease Undergoing Primary Percutaneous Coronary Intervention.

BACKGROUND: More than half of the patients undergoing primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI) have multi-vessel coronary artery disease. This is associated with worse outcomes compared with single vessel disease. Whilst evidence now exists to support complete revascularisation for bystander disease the optimal timing is still debated. This study aimed to compare clinical outcomes in patients with STEMI and multi-vessel disease who underwent complete revascularisation as inpatients in comparison to patients who had staged PCI as early outpatients. METHODS AND RESULTS: We conducted an observational cohort study consisting of 1522 patients who underwent primary PCI with multi-vessel disease from 2012 to 2019. Exclusions included patients with cardiogenic shock and previous CABG. Patients were split into 2 groups depending on whether they had complete revascularisation performed as inpatients or as staged PCI at later outpatient dates. The primary outcome of this study was major adverse cardiac events (consisting of myocardial infarction, target vessel revascularisation and all-cause mortality).834 (54.8%) patients underwent complete inpatient revascularisation and 688 patients (45.2%) had outpatient PCI (median 43 days post discharge). Of the inpatient group, 652 patients (78.2%) underwent complete revascularisation during the index procedure whilst 182 (21.8%) patients underwent inpatient bystander PCI in a second procedure. Overall, there were no significant differences between the groups with regards to their baseline or procedural characteristics. Over the follow-up period there was no significant difference in MACE between the cohorts (P = .62), which persisted after multivariate adjustment (HR 1.21 [95% CI 0.72-1.96]). Furthermore, in propensity-matched analysis there was no significant difference in outcome between the groups (HR: 0.86 95% CI: 0.75-1.25). CONCLUSIONS: Our study demonstrated that the timing of bystander PCI after STEMI did not appear to have an effect on cardiovascular outcomes. We suggest that patients with multi-vessel disease can potentially be discharged promptly and undergo early outpatient bystander PCI. This could significantly reduce length of stay in hospital.

Randomised, double-blind, placebo-controlled clinical trial investigating the effects of inorganic nitrate in hypertension-induced target organ damage: protocol of the NITRATE-TOD study in the UK.

INTRODUCTION: Arterial stiffness and left ventricular (LV) hypertrophy are the key markers of hypertensive target organ damage (TOD) associated with increased cardiovascular morbidity and mortality. We have previously shown that dietary inorganic nitrate supplementation lowers blood pressure (BP) in hypertension, however, whether this approach might also improve markers of hypertensive TOD is unknown. In this study, we will investigate whether daily dietary inorganic nitrate administration reduces LV mass and improves measures of arterial stiffness. METHODS AND DESIGN: NITRATE-TOD is a double-blind, randomised, single-centre, placebo-controlled phase II trial aiming to enrol 160 patients with suboptimal BP control on one or more antihypertensives. Patients will be randomised to receive 4 months once daily dose of either nitrate-rich beetroot juice or nitrate-deplete beetroot juice (placebo). The primary outcomes are reduction in LV mass and reduction in pulse wave velocity (PWV) and central BP.The study has a power of 95% for detecting a 9 g LV mass change by cardiovascular MRI (~6% change for a mildly hypertrophied heart of 150 g). For PWV, we have a power of >95% for detecting a 0.6 m/s absolute change. For central systolic BP, we have a>90% power to detect a 5.8 mm Hg difference in central systolic BP.Secondary end points include change in ultrasound flow-mediated dilation, change in plasma nitrate and nitrite concentration and change in BP. ETHICS AND DISSEMINATION: The study was approved by the London-City and East Research Ethics Committee (10/H0703/98). Trial results will be published according to the Consolidated Standards of Reporting Trials statement and will be presented at conferences and reported in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03088514.

A 'green' diet-based approach to cardiovascular health? Is inorganic nitrate the answer?

Ingestion of fruit and vegetables rich in inorganic nitrate (NO(3)(-)) has emerged as an effective method for acutely elevating vascular nitric oxide (NO) levels through formation of an NO(2)(-) intermediate. As such a number of beneficial effects of NO(3)(-) and NO(2)(-) ingestion have been demonstrated including reductions in blood pressure, measures of arterial stiffness and platelet activity. The pathway for NO generation from such dietary interventions involves the activity of facultative oral microflora that facilitate the reduction of inorganic NO(3)(-), ingested in the diet, to inorganic NO(2)(-). This NO(2)(-) then eventually enters the circulation where, through the activity of one or more of a range of distinct NO(2)(-) reductases, it is chemically reduced to NO. This pathway provides an alternative route for in vivo NO generation that could be utilized for therapeutic benefit in those cardiovascular disease states where reduced bioavailable NO is thought to contribute to pathogenesis. Indeed, the cardiovascular benefits of NO(2)(-) and NO(3)(-) are now starting to be translated in patients in several clinical trials. In this review, we discuss recent evidence supporting the potential utility of delivery of NO(3)(-) or NO(2)(-) for the treatment of cardiovascular diseases.

An incidental finding of a calcified right-atrial mass in a young patient treated with chemotherapy 20 years ago.

We describe a case of a young woman presenting with lethargy and pleuritic chest pain. She had a medical history of leukaemia treated successfully 20 years ago with chemotherapy via a long line. Although initial investigations suggested a diagnosis of pulmonary embolism (PE; on CT pulmonary angiogram (CTPA)) and a possible thrombus in the right atrium, her symptoms appeared out of proportion in relation to this diagnosis. Further imaging using transthoracic echocardiography suggested the presence of a calcified mass in the right atrium. She underwent successful surgical resection of the mass which was found to be attached to the lateral wall of the right atrium. She made an uneventful recovery and continued on warfarin therapy for 6 months in view of the diagnosis of PE on CTPA. We believe the calcified mass was probably caused by the presence of a long line at the time of her chemotherapy.

Chest pain in a young patient: an unusual complication of Epstein-Barr virus.

A 29-year-old man presented with sudden left-sided pleuritic chest pain on a background of sore throat during the preceding week. On examination he had tender cervical lymphadenopathy, he was tachycardic and had a 24 mm Hg blood pressure difference between the left and right arms. Bloods revealed deranged liver function tests and a lymphocytosis. His D-dimer was raised, hence he was treated for presumed pulmonary embolism before imaging was available. Monospot test was positive. He subsequently had both a CT pulmonary angiogram and a CT angiogram of the aorta to exclude pulmonary embolism and aortic dissection. The CT revealed splenomegaly with a large subdiaphragmatic haematoma secondary to splenic rupture. This had likely caused referred pain through diaphragmatic irritation. He was taken to theatre for urgent splenectomy. The unifying diagnosis was infectious mononucleosis complicated by spontaneous splenic rupture secondary to Epstein-Barr virus infection.

Chest pain symptom scoring can improve the quality of referrals to Rapid Access Chest Pain Clinic.

Typical stable angina is a clinical diagnosis based on history. The challenge for GPs in primary care is to identify those patients who are presenting with either possible or typical angina symptoms and refer onwards for specialist assessment in the local Rapid Access Chest Pain Clinic (RACPC). Our initial information gathering study suggested that referring GPs may be cautiously overdiagnosing angina in primary care, potentially resulting in avoidable or unnecessary referrals to RACPC. We sought a practical and cost effective solution to reducing avoidable referrals by assisting GPs with chest pain discrimination. We tested a change of referral form incorporating chest pain symptom scoring to see whether GP referral quality could be improved and then assessed its impact post implementation. GPs that used the chest pain symptom scoring questionnaire were more than twice as likely to correctly discriminate non-cardiac chest pain. Our post implementation study of the new referral form showed that the proportion of referrals to RACPC with diagnosis of non-cardiac chest pain reduced by almost 19%, and there was a statistically significant 30% fall in the total number of referrals to RACPC. This was likely to be driven by the deterrent effect of the novel referral form on avoidable referrals. Fewer avoidable referrals results in shorter wait times for specialist review, reduces the risk of waiting time breach, and improves RACPC efficiency. In summary, chest pain symptom scoring resulted in improved GP discrimination of chest pain, improved referral quality, fewer overall referrals to RACPC and shorter patient wait times. These benefits were achieved without using additional financial resources and without the time or capital expense of training GPs. These findings could assist GPs and Clinical Commisioning Groups to achieve cost savings by reducing avoidable secondary care referrals.

An unusual cause of sustained ventricular tachycardia in a 27-year-old man.

We present an interesting, unusual and complex case of a young man who initially presented with symptoms suggestive of tuberculosis and later developed malignant ventricular arrhythmias. A diagnosis of cardiac sarcoidosis was made only after histological evidence was paired with his presentation of monomorphic ventricular tachycardia. In this case we highlight the current challenges faced in the choice of investigations and diagnostic criteria. Additionally, we have identified the difficulties in treatment and long-term management of such a multisystem disorder. Ultimately by doing so, we hope to encourage clinicians to be aware of making a diagnosis of cardiac sarcoidosis.

Wellens' syndrome in a 24-year-old woman.

Wellens' syndrome refers to specific ECG abnormalities in the precordial T-wave segment, which are associated with critical stenosis of the proximal left anterior descending (LAD) coronary artery culminating in an acute anterior wall myocardial infarction (MI) if the patient is not urgently revascularised. We describe the youngest reported presentation of Wellens' syndrome in a 24-year-old woman with unstable chest pain, characteristic ECG changes and slight troponin biomarker elevation. This was initially unrecognised by the emergency department as unstable coronary syndrome and she subsequently progressed to an anterior non-ST elevation MI (NSTEMI). Her coronary angiogram showed critical narrowing of the proximal LAD which was successfully treated with a drug-eluting stent.