Aortic stiffness is strikingly increased with age ≥50 years in clinically normal individuals and preclinical patients with cardiovascular risk factors: Assessment by the new technique of 2D strain echocardiography

SummaryBackgroundVarious measures of aortic stiffness have been proposed as cardiovascular risk markers, but interest has now shifted to more direct and easier evaluation of aortic function. The present study was conducted to determine the feasibility of measuring aortic stiffness (β) with two-dimensional (2D) strain echocardiography and the impact of age and gender on preclinical atherosclerosis.Methods and resultsThe peak circumferential strain of the abdominal aorta was measured using 2D strain echocardiography, and β was determined in 54 clinically normal individuals and 104 patients with cardiovascular risk factors and no evidence of cardiovascular disease. The β correlated significantly with age in all 158 patients. However, the relationship was nonlinear, and β was markedly greater in patients ≥50 years. In 54 clinically normal individuals, the relationship was comparatively linear. The systolic blood pressure and pulse pressure were significantly greater in patients ≥50 years. There were no significant differences in β and blood pressure parameters between genders.ConclusionsThe β increased dramatically with advanced age (≥50 years), regardless of gender, in clinically healthy and community-based patients with cardiovascular risk factors. The aortic circumferential strain was measured with 2D strain echocardiography which is a new tool that can be used to directly and easily evaluate aortic stiffness

A cell-based high-throughput screening method to directly examine transthyretin amyloid fibril formation at neutral pH

Transthyretin (TTR) is a major amyloidogenic protein associated with hereditary (ATTRm) and nonhereditary (ATTRwt) intractable systemic transthyretin amyloidosis. The pathological mechanisms of ATTR-associated amyloid fibril formation are incompletely understood, and there is a need for identifying compounds that target ATTR. C-terminal TTR fragments are often present in amyloid-laden tissues of most patients with ATTR amyloidosis, and on the basis of in vitro studies, these fragments have been proposed to play important roles in amyloid formation. Here, we found that experimentally-formed aggregates of full-length TTR are cleaved into C-terminal fragments, which were also identified in patients' amyloid-laden tissues and in SH-SY5Y neuronal and U87MG glial cells. We observed that a 5-kDa C-terminal fragment of TTR, TTR81–127, is highly amyloidogenic in vitro, even at neutral pH. This fragment formed amyloid deposits and induced apoptosis and inflammatory gene expression also in cultured cells. Using the highly amyloidogenic TTR81–127 fragment, we developed a cell-based high-throughput screening method to discover compounds that disrupt TTR amyloid fibrils. Screening a library of 1280 off-patent drugs, we identified two candidate repositioning drugs, pyrvinium pamoate and apomorphine hydrochloride. Both drugs disrupted patient-derived TTR amyloid fibrils ex vivo, and pyrvinium pamoate also stabilized the tetrameric structure of TTR ex vivo in patient plasma. We conclude that our TTR81–127–based screening method is very useful for discovering therapeutic drugs that directly disrupt amyloid fibrils. We propose that repositioning pyrvinium pamoate and apomorphine hydrochloride as TTR amyloid-disrupting agents may enable evaluation of their clinical utility for managing ATTR amyloidosis

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)

Risk profiles and one-year outcomes of patients with newly diagnosed atrial fibrillation in India: Insights from the GARFIELD-AF Registry.

BACKGROUND: The Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) is an ongoing prospective noninterventional registry, which is providing important information on the baseline characteristics, treatment patterns, and 1-year outcomes in patients with newly diagnosed non-valvular atrial fibrillation (NVAF). This report describes data from Indian patients recruited in this registry. METHODS AND RESULTS: A total of 52,014 patients with newly diagnosed AF were enrolled globally; of these, 1388 patients were recruited from 26 sites within India (2012-2016). In India, the mean age was 65.8 years at diagnosis of NVAF. Hypertension was the most prevalent risk factor for AF, present in 68.5% of patients from India and in 76.3% of patients globally (P < 0.001). Diabetes and coronary artery disease (CAD) were prevalent in 36.2% and 28.1% of patients as compared with global prevalence of 22.2% and 21.6%, respectively (P < 0.001 for both). Antiplatelet therapy was the most common antithrombotic treatment in India. With increasing stroke risk, however, patients were more likely to receive oral anticoagulant therapy [mainly vitamin K antagonist (VKA)], but average international normalized ratio (INR) was lower among Indian patients [median INR value 1.6 (interquartile range {IQR}: 1.3-2.3) versus 2.3 (IQR 1.8-2.8) (P < 0.001)]. Compared with other countries, patients from India had markedly higher rates of all-cause mortality [7.68 per 100 person-years (95% confidence interval 6.32-9.35) vs 4.34 (4.16-4.53), P < 0.0001], while rates of stroke/systemic embolism and major bleeding were lower after 1 year of follow-up. CONCLUSION: Compared to previously published registries from India, the GARFIELD-AF registry describes clinical profiles and outcomes in Indian patients with AF of a different etiology. The registry data show that compared to the rest of the world, Indian AF patients are younger in age and have more diabetes and CAD. Patients with a higher stroke risk are more likely to receive anticoagulation therapy with VKA but are underdosed compared with the global average in the GARFIELD-AF. CLINICAL TRIAL REGISTRATION-URL: http://www.clinicaltrials.gov. Unique identifier: NCT01090362

Successful treatment of out-of-hospital cardiopulmonary arrest due to streptococcal toxic shock syndrome – effectiveness of extracorporeal membrane oxygenation and the rapid antigen group A streptococcus test: a case report

Abstract Background Streptococcal toxic shock syndrome caused by Streptococcus pyogenes, a group A streptococcus, infection is a rare condition that rapidly progresses to multiple organ failure, shock, and death. It is thus important to promptly establish a diagnosis, provide hemodynamic support, and initiate appropriate antibiotics therapy. Case presentation A 70-year-old Asian man presented with ventricular fibrillation. Extracorporeal membrane oxygenation was initiated 20 minutes after admission after unsuccessful conventional cardiopulmonary resuscitation including five attempts of electrical cardioversion. On the sixth attempt, a sinus rhythm was obtained. A physical examination revealed a large abscess in his right gluteal region, and computed tomography showed a large low-density area in the right gluteus maximus. Blood examination revealed elevated levels of inflammatory markers, hepatic enzymes, creatinine, and creatinine kinase. Transthoracic echocardiography demonstrated diffuse hypokinesis with an ejection fraction of 25%. A subsequent coronary angiography revealed normal findings. Therefore, we diagnosed our patient as having septic shock and conducted surgical drainage. A rapid antigen group A streptococcus test yielded positive results, which necessitated treatment comprising benzylpenicillin and clindamycin. He was successfully weaned from extracorporeal membrane oxygenation and continuous hemodiafiltration 4 days later and ventilation 9 days later; he was later transferred to another hospital to receive a skin graft. Conclusions Our case report is the first to demonstrate the successful treatment of cardiac arrest caused by streptococcal toxic shock syndrome via extracorporeal membrane oxygenation and prompt initiation of antibiotic therapy. The rapid antigen group A streptococcus test may be an effective approach to promptly diagnose streptococcal toxic shock syndrome caused by group A streptococcus infection