Non-eligibility for pivotal HFpEF/HFmrEF outcome trials and mortality in a contemporary heart failure cohort.

Pivotal outcome trials targeting heart failure with preserved (HFpEF) and mildly-reduced ejection fraction (HFmrEF) may have excluded patients at highest risk of poor outcomes. We aimed to assess eligibility for HFpEF/HFmrEF outcome trials in an unselected heart failure cohort and its association with all-cause mortality. Among 32.028 patients presenting to a tertiary care center emergency unit for any reason between August 2018 and July 2019, we identified 407 admissions with evident HFpEF and HFmrEF. Eligibility criteria for pivotal trials CHARM-Preserved, I-PRESERVE, TOPCAT, PARAGON-HF, EMPEROR-Preserved and DELIVER were assessed by chart review. The proportions of admissions fulfilling HFpEF/HFmrEF trial eligibility criteria were 88% for CHARM-Preserved, 40% for I-PRESERVE, 35% for TOPCAT, 28% for PARAGON-HF, 51% for EMPEROR-Preserved, and 49% for DELIVER. During a median follow-up of 1.9 years, death-from-any-cause occurred in 121 cases (30%). Twenty-four-month overall survival estimates for non-eligible and eligible admissions were 53% vs. 76% for CHARM-Preserved (HR=2.32, 95% CI: 1.47-3.67, p<0.001), 62% vs. 87% for I-PRESERVE (HR=2.97, 1.85-4.77, p<0.001), 67% vs. 84% for TOPCAT (HR=2.04, 1.29-3.24, p = 0.002), 68% vs. 85% for PARAGONHF (HR=2.28, 1.33-3.90, p = 0.003), 64% vs. 81% for EMPEROR-Preserved (HR=1.90, 1.27-2.84, p = 0.002), and 65% vs. 80% for DELIVER (HR=1.71, 1.14-2.57, p = 0.010). Exclusion criteria independently predicting death were eGFR <20 ml/min/1.73 m2, COPD with home oxygen therapy, and severe valvular heart disease. Conclusively, in a contemporary HFpEF/HFmrEF cohort, non-eligibility for outcome trials predicted for strongly increased mortality. HFpEF/HFmrEF patients at highest mortality risk were likely underrepresented in previous outcome trials and their treatment remains an unmet medical need.

Identification of contagious SARS-CoV-2 infected individuals by Roche's Rapid Antigen Test.

OBJECTIVES: Rapid antigen tests (RAT) can provide valuable information on the presence or absence SARS-CoV-2 within 15 min without the need of a laboratory. The analytical and diagnostic characteristics of available RATs has led to the question whether they can safely distinguish between infectious and non-infectious patients in an acute care setting. METHODS: Three nasopharyngeal swabs for the analysis by RAT, reverse transcriptase real time polymerase chain reaction (RT-qPCR), and a cell culture based infection assay were collected from 67 patients that presented to the emergency department of the University Hospital of Graz (Austria). The first swab was used for on-site RAT testing in the emergency department using the Roche SARS-CoV-2 RAT. The second swab was sent to the central laboratory of the hospital for RT-qPCR with two independent methods (Cepheid Xpert® Xpress SARS-CoV-2 assay and Roche Cobas SARS-CoV-2 Test) and repeat RAT testing using the same commercial test. With the third swab a cell culture-based infection assay was performed. RESULTS: The RATs performed from independent samples showed substantial agreement (Cohen's-kappa: 0.73, p<0.001). All patients with a positive RAT had positive RT-qPCR with cycle threshold (ct) values <25. Fifteen out of 55 RAT-negative samples were RT-qPCR positive with ct values between 25 and 40. The inoculation of cell cultures with RT-qPCR negative swabs and RT-qPCR positive swabs with ct values >25 did not induce cytopathic effects that were related to SARS-CoV-2. The infection assays from four RAT-negative patients showed cytopathic effects that were induced by other pathogens. CONCLUSIONS: The SARS-CoV-2 RAT from Roche Diagnostics is a valuable tool for managing symptomatic patients. RAT-negative patients may be regarded as non-contagious.

Arterial hypertension drives arrhythmia progression via specific structural remodeling in a porcine model of atrial fibrillation.

BACKGROUND: Arterial hypertension (HT) contributes to progression of atrial fibrillation (AF) via unknown mechanisms. OBJECTIVE: We aimed to characterize electrical and structural changes accounting for increased AF stability in a large animal model of rapid atrial pacing (RAP)-induced AF combined with desoxycorticosterone acetate (DOCA)-induced HT. METHODS: Eighteen pigs were instrumented with right atrial endocardial pacemaker leads and custom-made pacemakers to induce AF by continuous RAP (600 beats/min). DOCA pellets were subcutaneously implanted in a subgroup of 9 animals (AF+HT group); the other 9 animals served as controls (AF group). Final experiments included electrophysiology studies, endocardial electroanatomic mapping, and high-density mapping with epicardial multielectrode arrays. In addition, 3-dimensional computational modeling was performed. RESULTS: DOCA implantation led to secondary HT (median [interquartile range] aortic pressure 109.9 [100-137] mm Hg in AF+HT vs 82.2 [79-96] mm Hg in AF; P < .05), increased AF stability (55.6% vs 12.5% of animals with AF episodes lasting >1 hour; P < .05), concentric left ventricular hypertrophy, atrial dilatation (119 ± 31 cm2 in AF+HT vs 78 ± 23 cm2 in AF; P < .05), and fibrosis. Collagen accumulation in the AF+HT group was mainly found in non-intermyocyte areas (1.62 ± 0.38 cm3 in AF+HT vs 0.96 ± 0.3 cm3 in AF; P < .05). Left and right atrial effective refractory periods, action potential durations, endo- and epicardial conduction velocities, and measures of AF complexity were comparable between the 2 groups. A 3-dimensional computational model confirmed an increase in AF stability observed in the in vivo experiments associated with increased atrial size. CONCLUSION: In this model of secondary HT, higher AF stability after 2 weeks of RAP is mainly driven by atrial dilatation.

Stroke Referrals from Nursing Homes: High Rate of Mimics and Late Presentation.

BACKGROUND: Stroke has become a treatable condition with increasing evidence of treatment benefits in older people. However, stroke mimics in geriatric patients are especially prevalent, causing incorrect suspicion and consecutive burden to patients and emergency room resources. We therefore examined the dimension of this problem by investigating emergency room admissions from nursing homes for suspected stroke. METHODS: We performed a retrospective cohort study of all nursing home residents who were admitted to the neurological emergency room of our primary and tertiary care university hospital between 2013 and 2015. Patients were further divided into those with confirmed stroke and stroke mimics after diagnostic stroke work-up. RESULTS: Of 419 nursing home patients referred to the emergency room, nearly one third had suspected stroke (n = 126; mean age: 78 ± 14 years, polypharmacy rate: 77%). Of those, 43 (34%) had a confirmed stroke (ischaemic: n = 34; haemorrhagic: n = 9) and 83 (66%) had stroke mimics after diagnostic work-up. Only one patient underwent intravenous thrombolysis, followed by mechanical thrombectomy for middle cerebral artery occlusion. Prehospital delay (47%) and multimorbidity-associated contraindications (27%) were the main reasons for withholding recanalization therapy. Among the stroke-mimicking conditions, infectious diseases (24%) and epileptic seizures (20%) were the most frequent. Multivariate analysis identified focal deficits (OR 16.6, 95% CI 4.3-64.0), atrial fibrillation (OR 3.9, 95% CI 1.5-10.5) and previous stroke (OR 3.2, 95% CI 1.2-8.9) as indicators that were associated with stroke. CONCLUSIONS: In our region, nursing home referrals for suspected stroke have a high false positive rate and occur delayed, which most often precludes specific stroke treatment in addition to multimorbidity. Such problems may also exist in other centres and highlight the need for targeted educational and organizational efforts. Simple indicators as identified in this study may help to sort out patients with true stroke more efficiently.

A porcine model of early atrial fibrillation using a custom-built, radio transmission-controlled pacemaker.

Mechanisms underlying atrial remodeling toward atrial fibrillation (AF) are incompletely understood. We induced AF in 16 pigs by 6weeks of rapid atrial pacing (RAP, 600bpm) using a custom-built, telemetrically controlled pacemaker. AF evolution was monitored three times per week telemetrically in unstressed, conscious animals. We established a dose-response relationship between RAP duration and occurrence of sustained AF >60minutes. Left atrial (LA) dilatation was present already at 2weeks of RAP. There was no evidence of left ventricular heart failure after 6weeks of RAP. As a proof-of-principle, arterial hypertension was induced in 5/16 animals by implanting desoxycorticosterone acetate (DOCA, an aldosterone-analog) subcutaneously to accelerate atrial remodeling. RAP+DOCA resulted in increased AF stability with earlier onset of sustained AF and accelerated anatomical atrial remodeling with more pronounced LA dilatation. This novel porcine model can serve to characterize effects of maladaptive stimuli or protective interventions specifically during early AF.

Mild hypothermia attenuates circulatory and pulmonary dysfunction during experimental endotoxemia.

OBJECTIVE: We tested whether mild hypothermia impacts on circulatory and respiratory dysfunction during experimental endotoxemia. DESIGN: Randomized controlled prospective experimental study. SETTING: Large animal facility, Medical University of Graz, Austria. SUBJECTS: Thirteen anesthetized and mechanically ventilated pigs. INTERVENTIONS: Lipopolysaccharide was administered for 4 hours. With the beginning of lipopolysaccharide infusion, animals were assigned to either normothermia (38°C, n = 7) or mild hypothermia (33°C, n = 6, intravascular cooling) and followed for 8 hours in total. MEASUREMENTS AND MAIN RESULTS: At the end of the protocol, cardiac output was lower in mild hypothermia than in normothermia (4.5 ± 0.4 L/min vs 6.6 ± 0.4 L/min, p < 0.05), but systemic vascular resistance (885 ± 77 dyn·s/cm vs 531 ± 29 dyn·s/cm, p < 0.05) and (Equation is included in full-text article.)(77% ± 6% vs 54% ± 3%, p < 0.05) were higher. Indices of left ventricular contractility in vivo were not different between groups. The high-frequency band in spectral analysis of heart rate variability indicated a better preserved vagal autonomic modulation of sinuatrial node activity in mild hypothermia versus normothermia (87 ± 5 vs 47 ± 5, normalized units, p < 0.05). Plasma norepinephrine levels were elevated compared with baseline in normothermia (2.13 ± 0.27 log pg/mL vs 0.27 ± 0.17 log pg/mL, p < 0.05) but not in mild hypothermia (1.02 ± 0.31 vs 0.55 ± 0.26, p = not significant). At 38°C in vitro, left ventricular muscle strips isolated from the mild hypothermia group had a higher force response to isoproterenol. SaO2 (100% ± 0% vs 92% ± 3%, p < 0.05) and the oxygenation index (PO2/FIO2, 386 ± 52 mm Hg vs 132 ± 32 mm Hg, p < 0.05) were substantially higher in mild hypothermia versus normothermia. Plasma cytokine levels were not consistently different between groups (interleukin 10) or higher (tumor necrosis factor-α and interleukin 6 and 8) during mild hypothermia versus normothermia. CONCLUSION: The induction of mild hypothermia attenuates cardiac and respiratory dysfunction and counteracts sympathetic activation during experimental endotoxemia. This was not associated with lower plasma cytokine levels, indicating a reduction of cytokine responsiveness by mild hypothermia.

Biopsychosocial health care needs at the emergency room: challenge of complexity.

BACKGROUND: In an emergency room of internal medicine, triage and treatment of patients deserve first priority. However, biopsychosocial case complexity may also affect patient health outcome but has not yet been explored in this setting. Therefore, the aims of the study are (1) to estimate prevalence rates of complex patients in the emergency room (ER), (2) to describe biopsychosocial complexity in this population and (3) to evaluate possible correlations between patient profiles regarding case complexity and further clinical treatment. METHODS: During a study period of one week, all patients of an emergency room of internal medicine who were triaged to Manchester levels three to five were invited to participate in the study. Biopsychosocial case complexity was assessed by the INTERMED method. Psychosocial interventions were evaluated based on all documented interventions and recommendations given at the emergency room and during inpatient treatment. RESULTS: Study participants consisted of 167 patients with a subgroup of 19% (n = 32) receiving subsequent inpatient-treatment at the department. High biopsychosocial case complexity was found in 12% (n = 20) of the total sample (INTERMED score >20). This finding was paralleled by a cluster analysis suggesting three clusters with one highly complex patient group of 14%. These highly complex patients differed significantly from the other clusters as they had visited the emergency room more often within the last year and lived alone more frequently. In addition, admission rates were highest in this group. During ER treatment and subsequent inpatient treatment, 21% of highly complex patients received interventions addressing psychosocial factors as compared to 6% and 7%, respectively, in the other clusters. CONCLUSIONS: A standardized screening of biopsychosocial case complexity among 'frequent utilizers' of the ER would be helpful to detect specific multidisciplinary health care needs among this particularly burdened patient group.

The effect of the K+ agonist nicorandil on peripheral vascular resistance.

BACKGROUND: The vasoactive effect of nicorandil on coronary arteries is well known. Nicorandil exerts its vasodilatory effect through a dual mechanism of action: involving on the one hand cyclic guanosine monophosphate (c GMP) as a nitrovasodilatator, and on the other hand, acting as a potassium channel opener. OBJECTIVE: To address the question if nicorandil works in peripheral arteries, its effect on peripheral vascular resistance was evaluated in isolated perfused guinea pig hind limbs. METHODS: A catheter was inserted via the distal aorta and common iliac artery. Perfusion pressure was monitored under constant perfusion with Tyrode's solution, therefore changes in perfusion pressure represent changes in vascular resistance. After stabilization precontraction of the peripheral vascular bed was achieved with noradrenaline 3 microM and nicorandil was added in concentrations of 1, 10 and 100 microM. The effect of nicorandil (1, 10 and 100 microM) was tested in the presence of L-NAME and glybenclamide. RESULTS: A significant reduction of vascular peripheral resistance was already achieved at a concentration of 1 microM nicorandil (30.3+/-6.1%, mean S.E.M., p < 0.001). At a concentration of 100 microM nicorandil the reduction of peripheral vascular resistance was 94.4+/-16.4%. Peripheral vascular resistance was less but nearly comparable reduced by nicorandil (100 microM) if the endothelial NO effect was inhibited by L-NAME (58.6+/-18.6%) or if the ATP-dependent potassium channels were blocked by glybenclamide (56.4+/-14.6%). CONCLUSIONS: In peripheral arteries the nitrovasodilator effect of nicorandil is nearly comparable to the potassium agonistic effect, and the concentration, which is necessary to reduce peripheral vascular resistance significantly, is comparable with dosages necessary for reduction of coronary resistance.

A rapidly activating delayed rectifier K+ current regulates pacemaker activity in adult mouse sinoatrial node cells.

We have investigated the physiological role of the "rapidly activating" delayed rectifier K+ current (IKr) in pacemaker activity in isolated sinoatrial node (SAN) myocytes and the expression of mouse ether-a-go-go (mERG) genes in the adult mouse SAN. In isolated, voltage-clamped SAN cells, outward currents evoked by depolarizing steps (greater than -40 mV) were strongly inhibited by the class III methanesulfonanilide compound E-4031 (1-2.5 microM), and the deactivation "tail" currents that occurred during repolarization to a membrane potential of -45 mV were completely blocked. E-4031-sensitive currents (IKr) reached a maximum at a membrane potential of -10 mV and showed pronounced inward rectification at more-positive membrane potentials. Activation of IKr occurred at -40 to 0 mV, with half-activation at about -24 mV. The contribution of IKr to action potential repolarization and diastolic depolarization was estimated by determining the E-4031-sensitive current evoked during voltage clamp with a simulated mouse SAN action potential. IKr reached its peak value (approximately 0.6 pA/pF) near -25 mV, close to the midpoint of the repolarization phase of the simulated action potential, and deactivated almost completely during the diastolic interval. E-4031 (1 microM) slowed the spontaneous pacing rate of Langendorff-perfused, isolated adult mouse hearts by an average of 36.5% (n = 5). Expression of mRNA corresponding to three isoforms coded by the mouse ERG1 gene (mERG1), mERG1a, mERG1a', and mERG1b, was consistently found in the SAN. Our data provide the first detailed characterization of IKr in adult mouse SAN cells, demonstrate that this current plays an important role in pacemaker activity, and indicate that multiple isoforms of mERG1 can contribute to native SAN IKr.

The effect of caffeine on peripheral vascular resistance in isolated perfused guinea pig hind limbs.

BACKGROUND: The role of caffeine in cardiovascular disease is controversial. Most of its pharmacologic actions are attributed to its role as an adenosine antagonist. Adenosine is one of the most important endogenous vasodilatative substances and is released under ischemic conditions, for example, in the skeletal muscle of patients with peripheral arterial occlusive disease. We aimed to investigate the influence of caffeine on peripheral vascular resistance and on the beneficial vasodilatory effect of adenosine in isolated perfused guinea pig hind limbs. MATERIALS AND METHODS: (1) Caffeine was administered at 0.5, 5, and 50 micromol/L under normoxic conditions. (2) The vasculature of the perfused guinea pig hind limb was precontracted with noradrenaline (3 micromol/L), followed by adenosine (10 micromol/L) under normoxic conditions. When vascular resistance (VR) had reached a steady state, caffeine was administered additionally at dosages of 0.5, 5, and 50 micromol/L. (3) This protocol was repeated using iloprost 0.1 micromol/L instead of adenosine as vasodilatory substance. (4) Under hypoxia, caffeine was again administered at the above dosages. (5) Under hypoxia, experiments with adenosine A2-receptor antagonists (alloxazine 10 micromol/L and ZM 241385 100 nmol/L) were done. RESULTS: Under normoxic conditions, 0.5 and 5 micromol/L caffeine had nearly no effect on vascular resistance compared with baseline conditions. A slight, but statistically not significant decrease in VR was achieved with 50 micromol/L caffeine. In the presence of noradrenaline, the vasodilatory effect of adenosine was reduced by 7.6 +/- 1.6% after the addition of 0.5 micromol/L caffeine, and by 37.3 +/- 3.8% at a dosage of 5 micromol/L caffeine. A dosage of 50 micromol/L caffeine completely abolished the vasodilatative effect of adenosine. In the presence of iloprost, only a slight but statistically insignificant inhibitory influence (0.9%) of caffeine at a dosage of 50 micromol/L could be seen. Hypoxia significantly reduced VR. Caffeine at 0.5 micromol/L diminished this effect by about 53.2 +/- 4.6% and abolished it at 5 and 50 micromol/L. The hypoxia-induced adenosine-mediated vasodilatation seems to be an adenosine A2A-receptor-mediated effect. CONCLUSIONS: The observed effect of hypoxia-induced vasodilatation in peripheral arteries may be the result of the vasodilatory effect of elevated endogenous adenosine during hypoxia. For patients with peripheral arterial disease, drinking of caffeine-containing beverages may reduce the beneficial vasodilatory effect of elevated endogenous adenosine levels.

The influence of magnesium on the electrophysiological effects of erythromycin in the isolated Guinea pig heart.

There have been several case reports that erythromycin can prolong the QT interval, resulting in torsades de pointes. As magnesium is well established in the treatment of torsades de pointes, we aimed to investigate how this trace element influences the electrophysiological effects of erythromycin. The effects of erythromycin and magnesium on cardiac conduction and refractoriness were evaluated in isolated guinea pig hearts perfused by the method of Langendorff. Erythromycin was given in concentrations of 10, 30 and 100 microM. In the magnesium group MgSO4 was elevated to 3.4 mM. Magnesium at a concentration of 3.4 mM did not affect cardiac conduction and refractoriness. Erythromycin prolongs the QT interval in a dose-dependent manner. The prolongation of the QT interval by erythromycin was diminished by the elevated magnesium concentration (3.4 mM) at high rates (pacing cycle length 180 vs. 220 ms). The most pronounced effect of erythromycin (100 microM) was the prolongation of the atrial effective refractory period. This effect was nearly abolished by the elevated magnesium concentration (129.0 +/- 8.3% vs. 41.9 +/- 10.6%, P < 0.01, n = 6, x +/- SEM). In summary, magnesium minimizes the effects of erythromycin on the repolarization period in the ventricle and on the effective refractory period of the atrium.

Comparison of the Effect of Prostaglandin E(1), Prostacycline and Adenosine on Peripheral Vascular Resistance.

Prostacycline, prostaglandin E(1), and adenosine are highly effective vasodilators. These three drugs are widely used in the treatment of peripheral arterial occlusive disease. The aim of the study was to compare the vasodilatory potency of these substances in the isolated perfused guinea pig hind limb. After equilibration with Tyrode's solution and precontraction with noradrenaline 3µM, prostaglandin E(1) and adenosine were administered at dosages of 0.1, 0.3, and 1µM, whereas prostacycline was administered at a dosage of 0.01, 0.03 and 0.1µM. 0.01µM prostacycline, 0.1 µM prostaglandin E(1), and 0.1µM adenosine were the lowest dosages at which a significant vasodilation could be reached for each substance. The reduction of peripheral vascular resistance at comparable dosages of 0.1µM was 11.0 +/- 2.6% (x +/- SEM, n = 5) for adenosine, 12.0 +/- 1.0% (n = 5) for prostaglandin E(1), but 28.0 +/- 9.3% (n = 5) for prostacycline (p < 0.05 versus adenosine and prostaglandin E(1)). Even at a dosage of 0.01 µM prostacycline, a comparable reduction in peripheral vascular resistance (16.0 +/- 2.8%) could be reached, compared to a ten-fold higher dosage of prostaglandin E(1) and adenosine. At the highest concentration of 1 µM, the vasodilatory effect of adenosine was significantly less expressed, compared to that of prostaglandin E(1) (18.0 +/- 3.4% versus 33.0 +/- 4.7%). In summary, prostacycline, at a ten-fold lower concentration, showed comparable vasodilatory effects to adenosine and prostaglandin E(1). The rank order at the vasodilatory potency is prostacycline > prostaglandin E(1) > adenosine.