Atrial Tachyarrhythmias and Stroke: Temporal Relationship and Stroke Subtypes.

BACKGROUND AND PURPOSE: Research into the temporal relationship between atrial tachyarrhythmias (atrial tachycardia [AT] and atrial fibrillation [AF]) and stroke has produced conflicting findings. Systematic categorization of stroke subtypes may help clarify the discussion. OBJECTIVES: The objective of the study was to examine the presence and timing of AT/AF in relation to ischemic stroke subtypes, categorized as either cardioembolic (CE) or non-CE. METHODS: Consecutive patients presenting to the Austin Hospital with acute stroke from 2012 to 2019 and a cardiac implantable electronic device (CIED) were identified. Using a case-control design, the temporal proximity of AT/AF episodes in the 90 days prior to stroke was compared in the CE and non-CE stroke groups. RESULTS: 5,591 patients presented to the Austin Hospital with acute stroke from 2012 to 2019, of whom 31 patients with an ischemic stroke and a CIED with ≥90 days of monitoring were identified. Twelve strokes were adjudicated as CE and 19 as non-CE by a stroke neurologist. Six of the 12 CE stroke patients (50%) experienced AT/AF within 30 days preceding their stroke, while none of the 19 non-CE stroke patients recorded any AT/AF in the same period (p = 0.001). Four CE stroke patients (33%) had no AT/AF preceding their strokes at any time. The odds ratio for CE stroke was highest (39; 95% confidence interval [CI]: 1.92-791.5) when AT/AF occurred in the 30 days prior, declining to 20.65 (95% CI: 1.00-427.66) and 6.07 (95% CI: 0.94-39.04) in the subsequent 31-60- and 61-90-day windows, respectively. CONCLUSIONS: CE strokes were associated with a significantly higher proportion of preceding AT/AF compared with non-CE strokes. These findings support a potential temporal relationship between AT/AF and CE stroke and demonstrate that stroke subtyping can better characterize the relationship between AF and ischemic stroke. However, this study's findings are limited by its sample size and small number of informative cases.

Inducible Left Ventricular Outflow Tract Obstruction in Patients Undergoing Liver Transplantation: Prevalence, Predictors, and Association With Cardiovascular Events.

BACKGROUND: Inducible left ventricular outflow tract obstruction (LVOTO) is often encountered in liver transplantation (LT) candidates during cardiac workup. While the impact of LVOTO on adverse cardiovascular hemodynamics is well reported, it is unclear whether it predisposes to perioperative cardiovascular complications. METHODS: Consecutive patients with end-stage liver disease undergoing dobutamine stress echocardiography (DSE) were evaluated at an LT center between 2010 and 2017. Perioperative major adverse cardiovascular events (MACEs) at 30 days and all-cause death were recorded from a prospectively maintained LT database. RESULTS: We evaluated 560 patients who underwent DSE during LT workup, with LVOTO identified in 24.3% (n = 136). Of these, 309 patients progressed to transplant. Patients with LVOTO demonstrated a lower peak systolic blood pressure (SBP) and an overall reduction in SBP on DSE. A total of 85 MACEs were recorded in 72 patients (23.3%) including 3 deaths, 19 cases of heart failure, 11 cardiac arrests, 8 acute coronary syndromes, and 44 arrhythmias. MACE occurred in 15/64 patients (23.4%) with LVOTO and 57/245 (23.3%) without (P = 0.92). There was an increased risk of perioperative cardiac arrest in patients with LVOTO (7.4% versus 2.4%, P = 0.04). Intraoperatively, patients with LVOTO required higher doses of vasopressors (P = 0.01) and received greater volumes of fluid (10.5 ± 8.1 versus 8.4 ± 6.4 L, P = 0.03). CONCLUSIONS: Patients with end-stage liver disease and LVOTO demonstrate a reduction in SBP during physiological stress that may translate to hemodynamic instability during LT. LVOTO was not associated with an increased rate of perioperative MACE or death.

Impaired Cardiac Reserve on Dobutamine Stress Echocardiography Predicts the Development of Hepatorenal Syndrome.

OBJECTIVES: Cardiac dysfunction has been implicated in the genesis of hepatorenal syndrome (HRS). It is unclear whether a low cardiac output (CO) or attenuated contractile response to hemodynamic stress can predict its occurrence. We studied cardiovascular hemodynamics in cirrhosis and assessed whether a diminished cardiac reserve with stress testing predicted the development of HRS on follow-up. METHODS: Consecutive patients undergoing liver transplant workup with dobutamine stress echocardiography (DSE) were included. CO was measured at baseline and during low-dose dobutamine infusion at 10 µg/kg/min. HRS was diagnosed using guideline-based criteria. RESULTS: A total of 560 patients underwent DSE, of whom 488 were included after preliminary assessment. There were 64 (13.1%) patients with established HRS. The HRS cohort had a higher baseline CO (8.0 ± 2 vs 6.9 ± 2 L/min; P < 0.001) and demonstrated a blunted response to low-dose dobutamine (ΔCO 29 ± 22% vs 44 ± 32%, P < 0.001) driven primarily by inotropic incompetence. Optimal cutpoint for ΔCO in patients with HRS was determined to be <25% and was used to define a low cardiac reserve. Among the 424 patients without HRS initially, 94 (22.1%) developed HRS over a mean follow-up of 1.5 years. Higher proportion with a low cardiac reserve developed HRS (52 [55.0%] vs 56 [16.9%]; hazard ratio 4.5; 95% confidence interval 3.0-6.7; P < 0.001). In a Cox multivariable model, low cardiac reserve remained the strongest predictor for the development of HRS (hazard ratio 3.9; 95% confidence interval 2.2-7.0; P < 0.001). DISCUSSION: Patients with HRS demonstrated a higher resting CO and an attenuated cardiac reserve on stress testing. On longitudinal follow-up, low cardiac reserve was an independent predictor for the development of HRS. Assessment of cardiac reserve with DSE may provide a novel noninvasive risk marker for developing HRS in patients with advanced liver disease.HRS is a life-threatening complication of liver disease. We studied whether an inability to increase cardiac contraction in response to stress can assist in the prediction of HRS. We demonstrate that patients with liver disease who exhibit cardiac dysfunction during stress testing had a 4-fold increased risk of developing HRS. This may improve our ability for early diagnosis and treatment of patients at a higher risk of developing HRS.

Mitral Valve Prolapse and Sudden Cardiac Death: A Systematic Review.

Background The relationship between mitral valve prolapse ( MVP ) and sudden cardiac death ( SCD ) remains controversial. In this systematic review, we evaluate the relationship between isolated MVP and SCD to better define a potential high-risk subtype. In addition, we determine whether premortem parameters could predict SCD in patients with MVP and the incidence of SCD in MVP . Methods and Results Electronic searches were conducted in PubMed and Embase for all English literature articles published between 1960 and 2018 regarding MVP and SCD or cardiac arrest. We also identified articles investigating predictors of ventricular arrhythmias or SCD and cohort studies reporting SCD outcomes in MVP . From 2180 citations, there were 79 articles describing 161 cases of MVP with SCD or cardiac arrest. The median age was 30 years and 69% of cases were female. Cardiac arrest occurred during situations of stress in 47% and was caused by ventricular fibrillation in 81%. Premature ventricular complexes on Holter monitoring (92%) were common. Most cases had bileaflet involvement (70%) with redundancy (99%) and nonsevere mitral regurgitation (83%). From 22 articles describing predictors for ventricular arrhythmias or SCD in MVP , leaflet redundancy was the only independent predictor of SCD . The incidence of SCD with MVP was estimated at 217 events per 100 000 person-years. Conclusions Isolated MVP and SCD predominantly affects young females with redundant bileaflet prolapse, with cardiac arrest usually occurring as a result of ventricular arrhythmias. To better understand the complex relationship between MVP and SCD , standardized reporting of clinical, electrophysiological, and cardiac imaging parameters with longitudinal follow-up is required.

Clopidogrel plus aspirin versus warfarin in patients with stroke and aortic arch plaques.

BACKGROUND AND PURPOSE: Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear. METHODS: This prospective randomized controlled, open-labeled trial, with blinded end point evaluation (PROBE design) tested superiority of aspirin 75 to 150 mg/d plus clopidogrel 75 mg/d (A+C) over warfarin therapy (international normalized ratio 2-3) in patients with ischemic stroke, transient ischemic attack, or peripheral embolism with plaque in the thoracic aorta>4 mm and no other identified embolic source. The primary end point included cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage. Follow-up visits occurred at 1 month and then every 4 months post randomization. RESULTS: The trial was stopped after 349 patients were randomized during a period of 8 years and 3 months. After a median follow-up of 3.4 years, the primary end point occurred in 7.6% (13/172) and 11.3% (20/177) of patients on A+C and on warfarin, respectively (log-rank, P=0.2). The adjusted hazard ratio was 0.76 (95% confidence interval, 0.36-1.61; P=0.5). Major hemorrhages including intracranial hemorrhages occurred in 4 and 6 patients in the A+C and warfarin groups, respectively. Vascular deaths occurred in 0 patients in A+C arm compared with 6 (3.4%) patients in the warfarin arm (log-rank, P=0.013). Time in therapeutic range (67% of the time for international normalized ratio 2-3) analysis by tertiles showed no significant differences across groups. CONCLUSIONS: Because of lack of power, this trial was inconclusive and results should be taken as hypothesis generating. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00235248.

Intraobserver and interobserver variability of transesophageal echocardiography in aortic arch atheroma measurement.

BACKGROUND: The risk of stroke associated with aortic arch atheroma is proportional to plaque thickness, the accurate measurement of which may influence future therapeutic decisions. Transesophageal echocardiography is the procedure of choice for plaque measurement. This study examines the reproducibility of such measurements within the context of the Aortic Arch Related Cerebral Hazard Trial of antithrombotic therapy. METHODS: Atheroma images were remeasured by 3 independent blinded observers of varying expertise. Intraobserver and interobserver variability were calculated using Lin's concordance correlation coefficient (rho-c), the Bland-Altman method, and the kappa statistic. RESULTS: A total of 160 images were obtained from 96 patients (68% male; mean age 74 +/- 9 years). Mean plaque thickness was 5.1 +/- 2.3 mm, range 1.2 to 19.3 mm. For intraobserver variability, rho-c = 0.95, mean difference = 0.01 mm, and kappa = 0.71. For interobserver variability, rho-c ranged from 0.80 to 0.91; mean difference was 0.13 to 0.48 mm; and kappa was 0.61 to 0.69. By all statistical methods, agreement was at least substantial, although lower at greater plaque thicknesses. For the clinically relevant 4 mm, agreement was 84% to 88%. CONCLUSIONS: Transesophageal echocardiography measurement of aortic plaque is substantially reproducible across a range of observer experience and, thus, is a widely applicable, adequately reliable tool for clinical and research purposes.

Aortic arch atheroma.

Severe atheroma of the aortic arch has now been established as an important risk factor and mechanism for stroke and peripheral embolism. The odds ratio for stroke or peripheral embolism in patients with severe arch atheroma is greater than four, and for mobile atheroma it is greater than 12. The prevalence of severe arch atheroma among patients presenting with acute ischaemic stroke, at over 20%, is in the same order as that of atrial fibrillation and carotid atherosclerosis. In patients with ischaemic stroke for which no cause has been identified, it is reasonable to determine as to whether they have severe arch atheroma by performing a transoesophageal echocardiogram. Recurrent stroke is common in patients with aortic arch atheroma that are thicker than 4 mm or with mobile components, particularly in the elderly, cigarette smokers, and those with hypertension or diabetes. Patients found to have severe atheroma are at high risk of recurrent events (14.2% per year) and may, therefore, need an aggressive secondary prevention strategy. Currently, there is uncertainty as to what this should be, but either combination antiplatelet therapy (aspirin plus clopidogrel) or anticoagulation with warfarin (target INR 2.0-3.0) are commonly used. Which of these is most effective will be evident after the completion of the aortic arch related cerebral hazard trial.

Aortic Source of Brain Embolism.

Aortic arch atheroma has more recently been identified as an independent risk factor for ischemic stroke. Initially, this was a result of careful autopsy observations, then followed by a series of in vivo studies in which aortic arch atheroma was identified by transesophageal echocardiography. The association of aortic arch atheroma with ischemic stroke is most likely causal, given that the stroke risk increases with increasing thickness of arch atheroma. There is quite a sharp increase in stroke risk for atheroma of 4 mm or greater compared with lesser thicknesses. The clinical diagnosis is suggested when transient ischemic attack or ischemic stroke has occurred in which no obvious cardiac or arterial source of embolism is found. The presence of aortic arch atheroma is usually detected by transesophageal echocardiography and sometimes by magnetic resonance imaging or computed tomography. There is uncertainty about clinical management, particularly for secondary prevention. Options include the use of antiplatelet agents, anticoagulants, thrombolysis, or surgery. The latter two options have only been described rarely in case reports. Of the less invasive approaches, combination antiplatelet therapy with aspirin and clopidogrel is favored, or the use of warfarin. The Aortic arch Related Cerebral Hazard (ARCH) trial is being conducted to determine which of these is more effective in minimizing a composite outcome cluster of ischemic stroke, intracranial hemorrhage, myocardial infarction, peripheral embolism, or vascular death. Other more general management strategies should include reasonably aggressive risk factor control with blood pressure and lipid-lowering therapies and, if indicated, careful diabetic control.

The hypertrophic heart rat: a new normotensive model of genetic cardiac and cardiomyocyte hypertrophy.

We describe a new line of rats with inherited cardiomyocyte and ventricular hypertrophy. From a second-generation cross of spontaneously hypertensive and Fischer 344 rats, we selected for low blood pressure and either high or low echocardiographic left ventricular (LV) mass over four generations to establish the hypertrophic heart rat (HHR) and normal heart rat (NHR) lines, respectively. After 13 generations of inbreeding, HHR had significantly greater (P < 0.0001) LV mass-to-body weight ratio (2.68 g/kg, SE 0.14) than NHR matched for age (1.94 g/kg, SE 0.02) or body weight (2.13 g/kg, SE 0.03). The isolated cardiomyocytes of HHR were significantly (P < 0.0001) longer and wider (161 microm, SE 0.83; 35.6 microm, SE 2.9) than NHR (132 microm, SE 1.2; 29.5 microm, SE 0.35). Telemetric 24-h recordings of mean arterial pressure revealed no significant differences between HHR and NHR. The HHR offers a new model of primary cardiomyocyte hypertrophy with normal blood pressure in which to examine genotypic causes and pathogenetic mechanisms of hypertrophy and its complications.