Atrial nitroso-redox balance and refractoriness following on-pump cardiac surgery: a randomized trial of atorvastatin.

AIMS: Systemic inflammation and increased activity of atrial NOX2-containing NADPH oxidases have been associated with the new onset of atrial fibrillation (AF) after cardiac surgery. In addition to lowering LDL-cholesterol, statins exert rapid anti-inflammatory and antioxidant effects, the clinical significance of which remains controversial. METHODS AND RESULTS: We first assessed the impact of cardiac surgery and cardiopulmonary bypass (CPB) on atrial nitroso-redox balance by measuring NO synthase (NOS) and GTP cyclohydrolase-1 (GCH-1) activity, biopterin content, and superoxide production in paired samples of the right atrial appendage obtained before (PRE) and after CPB and reperfusion (POST) in 116 patients. The effect of perioperative treatment with atorvastatin (80 mg once daily) on these parameters, blood biomarkers, and the post-operative atrial effective refractory period (AERP) was then evaluated in a randomized, double-blind, placebo-controlled study in 80 patients undergoing cardiac surgery on CPB. CPB and reperfusion led to a significant increase in atrial superoxide production (74% CI 71-76%, n = 46 paired samples, P < 0.0001) and a reduction in atrial tetrahydrobiopterin (BH4) (34% CI 33-35%, n = 36 paired samples, P < 0.01), and in GCH-1 (56% CI 55-58%, n = 26 paired samples, P < 0.001) and NOS activity (58% CI 52-67%, n = 20 paired samples, P < 0.001). Perioperative atorvastatin treatment prevented the effect of CPB and reperfusion on all parameters but had no significant effect on the postoperative right AERP, troponin release, or NT-proBNP after cardiac surgery. CONCLUSION: Perioperative statin therapy prevents post-reperfusion atrial nitroso-redox imbalance in patients undergoing on-pump cardiac surgery but has no significant impact on postoperative atrial refractoriness, perioperative myocardial injury, or markers of postoperative LV function. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT01780740.

Intrinsic Adaptation of SHR Right Atrium Reduces Heart Rate.

Hypertension represents an autonomic dysfunction, characterized by increased sympathetic and decreased parasympathetic cardiovascular tone leading to resting tachycardia. Therefore, studies assessing hypertension-associated changes in isolated cardiac tissues were conducted under electric field stimulation to stimulate the neurons. Herein, we characterize the influence of the autonomic neurotransmitter on the baseline atrial chronotropism of unpaced isolated right atria of normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHR). Our results revealed a resting bradycardia in tissues from SHR in comparison to NWR. The release of autonomic neurotransmitters, acetylcholine or norepinephrine, still occurs in the electrically unstimulated right atrium, after excision of the sympathetic nerve, which could explain differences in basal heart rate between NWR and SHR. Nicotine and the acetylcholinesterase inhibitor physostigmine reduced the chronotropism of right atria from either NWR or SHR. Conversely, the muscarinic receptor antagonist atropine did not affect the basal chronotropism of tissues from both strains. Furthermore, tyramine increased the chronotropism of NWR and SHR atria indicating availability of the neuronal stocks of noradrenaline. Although the monoamine uptake inhibitor cocaine increased right atrium chronotropism in both strains, the basal heart rate was not affected by the ß-adrenoceptor antagonist propranolol. In summary, after acute section of the sympathetic nerve, autonomic neurotransmitters are still released either in resting conditions or upon pharmacological stimulation of right atria from both strains. Nevertheless, autonomic neurotransmission does not affect resting chronotropism, nor is the responsible for reduced basal heart rate of the isolated right atrium of hypertensive rats.

Acute effect of iloprost inhalation on right atrial function and ventricular dyssynchrony in patients with pulmonary artery hypertension.

BACKGROUND: Right atrium function and ventricular function have significant prognostic value in pulmonary arterial hypertension patients. Acute changes in right ventricular synchrony and right atrium function postiloprost inhalation have not been evaluated. METHODS: Cross-sectional study. Consecutive pulmonary arterial hypertension patients (group I from Nice classification) were included. Echocardiographic right atrium and right ventricular function pre- and postiloprost inhalation, including a right ventricular dyssynchrony index and right atrium function using speckle tracking, were performed in all patients. RESULTS: Twenty pulmonary arterial hypertension patients, 44±7 years and 90% females, were included. After iloprost inhalation, we observed a significant increment in right ventricular fractional area change and a significant decrease in right ventricular dyssynchrony index (21.4±5.6% vs 26.1±4.0 %, P=.007 and 79±44 vs 32±22 mseconds, P<.01, respectively), also an improvement in right atrium reservoir function (8.6±3.1% vs 11.7±3.5 %, P=.002). CONCLUSIONS: Iloprost inhalation induces acute changes in right ventricular function, dyssynchrony, and right atrium performance that may add relevant clinical information in the management and risk stratification of pulmonary arterial hypertension patients.

Decongestive effects of levosimendan in cardiogenic shock induced by postpartum cardiomyopathy.

BACKGROUND: Catecholamines and/or levosimendan have been proposed for haemodynamic restoration during cardiogenic shock (CS). In CS induced by post-partum cardiomyopathy (PPCM), levosimendan might be particularly favourable. The aim of this study was to evaluate the haemodynamic and echocardiographic effects of levosimendan in patients with CS, in particular in patients with PPCM-induced CS. METHODS: Twenty-eight patients with refractory CS were retrospectively included in the study. Among them, a cohort of 8 women with PPCM-induced CS was included. All patients were treated with levosimendan (loading dose followed by a continuous infusion for 24 h) and were invasively monitored, including a pulmonary artery catheter, for 48hours. Echocardiographic measurements were performed at baseline and during follow-up. RESULTS: Significant improvements in haemodynamic parameters were observed 48 h after starting levosimendan. The cardiac index increased (+1.2±0.6L/min, P<0.001) and filling pressures decreased (pulmonary artery occlusion pressure, PAOP: -11.2±4.3mmHg, P<0.001; right-atrial pressure, RAP: -6.1±4.9mmHg, P<0.001). The left ventricular ejection fraction was significantly higher at 48 h compared to baseline (38% [34-46%] versus 27% [22-30%], P<0.001). Despite similar characteristics at baseline, in the subgroup of patients with PPCM, more profound decongestive effects at 48hours were observed: PAOP (13±2 versus 17±4mmHg, P=0.007) and RAP (12±4 versus 17±4mmHg, P=0.006) were significantly lower in the PPCM subgroup compared to the non-PPCM subgroup. CONCLUSIONS: Haemodynamics and left-ventricular ejection fraction rapidly improved after treatment with levosimendan. In patients with PPCM-induced CS, a more profound reduction of congestion was observed.

IL-1 provokes electrical abnormalities in rat atrial myocardium.

Using a micro-electrode technique we studied the effects of interleukin 1α and interleukin 1ß on bio-electric activity of rat atrial myocardium under normal conditions and after gradual stretching. Perfusion with interleukin 1α increased the duration of the action potential at the level of 90% re-polarization. Stretch induced tachy-arrhythmia in the presence of interleukin 1α is mainly regulated via stretch increased nitric oxide production, while the ionotropic effect of the interleukin-1α during stretching is not pronounced. The perfusion with interleukin 1ß did not change the values of the duration of the action potentials at the levels of 25, 50 and 90% repolarization. The interleukin lß caused an appearance of extra-systolic patterns which turned into normal rhythm, alternating with periods of normal activity. The total intracellular nitric oxide level induced by both interleukin 1ß and stretching is balanced by interleukin-1ß induced cation influx.

Atrial chronotropic reactivity to catecholamines in neonatal rats: Contribution of ß-adrenoceptor subtypes.

Although increase in heart rate is a crucial determinant for enhancement of cardiac output in the neonate, information on the chronotropic reactivity to catecholamines during postnatal development is scarce. The present study was aimed at investigating the role of ß-adrenoceptor subtypes and catecholamine removal mechanisms in the adrenergic chronotropic response during the early post-natal period. Right atria isolated from immature (0-21 day old) and adult (4-6 month old) rats were used for determination of the responsiveness to agonists and quantitation of the transcripts of proteins involved in ß-adrenergic signaling. The main results were: (a) the maximum response (Rmax) to norepinephrine increased with age, whereas sensitivity decreased; (b) age-dependent differences in sensitivity to norepinephrine were abolished by inhibition of the neuronal norepinephrine transporter; (c) Rmax to isoproterenol was similar in immature and adult atria, and depressed only in the former by ß2-adrenoceptor blockade with ICI118,551; (d) neonatal atria showed greater ß2-adrenoceptor mRNA levels, and more prominent positive chronotropic response to the ß2- and ß3-adrenoceptor agonists zinterol and YM178, respectively (nanomolar range); (e) in atria of immature rats, transcript levels of the extraneuronal monoamine transporter were lower, and its inhibition did not affect sensitivity to isoproterenol; and (f) reactivity to forskolin and 3-isobutyl-1-methylxanthine was not affected by age. The increased ß2- and ß3-adrenoceptor participation in the adrenergic chronotropic response, in addition to weaker catecholamine removal, may compensate for the immature cardiac innervation and the apparently reduced efficiency of ß1-adrenoceptor signaling in the neonate, increasing the responsiveness to endogenous and exogenous ß2-adrenoceptor agonists.

Glucagon Increases Beating Rate but Not Contractility in Rat Right Atrium. Comparison with Isoproterenol.

This study evaluated the chronotropic and inotropic responses to glucagon in spontaneously beating isolated right atria of rat heart. For comparison, we also investigated the effects resulting from stimulating ß-adrenoceptors with isoproterenol in this tissue. Isoproterenol increased both atrial frequency and contractility but glucagon only enhanced atrial rate. The transcript levels of glucagon receptors were about three times higher in sinoatrial node than in the atrial myocardium. Chronotropic responses to glucagon and isoproterenol were blunted by the funny current (If) inhibitor ZD 7288. Inhibitors of protein kinase A, H-89 and KT-5720 reduced the chronotropic response to glucagon but not to isoproterenol. Inhibition of ryanodine receptors and calcium/calmodulin dependent protein kinase II (important regulators of sarcoplasmic reticulum Ca2+ release), with ruthenium red and KN-62 respectively, failed to alter chronotropic responses of either glucagon or isoproterenol. Non selective inhibition of phosphodiesterase (PDE) with 3-isobutylmethylxantine or selective inhibition of PDE3 or PDE4 with cilostamide or rolipram respectively did not affect chronotropic effects of glucagon or isoproterenol. Our results indicate that glucagon increases beating rate but not contractility in rat right atria which could be a consequence of lower levels of glucagon receptors in atrial myocardium than in sinoatrial node. Chronotropic responses to glucagon or isoproterenol are mediated by If current but not by sarcoplasmic reticulum Ca2+ release, neither are regulated by PDE activity.

Change of right heart size and function by long-term therapy with riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.

BACKGROUND: Riociguat is a soluble guanylate cyclase stimulator approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The objective of this study was to evaluate the change of right heart size and function assessed by echocardiography during long-term treatment with riociguat. METHODS: We assessed patients who started riociguat treatment (1.0-2.5mg tid) within the trials PATENT, PATENTplus, EAS and CHEST and continued for 3-12 months. Echocardiography, 6-minute walking distance (6MWD) and further clinical parameters were analyzed at baseline, after 3, 6 and 12 months. Right heart catheterization was performed at baseline and after 3 months. For missing data we performed the last and baseline observation carried forward (LOCF, BOCF) method as sensitivity analyses. RESULTS: Thirty-nine patients (21 PAH, 18 CTEPH, mean pulmonary arterial pressure 43 ± 2 mmHg, PVR 600 ± 43 dyn ∗ s ∗ cm(-5), 56.4% treatment-naïve) were included. Mean right ventricular (RV) area significantly decreased after 3 (-2.1 ± 3.9 cm(2), equals -7.4 ± 15.3%, p = 0.002), 6 (-4.2 ± 3.2 cm(2), equals -16.1 ± 11.5%, p < 0.001) and 12 months (-5.9 ± 4.6 cm(2), equals -22.1 ± 14.2%, p < 0.001) compared to baseline. Right atrial area significantly decreased after 12 months (-3.5 ± 4.1cm(2), equals -16.8 ± 19.2%, p < 0.001) and TAPSE significantly improved after 6 (+ 2 ± 4.7, equals 12 ± 25.8%, p = 0.025) and 12 months (+ 3.6 ± 5.4, equals 21.0 ± 29.6%, p = 0.002). Furthermore, RV wall thickness and 6MWD significantly improved after 3, 6 and 12 months (p < 0.05). Invasive hemodynamics significantly improved after 3 months. Both LOCF and BOCF showed similar significance and lower effect sizes. CONCLUSION: Long-term treatment with riociguat significantly reduced right heart size and improved RV function in PAH and CTEPH. Further prospective studies are needed to confirm these results.

Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension.

OBJECTIVE: We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine. PATIENTS AND METHODS: ADMA, SDMA, and arginine were measured (0-540 min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60 min. RESULTS: A reduction in ADMA was observed at 30 and 45 min with a median change of -11.1% (P=0.021) and -12.5% (P=0.002). SDMA decreased with a median -5.3% change (P=0.032) at 45 min. An increase in arginine, median 40.3% (P=0.002), 45.0% (P=0.010), and 77.1% (P=0.008) was observed at 120, 300, and 540 min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P=0.012), 32.5% (P=0.003), 26.5% (P=0.021), 33% (P=0.007), 48.5% (P=0.007), and 63.1% (P=0.008) was observed at 15, 45, 60, 120, 300, and 540 min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540 min (r=0.80; P=0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r=0.65; P=0.023), and baseline SDMA (r=0.61; P=0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r=0.59; P=0.045) and baseline cardiac index (CI) (r=0.61; P=0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r=-0.79; P=0.002). A correlation between change (0-60 min) in CI and change in arginine (r=0.77; P=0.003) as well as change in the arginine/ADMA ratio (r=0.61; P=0.037) was observed. CONCLUSIONS: Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in CI.

Antiarrhythmic Mechanisms of SK Channel Inhibition in the Rat Atrium.

INTRODUCTION: SK channels have functional importance in the cardiac atrium of many species, including humans. Pharmacological blockage of SK channels has been reported to be antiarrhythmic in animal models of atrial fibrillation; however, the exact antiarrhythmic mechanism of SK channel inhibition remains unclear. OBJECTIVES: We speculated that together with a direct inhibition of repolarizing SK current, the previously observed depolarization of the atrial resting membrane potential (RMP) after SK channel inhibition reduces sodium channel availability, thereby prolonging the effective refractory period and slowing the conduction velocity (CV). We therefore aimed at elucidating these properties of SK channel inhibition and the underlying antiarrhythmic mechanisms using microelectrode action potential (AP) recordings and CV measurements in isolated rat atrium. Automated patch clamping and two-electrode voltage clamp were used to access INa and IK,ACh, respectively. RESULTS: The SK channel inhibitor N-(pyridin-2-yl)-4-(pyridin-2-yl)thiazol-2-amine (ICA) exhibited antiarrhythmic effects. ICA prevented electrically induced runs of atrial fibrillation in the isolated right atrium and induced atrial postrepolarization refractoriness and depolarized RMP. Moreover, ICA (1-10 µM) was found to slow CV; however, because of a marked prolongation of effective refractory period, the calculated wavelength was increased. Furthermore, at increased pacing frequencies, SK channel inhibition by ICA (10-30 µM) demonstrated prominent depression of other sodium channel-dependent parameters. ICA did not inhibit IK,ACh, but at concentrations above 10 µM, ICA use dependently inhibited INa. CONCLUSIONS: SK channel inhibition modulates multiple parameters of AP. It prolongs the AP duration and shifts the RMP towards more depolarized potentials through direct ISK block. This indirectly leads to sodium channel inhibition through accumulation of state dependently inactivated channels, which ultimately slows conduction and decreases excitability. However, a contribution from a direct sodium channel inhibition cannot be ruled. We here propose that the primary antiarrhythmic mechanism of SK channel inhibition is through direct potassium channel block and through indirect sodium channel inhibition.

Cambios agudos en la función auricular derecha post uso de iloprost inhalatorio en pacientes con hipertensión arterial pulmonar: estudio con técnicas de deformación de imagen / Acute changes in right atrial funcion after Iloprost inhalation in patients with pulmonary hypertension: a study using image deformation techniques

Introducción: El efecto de prostanoides inhalatorios sobre la función auricular derecha (AD) en hipertensión arterial idiopática (HAP) no ha sido estudiado. Objetivo: Evaluar cambios agudos en la función AD y función diastólica del ventrículo derecho en pacientes con HAP post uso de Iloprost inhalatorio. Métodos: Se incluyeron pacientes con HAP sin uso previo de prostanoides. Se realizó un ecocardiograma transtorácico basal y 30 min posterior a la inhalación de iloprost. Se midió dimensión AD, relación E/e' y strain de la AD por speckle tracking, registrando la onda negativa de contracción auricular (SaAD) y la onda positiva de la fase de reservorio (SsAD). Se midió el tiempo de inicio de la fase de reservorio AD durante el sístole ventricular. Resultados: Se estudiaron 16 pacientes (15 mujeres), con edad promedio 44 ± 7,8 años. Post Iloprost disminuyó el volumen AD (basal: 140ml, post Iloprost: 109 ml; p 0,008) y las presiones de llenado (E/e’ basal: 13, post Iloprost: 9,8; p 0,028). No se registraron diferencias en el SaAD (basal: -8,4%, post Iloprost: -8,5%; p 0,834). El SsAD fue mayor post Iloprost (basal: 8,6%, post Iloprost: 11,7%; p 0,002) iniciándose antes durante el sístole ventricular (basal: 445ms, post Iloprost: 368ms; p 0,001). Conclusión: Con Iloprost inhalatorio en pacientes con HAP se observa una reducción aguda en el tamaño de la AD y en las presiones de llenado del VD. La deformación durante la fase de reservorio de la AD aumenta y se inicia significativamente antes. Esto sugiere que el Iloprost podría mejorar en forma aguda el trabajo mecánico de la AD en paciente con HAP.

Background: The effects of inhaled prostanoids on right atrial (RA) function in patients with Pulmonary Arterial Hypertension (PAH) have not been studied. We evaluated acute changes in RA function and right ventricular diastolic function after inhaled iloprost. Methods: We included PAH patients without prior prostanoid treatment. A surface echocardiogram was performed at baseline and 30 minutes after iloprost inhalation. Measurements included RA dimensions, right E/e’ ratio and RA strain by speckle tracking, registering a RA contraction wave (RASa) and RA reservoir wave (RASs). RA time to peak of deformation during the reservoir phase was also measured. Results: We included 16 patients (15 females, aged 44±7.8 years. Post iloprost there was a reduction in RA volume (baseline: 140ml, post iloprost: 109ml; p 0.008) and right ventricular filling pressure (baseline E/e’: 13, post iloprost: 9.8; p 0.028). There was no difference in the magnitude of the RASa wave (baseline: -8.4%, post iloprost: -8.5%; p 0.834). The RASs wave was larger post iloprost (baseline: 8.6%, post iloprost: 11.7%; p 0.002), and began earlier (baseline RA time to peak of deformation during reservoir phase: 445ms, post iloprost: 368ms; p 0.001). Conclusion: Inhaled iloprost acutely reduces RA size and right ventricular filling pressure in patients with HAP It also significantly increases the magnitude of RA systolic deformation as well as making it occur earlier in RA filling phase. This suggests that iloprost might improve RA mechanical performance.

Prognosis and response to first-line single and combination therapy in pulmonary arterial hypertension.

OBJECTIVES: To investigate survival, treatment escalation, effects of first-line single- and first-line combination therapy and prognostic markers in idiopathic- (IPAH), hereditary- (HPAH) and connective tissue disease-associated (CTD-PAH) pulmonary arterial hypertension (PAH). DESIGN: Retrospective analysis of medical journals from PAH patients at Skåne University Hospital 2000-2011. RESULTS: 1-, 2- and 3-year survival was 87%, 67%, and 54%, respectively, for the entire population, but worse (p = 0.003) in CTD-PAH than IPAH/HPAH. After 1, 2 and 3 years, 58%, 41% and 24% of patients starting on single therapy were alive on single therapy. 37.5% of patients on first-line single therapy received escalated treatment at first follow-up. First-line combination therapy more greatly decreased pulmonary vascular resistance index (PVRI, p = 0.017) than first-line single therapy. Only first-line combination therapy improved (p = 0.042) cardiac index (CI). Higher mean right atrial pressure (MRAP, p = 0.018), MRAP/CI (p = 0.021) and WHO functional class (p < 0.001) and lower 6-min walking distance (6MWD, p = 0.001) at baseline, and higher PVRI (p = 0.008) and lower 6MWD (p = 0.004) at follow-up were associated with worse outcome. CONCLUSIONS: We confirm improved survival with PAH-targeted therapies. Survival is still poor and early treatment escalation frequently needed. First-line combination therapy may more potently improve haemodynamics. MRAP/CI may represent a new prognostic marker in PAH.

Prognostic value of echocardiographic changes in patients with pulmonary arterial hypertension receiving parenteral prostacyclin therapy.

BACKGROUND: It is unknown whether the echocardiographic changes observed after treatment of patients with pulmonary arterial hypertension have prognostic value. METHODS: Subjects with pulmonary arterial hypertension, confirmed by right heart catheterization, who underwent Doppler echocardiography before (baseline) and after 1 year of treatment (follow-up) with parenteral prostacyclin analogues were retrospectively identified. Echocardiographic parameters were measured offline by two investigators. RESULTS: A total of 48 patients were included (mean age, 45 ± 14 years; 83% women). Compared with baseline, follow-up echocardiography showed reductions in right atrial area (mean percentage change, 12 ± 25%; P < .001), right ventricular (RV) basal and middle cavity dimensions (mean percentage change, 8.5 ± 14% [P < .001] and 6.8 ± 17% [P = .005], respectively), and peak tricuspid regurgitant velocity (mean percentage change, 10 ± 14%; P < .001). Tricuspid annular plane systolic excursion (mean percentage change, 36 ± 43%; P < .001) and RV outflow tract time-velocity integral (mean percentage change, 48 ± 66%; P < .001) increased. During a median follow-up period of 52.5 months (interquartile range, 20.5-80 months), 18 patients (37.5%) died, mostly (n = 15 [83%]) from progression of pulmonary arterial hypertension. The changes in RV end-diastolic area (hazard ratio [HR per 10% decrease, 0.73; 95% confidence interval [CI], 0.57-0.93), tricuspid valve regurgitation velocity (HR per 10 cm/sec decrease, 0.58; 95% CI, 0.37-0.89), RV outflow tract velocity-time integral (HR per 10% increase, 0.90; 95% CI, 0.83-0.98), and subjective RV function (HR per 1 unit of improvement [e.g., from moderate to mild], 0.55; 95% CI, 0.31-0.96) were associated with overall mortality. CONCLUSIONS: Echocardiographic parameters that estimate RV systolic pressure and assess RV morphology and function improve after 1 year of prostacyclin analogue treatment, and the degree of change has prognostic implications.

Right ventricular and right atrial function and deformation in patients with subclinical hypothyroidism: a two- and three-dimensional echocardiographic study.

BACKGROUND: We sought to investigate right ventricular (RV) function and deformation assessed by three-dimensional echocardiography (3DE) and speckle tracking in patients with subclinical hypothyroidism (SHT), and to evaluate the influence of levothyroxine (L-T4) therapy on RV remodeling. METHODS: We included 50 untreated women with SHT and 45 healthy control women matched by age. The L-T4 therapy was prescribed to all SHT patients who were followed 1 year after euthyroid status was achieved. All study participants underwent laboratory analyses which included thyroid hormone levels, and complete two-dimensional echocardiography (2DE) and 3DE examinations. RESULTS: 3DE RV end-diastolic volume and ejection fraction were significantly reduced in the SHT patients before therapy in comparison with the healthy controls and treated SHT subjects. RV longitudinal strain, systolic, and early diastolic strain rates (SRs) were significantly decreased, whereas RV late diastolic SR was increased in the SHT patients before therapy when comparing with the controls. 2DE speckle tracking imaging revealed that L-T4 substitution therapy significantly improved RV systolic mechanics, whereas RV diastolic deformation was not completely recovered. Right atrial (RA) function and deformation were significantly impacted by SHT. Replacement L-T4 treatment improved but did not completely restore RA mechanics in the SHT patients. CONCLUSION: RV and RA function and mechanics are significantly affected by SHT. L-T4 therapy and 1-year maintenance of euthyroid status improved but did not completely recover RV and RA function and deformation in the SHT patients, which implies that right heart remodeling caused by SHT is not reversible in a 1-year period.

Electrophysiological effects of an anti-influenza drug oseltamivir on the guinea-pig atrium: comparison with those of pilsicainide.

We assessed the effects of oseltamivir on the conduction velocity and effective refractory period in the guinea-pig atrium in comparison with those of a class Ic antiarrhythmic drug pilsicainide. The recording and stimulating electrodes were attached on the epicardium close to the sinus nodal region and on the left atrial appendage. Oseltamivir (10-100 µM) as well as pilsicainide (1-10 µM) decreased the atrial conduction velocity in a frequency-dependent manner. Both drugs also increased the effective refractory period in both atria; but the frequency-dependent property of oseltamivir was lacking in the left atrium, and it was less obvious in the right atrium compared with that of pilsicainide. These results suggest that oseltamivir can directly modify the electrophysiological functions in the guinea-pig atrium possibly via combination of Na(+) and K(+) channel-blocking actions.

The co-application of hypoxic preconditioning and postconditioning abolishes their own protective effect on systolic function in human myocardium.

BACKGROUND: Ischemic preconditioning (IPC) and postconditioning (POC) are well documented to trigger cardioprotection against ischemia/reperfusion (I/R) injury, but the effect oftheir both co-application remains unclear in human heart. The present study sought to assessthe co-application of IPC and POC on fragments of human myocardium in vitro. METHODS: Muscular trabeculae of the human right atrial were electrically driven in the organbath and subjected to simulated I/R injury - hypoxia/re-oxygenation injury in vitro. To achieveIPC of trabeculae the single brief hypoxia period preceded the applied lethal hypoxia, and to achieve POC triple brief hypoxia periods followed the lethal hypoxia. Additional muscular trabeculae were exposed only to the hypoxic stimulation (Control) or were subjected to the non-hypoxic stimulation (Sham). 10 µM norepinephrine (NE) application ended every experiment to assess viability of trabeculae. The contraction force of the myocardium assessed as a maximal amplitude of systolic peak (%Amax) was obtained during the whole experiment's period. RESULTS: Co-application of IPC and POC resulted in decrease in %Amax during the re-oxygentaionperiod and after NE application, as compared to Control (30.35 ± 2.25 vs. 41.89 ± 2.25, 56.26 ± 7.73 vs. 65.98 ± 5.39, respectively). This was in contrary to the effects observed when IPC and POC were applied separately. CONCLUSIONS: The co-application of IPC and POC abolishes the cardioprotection of either intervention alone against simulated I/R injury in fragments of the human right heart atria.

[Influence of new III class antiarrhythmic drug Niferidil (RG-2) on bioelectrical activity of rat pulmonary veins myocardium].

Myocardial cells in pulmonary veins are thought to play a major role in the initiation and maintenance of atrial arrhythmias, including atrial fibrillation. In experiments on rat pulmonary veins, antiarrhythmic drug niferidil (RG-2) produced increase of APD90% and functional refractory period and decrease of action potential amplitude and slope of APD restitution curve. Thus niferidil (RG-2) exerts stronger action on pulmonary veins than left atrium. This can take important part in Niferidil (RG-2) antiarrhythmic activity.

Cardiac responses to the intrapericardial delivery of metoprolol: targeted delivery compared to intravenous administration.

Anti-arrhythmic drugs have narrow therapeutic ranges and typically can engender harmful side effects. The intrapericardial (IP) delivery of anti-arrhythmic agents proposes to achieve higher myocardial levels while minimizing plasma concentrations, thus diminishing systemic side effects. Furthermore, IP delivery enables concentrations at the target site to be more precisely controlled. Our study objective was to compare the relative cardiac effects of intrapericardial administration of metoprolol to standard intravenous (IV) delivery in a swine surgical model. In order to answer the question of how IP metoprolol affects sinus tachycardia, atrial electrophysiology, and pharmacokinetics compared with IV delivery, a medial sternotomy was performed on 21 swine that were divided into three groups: (1) After inducing sinus tachycardia, metoprolol boluses were delivered IP (n = 4) or IV (n = 4); (2) metoprolol was administered either IP (n = 3) or IV (n = 3) with saline controls (n = 3), and electrophysiologic data were collected; (3) metoprolol levels were tracked both in the blood (IV, n = 2) and pericardial (IP, n = 2) fluid. After either IP or IV delivery of metoprolol, heart rates were lowered significantly to 70% and 73% of control rate, respectively. The therapeutic effect of IV-administered metoprolol was considerably reduced after 1 h but was sustained longer in the IP group. Additionally, ventricular contractility and mean arterial pressure parameters were significantly lower in IV-treated animals but were nearly unaffected in IP-treated animals. With IP administration, the elimination half-life of metoprolol in pericardial fluid was 14.4 min with negligible accumulations in the plasma, whereas with IV delivery, the elimination half-life in plasma was 11.1 min with negligible amounts found in the pericardial fluid. The targeted intrapericardial delivery of metoprolol effectively lowers heart rates for sustained periods of time, with minimal effect on either ventricular contractility or mean arterial pressure. We did not observe dramatic changes in induced atrial fibrillation times or refractory periods using this model.

Synthesis and pharmacological evaluation of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives as novel antihypertensive agents.

We synthesized and evaluated inhibitory activity against T-type Ca(2+) channels for a series of 1-alkyl-N-[2-ethyl-2-(4-fluorophenyl)butyl]piperidine-4-carboxamide derivatives. Structure-activity relationship studies have revealed that dialkyl substituents at the benzylic position play an important role in increasing inhibitory activity. Oral administration of N-[2-ethyl-2-(4-fluorophenyl)butyl]-1-(2-phenylethyl)piperidine-4-carboxamide (20d) lowered blood pressure in spontaneously hypertensive rats without inducing reflex tachycardia, which is often caused by traditional L-type Ca(2+) channel blockers.

Long-term pulmonary hemodynamic effects of ambrisentan in pulmonary arterial hypertension.

The long-term effects of endothelin receptor antagonists on pulmonary arterial pressure (PAP) and pulmonary vascular resistance (PVR) in patients with pulmonary arterial hypertension (PAH) are not well studied. This post hoc analysis examined changes in pulmonary hemodynamics in a cohort of patients with PAH who underwent follow-up right heart catheterization (RHC) in a long-term ambrisentan study (ARIES-E). A retrospective review was conducted of patients who underwent RHC after >3 months of ambrisentan therapy. Changes from baseline in mean PAP, mean right atrial pressure, cardiac index, and PVR were assessed and correlations between these hemodynamic changes and exercise capacity were examined. Sixty-eight patients who received ambrisentan in the ARIES studies had ≥1 follow-up RHC while receiving ambrisentan. Fifty-eight patients were on ambrisentan alone at the time of the first RHC. Median time from initiation of ambrisentan therapy to follow-up RHC was 60 weeks (range 14 to 158). Significant improvements compared to baseline were observed for mean PAP (-7.6 mm Hg, 95% confidence interval [CI] -10.0 to -5.1), PVR (-266 dyne × s/cm(5), 95% CI -350 to -180), and cardiac index (0.4 L/min/m(2), 95% CI 0.2 to 0.6 L/min/m(2)); for patients on ambrisentan alone, changes in mean PAP and PVR were inversely correlated with change from baseline 6-minute walking distance (r = -0.41 and -0.43, respectively, p <0.001 for the 2 comparisons) at time of follow-up RHC. In conclusion, ambrisentan may provide sustained improvements in pulmonary hemodynamics in patients with PAH who receive long-term treatment and these changes correlate with improvements in exercise capacity.