Objectives To evaluate the individual risk factors composing the CHADS 2 (Congestive heart failure, Hypertension, Age≥75 years, Diabetes, previous Stroke) score and the CHA 2 DS 2 -VASc (CHA 2 DS 2 -Vascular disease, Age 65-74 years, Sex category) score and to calculate the capability of the schemes to predict thromboembolism. Design Registry based cohort study. Setting Nationwide data on patients admitted to hospital with atrial fibrillation. Population All patients with atrial fibrillation not treated with vitamin K antagonists in Denmark in the period 1997-2006. Main outcome measures Stroke and thromboembolism. Results Of 121 280 patients with non-valvular atrial fibrillation, 73 538 (60.6%) fulfilled the study inclusion criteria. In patients at "low risk" (score=0), the rate of thromboembolism per 100 person years was 1.67 (95% confidence interval 1.47 to 1.89) with CHADS 2 and 0.78 (0.58 to 1.04) with CHA 2 DS 2 -VASc at one year's follow-up. In patients at "intermediate risk" (score=1), this rate was 4.75 (4.45 to 5.07) with CHADS 2 and 2.01 (1.70 to 2.36) with CHA 2 DS 2 -VASc. The rate of thromboembolism depended on the individual risk factors composing the scores, and both schemes underestimated the risk associated with previous thromboembolic events. When patients were categorised into low, intermediate, and high risk groups, C statistics at 10 years' follow-up were 0.812 (0.796 to 0.827) with CHADS 2 and 0.888 (0.875 to 0.900) with CHA 2 DS 2 -VASc. Conclusions The risk associated with a specific risk stratification score depended on the risk factors composing the score. CHA 2 DS 2 -VASc performed better than CHADS 2 in predicting patients at high risk, and those categorised as low risk by CHA 2 DS 2 -VASc were truly at low risk for thromboembolism.

IMPORTANCE It has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2.OBJECTIVE To examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19. DESIGN, SETTING, AND PARTICIPANTSTo examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020.EXPOSURES ACEI/ARB use was defined as prescription fillings 6 months prior to the index date. MAIN OUTCOMES AND MEASURESIn the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis. RESULTSIn the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age-and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]). CONCLUSIONS AND RELEVANCEPrior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

Heart failure is the leading cause of an increased cardiovascular mortality in both overt and subclinical hyperthyroidism. Subclinical hypothyroidism with TSH 5-10 mIU/L might be associated with a lower risk of all-cause mortality.

We sought to quantify the contribution of cardiac output (Q) and total vascular conductance (TVC) to carotid baroreflex (CBR)‐mediated changes in mean arterial pressure (MAP) during mild to heavy exercise. CBR function was determined in eight subjects (25 ± 1 years) at rest and during three cycle exercise trials at heart rates (HRs) of 90, 120 and 150 beats min−1 performed in random order. Acute changes in carotid sinus transmural pressure were evoked using 5 s pulses of neck pressure (NP) and neck suction (NS) from +40 to −80 Torr (+5.33 to −10.67 kPa). Beat‐to‐beat changes in HR and MAP were recorded throughout. In addition, stroke volume (SV) was estimated using the Modelflow method, which incorporates a non‐linear, three‐element model of the aortic input impedance to compute an aortic flow waveform from the arterial pressure wave. The application of NP and NS did not cause any significant changes in SV either at rest or during exercise. Thus, CBR‐mediated alterations in Q were solely due to reflex changes in HR. In fact, a decrease in the carotid‐HR response range from 26 ± 7 beats min−1 at rest to 7 ± 1 beats min−1 during heavy exercise (P= 0.001) reduced the contribution of Q to the CBR‐mediated change in MAP. More importantly, at the time of the peak MAP response, the contribution of TVC to the CBR‐mediated change in MAP was increased from 74 ± 14 % at rest to 118 ± 6 % (P= 0.017) during heavy exercise. Collectively, these findings indicate that alterations in vasomotion are the primary means by which the CBR regulates blood pressure during mild to heavy exercise.

Objectives To examine the risk of atrial fibrillation in relation to the whole spectrum of thyroid function in a large cohort of patients.Design Population based cohort study of general practice patients identified by linkage of nationwide registries at the individual level.Setting Primary care patients in the city of Copenhagen.Subjects Registry data for 586 460 adults who had their thyroid function evaluated for the first time by their general practitioner during 2000-10 and who were without previously recorded thyroid disease or atrial fibrillation.Main outcome measure Poisson regression models used to estimate risk of atrial fibrillation by thyroid function. Results Of the 586 460 individuals in the study population (mean (SD) age 50.2 (16.9) years, 39% men), 562 461 (96.0%) were euthyroid, 1670 (0.3%) had overt hypothyroidism, 12 087 (2.0%) had subclinical hypothyroidism, 3966 (0.7%) had overt hyperthyroidism, and 6276 (1.0%) had subclinical hyperthyroidism. Compared with the euthyroid individuals, the risk of atrial fibrillation increased with decreasing levels of thyroid stimulating hormone (TSH) from high normal euthyroidism (incidence rate ratio 1.12 (95% CI 1.03 to 1.21)) to subclinical hyperthyroidism with reduced TSH (1.16 (0.99 to 1.36)) and subclinical hyperthyroidism with supressed TSH (1.41 (1.25 to 1.59)). Both overt and subclinical hypothyroidism were associated with a lower risk of atrial fibrillation.Conclusion The risk of atrial fibrillation was closely associated with thyroid activity, with a low risk in overt hypothyroidism, high risk in hyperthyroidism, and a TSH level dependent association with risk of atrial fibrillation across the spectrum of subclinical thyroid disease.

During maximal exercise lactate taken up by the human brain contributes to reduce the cerebral metabolic ratio, O 2 /(glucose + 1/2 lactate), but it is not known whether the lactate is metabolized or if it accumulates in a distribution volume. In one experiment the cerebral arterio-venous differences (AV) for O 2 , glucose (glc) and lactate (lac) were evaluated in nine healthy subjects at rest and during and after exercise to exhaustion. The cerebrospinal fluid (CSF) was drained through a lumbar puncture immediately after exercise, while control values were obtained from six other healthy young subjects. In a second experiment magnetic resonance spectroscopy ( 1 H-MRS) was performed after exhaustive exercise to assess lactate levels in the brain (n = 5). Exercise increased the AV O2 from 3.2 ± 0.1 at rest to 3.5 ± 0.2 mM (mean ± S.E.M.; P < 0.05) and the AV glc from 0.6 ± 0.0 to 0.9 ± 0.1 mM (P < 0.01). Notably, the AV lac increased from 0.0 ± 0.0 to 1.3 ± 0.2 mM at the point of exhaustion (P < 0.01). Thus, maximal exercise reduced the cerebral metabolic ratio from 6.0 ± 0.3 to 2.8 ± 0.2 (P < 0.05) and it remained low during the early recovery. Despite this, the CSF concentration of lactate postexercise (1.2 ± 0.1 mM; n = 7) was not different from baseline (1.4 ± 0.1 mM; n = 6). Also, the 1 H-MRS signal from lactate obtained after exercise was smaller than the estimated detection limit of ∼1.5 mM. The finding that an increase in lactate could not be detected in the CSF or within the brain rules out accumulation in a distribution volume and indicates that the lactate taken up by the brain is metabolized.

Middle cerebral artery flow velocity and pulse pressure during dynamic exercise in humans. Am J Physiol Heart Circ Physiol 288: H1526 -H1531, 2005. First published December 9, 2004; doi:10.1152/ajpheart. 00979.2004.-Exercise challenges cerebral autoregulation (CA) by a large increase in pulse pressure (PP) that may make systolic pressure exceed what is normally considered the upper range of CA. This study examined the relationship between systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP) and systolic (V s), diastolic (Vd). and mean (Vm) middle cerebral artery (MCA) blood flow velocity during mild, moderate, and heavy cycling exercise. Dynamic CA and steady-state changes in MCA V in relation to changes in arterial pressure were evaluated using transfer function analysis. PP increased by 37% and 57% during moderate and heavy exercise, respectively (P Ͻ 0.05), and the pulsatility of MCA V increased markedly. Thus exercise increased MCA V m and Vs (P Ͻ 0.05) but tended to decrease MCA V d (P ϭ 0.06). However, the normalized low-frequency transfer function gain between MAP and MCA V m and between SBP and MCA Vs remained unchanged from rest to exercise, whereas that between DBP and MCA V d increased from rest to heavy exercise (P Ͻ 0.05). These findings suggest that during exercise, CA is challenged by a rapid decrease rather than by a rapid increase in blood pressure. However, dynamic CA remains able to modulate blood flow around the exercise-induced increase in MCA V m, even during high-intensity exercise. cerebral circulation; diastolic velocity; systolic velocity CEREBRAL AUTOREGULATION (CA) maintains steady-state cerebral blood flow relatively stable over a range of perfusion pressures from 60 to 150 mmHg (21), but it takes ϳ3 s for CA to be established (1), explaining why the velocity (V) in basal cerebral arteries fluctuates in parallel with blood pressure throughout the cardiac cycle. Thus exercise presents a challenge to CA by the rapid and large increases in pulse pressure (PP). This is exemplified during rowing where the rapid fluctuations in blood pressure associated with each stroke result in similar fluctuations in middle cerebral artery (MCA) mean blood flow velocity (V m ) (17). Equally, during rhythmic resistance exercise fluctuations in arterial pressure with each muscle contraction are too rapid to be countered by CA (9). Despite such large changes in the MCA V waveforms with exercise, the averaged MCA V m remains unchanged (9), slightly decreased (7), or increased when exercise does not cause large fluctuations in blood pressure (3,16,17). However, the MCA V m may not fully reflect the dynamic control of CA (15,24,26,27), and this may be relevant especially when PP increases systolic pressure beyond the CA range.Dynamic CA is frequency dependent (10,15,24,26,27), and frequency-domain analyses of CA allows for evaluation of the influence of exercise-induced changes in arterial blood pressure on MCA V. Brys et al. (3) used frequency-domain analysis to ev...

Objective To examine the effect of proton pump inhibitors on adverse cardiovascular events in aspirin treated patients with first time myocardial infarction.Design Retrospective nationwide propensity score matched study based on administrative data.Setting All hospitals in Denmark.Participants All aspirin treated patients surviving 30 days after a first myocardial infarction from 1997 to 2006, with follow-up for one year. Patients treated with clopidogrel were excluded.Main outcome measures The risk of the combined end point of cardiovascular death, myocardial infarction, or stroke associated with use of proton pump inhibitors was analysed using Kaplan-Meier analysis, Cox proportional hazard models, and propensity score matched Cox proportional hazard models.Results 3366 of 19 925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death. The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P<0.001) and for the propensity score matched model based on 8318 patients it was 1.61 (1.45 to 1.79; P<0.001). A sensitivity analysis showed no increase in risk related to use of H2 receptor blockers (1.04, 0.79 to 1.38; P=0.78).Conclusion In aspirin treated patients with first time myocardial infarction, treatment with proton pump inhibitors was associated with an increased risk of adverse cardiovascular events.