Colchicine and high-intensity rosuvastatin in the treatment of non-critically ill patients hospitalised with COVID-19: a randomised clinical trial.

OBJECTIVE: To evaluate the effect of colchicine and high-intensity rosuvastatin in addition to standard of care on the progression of COVID-19 disease in hospitalised patients. DESIGN: A pragmatic, open-label, multicentre, randomised controlled trial conducted from October 2020 to September 2021. Follow-up was conducted at 30 and 60 days. The electronic medical record was used at all stages of the trial including screening, enrolment, randomisation, event ascertainment and follow-up. SETTING: Four centres in the Yale New Haven Health System. PARTICIPANTS: Non-critically ill hospitalised patients with COVID-19. INTERVENTIONS: Patients were randomised 1:1 to either colchicine plus high-intensity rosuvastatin in addition to standard of care versus standard of care alone. Assigned treatment was continued for the duration of index hospitalisation or 30 days, whichever was shorter. PRIMARY AND SECONDARY OUTCOME MEASURES: The prespecified primary endpoint was progression to severe COVID-19 disease (new high-flow or non-invasive ventilation, mechanical ventilation, need for vasopressors, renal replacement therapy or extracorporeal membrane oxygenation, or death) or arterial/venous thromboembolic events (ischaemic stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism) evaluated at 30 days. RESULTS: Among the 250 patients randomised in this trial (125 to each arm), the median age was 61 years, 44% were women, 15% were Black and 26% were Hispanic/Latino. As part of the standard of care, patients received remdesivir (87%), dexamethasone (92%), tocilizumab (18%), baricitinib (2%), prophylactic/therapeutic anticoagulation (98%) and aspirin (91%). The trial was terminated early by the data and safety monitoring board for futility. No patients were lost to follow-up due to electronic medical record follow-up. There was no significant difference in the primary endpoint at 30 days between the active arm and standard of care arm (15.2% vs 8.8%, respectively, p=0.17). CONCLUSIONS: In this small, open-label, randomised trial of non-critically ill hospitalised patients with COVID-19, the combination of colchicine and rosuvastatin in addition to standard of care did not appear to reduce the risk of progression of COVID-19 disease or thromboembolic events, although the trial was underpowered due to a lower-than-expected event rate. The trial leveraged the power of electronic medical records for efficiency and improved follow-up and demonstrates the utility of incorporating electronic medical records into future trials. TRIAL REGISTRATION: NCT04472611.

Haemophilus Parainfluenzae mural endocarditis with large atrial septal defect and peripheral embolization.

Mural endocarditis is a rare subclass of infective endocarditis (IE) associated with intra-cardiac tumors, prosthesis, valvular vegetation's, or structural abnormalities such as ventricular septal defects. Bacteria classified as HACEK (Haemophilus species, Aggregatibacter actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) are rare causes of IE found in only 1.3% to 10% of cases. We describe the second reported case of mural endocarditis involving the left ventricle (LV) caused by a Haemophilus species. A young male with no prior intravenous drug use, valvular heart disease, or recent dental work presented with splenic infarcts. H. para-influenza was identified on blood cultures. Cardiac imaging revealed a 1.5 cm LV mass underneath the posterior leaflet of the mitral valve and a large Atrial Septal Defect (ASD). Awaiting surgery, the patient sustained embolic and hemorrhagic cerebral events. The patient underwent debulking of LV mass, ASD closure, and mitral valve repair complicated by post-pericardiotomy syndrome, and he completed six weeks of ceftriaxone therapy. The patient met modified Duke Criteria, but the diagnosis was challenging due to absence of risk factors, sub-acute symptom onset, delayed blood culture growth, and ambiguous characterization of the mass on imaging. .

Design and rationale of the colchicine/statin for the prevention of COVID-19 complications (COLSTAT) trial.

BACKGROUND: Despite improvement in the standard of care (SOC) for hospitalized COVID-19 patients, rates of morbidity and mortality remain high. There continues to be a need for easily available and cost-effective treatments. Colchicine and rosuvastatin are both safe and well-studied medications with anti-inflammatory and other pleiotropic effects that may provide additional benefits to hospitalized COVID-19 patients. METHODS AND RESULTS: The Colchicine/Statin for the Prevention of COVID-19 Complications (COLSTAT) trial is a pragmatic, open-label, multicenter, randomized trial comparing the combination of colchicine and rosuvastatin in addition to SOC to SOC alone in hospitalized COVID-19 patients. Four centers in the Yale New Haven Health network will enroll a total of 466 patients with 1:1 randomization. The trial will utilize the electronic health record (Epic® Systems, Verona, Wisconsin, USA) at all stages including screening, randomization, intervention, event ascertainment, and follow-up. The primary endpoint is the 30-day composite of progression to severe COVID-19 disease as defined by the World Health Organization ordinal scale of clinical improvement and arterial/venous thromboembolic events. The secondary powered endpoint is the 30-day composite of death, respiratory failure requiring intubation, and myocardial injury. CONCLUSIONS: The COLSTAT trial will provide evidence on the efficacy of repurposing colchicine and rosuvastatin for the treatment of hospitalized COVID-19 patients. Moreover, it is designed to be a pragmatic trial that will demonstrate the power of using electronic health records to improve efficiency and enrollment in clinical trials in an adapting landscape. CLINICAL TRIAL REGISTRATION: NCT04472611 (https://clinicaltrials.gov/ct2/show/NCT04472611).

The Challenges of ST-Elevation Myocardial Infarction in COVID-19 Patients.

By July 2021, the United States had over 34.4 million confirmed COVID-19 cases. Various cardiovascular manifestations of COVID-19 have been reported including ST-elevation myocardial infarction (STEMI), and there is concern that SARS-CoV-2 may be associated with a higher thrombus burden. We performed a retrospective chart review of 535 adult patients with COVID-19 admitted at Yale-New Haven Health Greenwich Hospital from February 1, 2020, to May 13, 2020. All admitted patients had undergone testing for serum troponin I and various inflammatory markers, and we identified three patients who were diagnosed with acute STEMI. Data was collected via manual chart review and included patient demographics, comorbidities, laboratory tests, electrocardiogram (ECG) results, echocardiography results, diagnoses during hospitalization, inpatient therapies, and outcomes including length of hospital stay, revascularization results, and mortality. Three of our patients had obstructive coronary artery disease confirmed via angiography. One subject was noted to display vasospasm in addition to coronary atherosclerotic obstruction and refractory thrombus formation. Among our patients with COVID-19 and STEMI, presentations were variable in terms of timing of onset of ECG changes, age, gender, race, comorbidities, symptomology, and outcomes.

Non-dissecting large thoracic aortic aneurysm leading to chronic aortic insufficiency presenting as acute heart failure.

Large, non-dissecting thoracic aortic aneurysms (TAA) up to 13 cm in size are typically found in elderly patients with non-specific respiratory symptoms yet must be detected quickly due to their mortality risk. We present a 31-year-old man with exertional dyspnea secondary to aortic insufficiency from a 9.4 cm TAA.

Selective serotonin reuptake inhibitors and endothelial function in women.

BACKGROUND: Among women worldwide, major depression (MDD) and heart disease rank first and second, respectively, in burden of disease. Although selective serotonin reuptake inhibitors (SSRIs) are frequently prescribed, possible inhibition of nitric oxide (NO) function has caused concerns about their effects on protective vascular mechanisms. Our study aimed to determine the effect of SSRIs on flow-mediated vascular dilatation (FMD), platelet aggregation, and platelet NO production among women. METHODS: Women (n=28) without known cardiovascular disease were recruited prior to undergoing SSRI treatment for MDD, postpartum depression (PPD), or premenstrual dysphoric disorder (PMDD). Symptoms were quantified using the Hamilton Depression/Anxiety and Beck Depression scales. FMD, platelet aggregation, and platelet NO production were measured before and after 1 month of SSRI (sertraline, fluoxetine, or paroxetine) therapy. RESULTS: Depression and anxiety symptoms decreased significantly with SSRI treatment (ps <0.01). FMD and platelet aggregation did not differ between pre- and posttreatment, although FMD rose to the normal range (≥ 8%) in two of three women with abnormal FMD prior to SSRI treatment. We observed a 21% decrease (p=0.024) in platelet NO production. CONCLUSIONS: SSRI treatment had little effect on FMD or platelet aggregation. The health impact of decreased NO production is unclear, particularly in this relatively young group of women without cardiovascular disease, but should be considered in future studies focusing on SSRI safety in patients with cardiovascular disease.

Cellularity and structure of fresh human coronary thrombectomy specimens; presence of cells with markers of progenitor cells.

Acute coronary syndromes and acute myocardial infarctions are often related to plaque rupture and the formation of thrombi at the site of the rupture. We examined fresh coronary thrombectomy specimens from patients with acute coronary syndromes and assessed their structure and cellularity. The thrombectomy specimens consisted of platelets, erythrocytes and inflammatory cells. Several specimens contained multiple cholesterol crystals. Culture of thrombectomy specimens yielded cells growing in various patterns depending on the culture medium used. Culture in serum-free stem cell enrichment medium yielded cells with features of endothelial progenitor cells which survived in culture for a year. Immunohistochemical analysis of the thrombi revealed cells positive for CD34, cells positive for CD15 and cells positive for desmin in situ, whereas cultured cell from thrombi was desmin positive but pancytokeratin negative. Cells cultured in endothelial cell medium were von Willebrand factor positive. The content of coronary thrombectomy specimens is heterogeneous and consists of blood cells but also possibly cells from the vascular wall and cholesterol crystals. The culture of cells contained in the specimens yielded multiplying cells, some of which demonstrated features of haematopoietic progenitor cells and which differentiated into various cell-types.

An inflammatory pathway of IFN-gamma production in coronary atherosclerosis.

Inflammation is associated with the pathogenesis of coronary atherosclerosis, although the mechanisms remain unclear. We investigated whether cytokine secretion by innate immune responses could contribute to the production of proarteriosclerotic Th1-type cytokines in human coronary atherosclerosis. Cytokines were measured by ELISA in the plasma of patients with coronary atherosclerosis undergoing cardiac catheterization. IL-18 was detected in all subjects, whereas a subset of patients demonstrated a coordinated induction of other IFN-gamma-related cytokines. Specifically, elevated plasma levels of IL-12 correlated with that of IFN-gamma and IFN-gamma-inducible chemokines, defining an IFN-gamma axis that was activated independently of IL-6 or C-reactive protein. Systemic inflammation triggered by cardiopulmonary bypass increased plasma levels of the IFN-gamma axis, but not that of IL-18. Activation of the IFN-gamma axis was not associated with acute coronary syndromes, but portended increased morbidity and mortality after 1-year follow-up. IL-12 and IL-18, but not other monokines, elicited secretion of IFN-gamma and IFN-gamma-inducible chemokines in human atherosclerotic coronary arteries maintained in organ culture. T cells were the principal source of IFN-gamma in response to IL-12/IL-18 within the arterial wall. This inflammatory response did not require, but was synergistic with and primed for TCR signals. IL-12/IL-18-stimulated T cells displayed a cytokine-producing, nonproliferating, and noncytolytic phenotype, consistent with previous descriptions of lymphocytes in stable plaques. In contrast to cognate stimuli, IL-12/IL-18-dependent IFN-gamma secretion was prevented by a p38 MAPK inhibitor and not by cyclosporine. In conclusion, circulating IL-12 may provide a mechanistic link between inflammation and Th1-type cytokine production in coronary atherosclerosis.

Comparison of coronary artery specific leukocyte-platelet conjugate formation in unstable versus stable angina pectoris.

This study evaluates transcoronary changes in neutrophil and platelet activation and conjugate formation in patients with angina pectoris secondary to coronary artery disease. We examined parameters of neutrophil and platelet activation as well as the neutrophil-platelet conjugate formation in patients who underwent diagnostic coronary angiography. Thirty-nine patients with chest pain referred for cardiac catheterization were studied (23 patients with unstable angina pectoris [UAP] and 16 with stable angina pectoris [SAP]). Before coronary angiography, blood samples were obtained simultaneously from the aortic root and coronary sinus to assess leukocyte (CD11b) and platelet (CD62P) activation and leukocyte-platelet conjugates. There was a 94% increase in CD62-expressing platelets from the aorta to the coronary sinus in patients with UAP compared with a 49% increase in patients with SAP. The percentage of neutrophil-platelet conjugates increased by 22% in patients with UAP compared with a 16% decrease in those with SAP (p <0.01). In contrast, monocyte-platelet binding across the coronary bed increased to a similar degree in both groups. This study demonstrates an increase in neutrophil-platelet conjugates across the coronary circulation in UAP, compatible with a higher activation state in both cell types.

Atrial Fibrillation in the Elderly: Who is at Risk?

Atrial fibrillation is recognized by all clinicians as an important arrhythmia. Its importance relates to the increased risk for cardioembolic stroke. The elderly are the most commonly affected. They have the highest incidence of atrial fibrillation and are the patients most vulnerable to the risk of stroke. It has been stated that the incidence of atrial fibrillation is only 0.2 per 1000 in patients aged 30-39. This figure increases to 39.0 per 1000 in patients 80-89 years old. Among patients seeking medical attention the prevalence can be even greater (Fig. 1). Atrial fibrillation's contribution to the risk of stroke increases with age. In patients 50-59 years of age it is estimated that 6.7% of strokes are associated with atrial fibrillation. In patients aged 80-89 this figure increases to 36.2%.1 This review will explore common etiologies leading to atrial fibrillation in the elderly. Important reversible causes will be emphasized. Some of the reasons this common arrhythmia is an especially important risk factor for cardioembolic stroke in this group will be illustrated.