Maria E. Marketou

Low-Dose Amiodarone Versus Sotalol for Suppression of Recurrent Symptomatic Atrial Fibrillation

To compare the safety and efficacy of amiodarone and sotalol in the treatment of patients with recurrent symptomatic atrial fibrillation (AF), 70 patients were entered into a randomized, double-blind study. Of these, 35 received amiodarone and 35 sotalol. There were no significant differences in baseline clinical characteristics between groups. Patients with ejection fraction < 40% or clinically significant heart disease were excluded. Patients randomized to amiodarone began with 800 to 1,600 mg/day for 7 to 14 days orally. After the initial loading phase, the drug dose was tapered to maintenance levels over 7 to 12 days; thereafter, therapy was generally maintained at a dosage of 200 mg/day. The sotalol dosage was 80 to 360 mg twice daily, as tolerated. Follow-up clinical evaluations were conducted at 1, 2, 4, 6, 9, and 12 months. The proportion of patients remaining in sinus rhythm on each agent was calculated for the 2 groups using the Kaplan-Meier method. Ten of the 35 patients who were taking amiodarone developed AF during the 12-month observation period, compared with 21 of the 35 who were taking sotalol (p = 0.008). No significant effect of sex, age, left atrial size, or type of AF could be detected that increased the risk of development of AF. We conclude that both amiodarone and sotalol can be used for the maintenance of normal sinus rhythm in patients with recurrent symptomatic AF but that amiodarone is the more effective of the 2 drugs for this purpose.

MicroRNA-9 and microRNA-126 expression levels in patients with essential hypertension: potential markers of target-organ damage

MicroRNAs (miRs), as essential gene expression regulators, modulate cardiovascular development and disease and thus they are emerging as potential biomarkers and therapeutic targets in cardiovascular disease, including hypertension. We assessed the expression levels of the microRNAs miR-9 and miR-126 in 60 patients with untreated essential hypertension and 29 healthy individuals. All patients underwent two-dimensional echocardiography and 24-hour ambulatory blood pressure monitoring. MicroRNA expression levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Hypertensive patients showed significantly lower miR-9 (9.69 ± 1.56 vs 41.08 ± 6.06; P < .001) and miR-126 (3.88 ± 0.47 vs 8.96 ± 1.69; P < .001) expression levels compared with healthy controls. In hypertensive patients, miR-9 expression levels showed a significant positive correlation (r = 0.437; P < .001) with left ventricular mass index. Furthermore, both miR-9 (r = 0.312; P = .015) and miR-126 (r = 0.441; P < .001) expression levels in hypertensive patients showed significant positive correlations with the 24-hour mean pulse pressure. Our data reveal that miR-9 and miR-126 are closely related to essential hypertension in humans, as they show a distinct expression profile in hypertensive patients relative to healthy individuals, and they are associated with clinical prognostic indices of hypertensive target-organ damage in hypertensive patients. Thus, they may possibly represent potential biomarkers and candidate therapeutic targets in essential hypertension.

Differential expression of vascular smooth muscle-modulating microRNAs in human peripheral blood mononuclear cells: novel targets in essential hypertension

Vascular smooth muscle cell (VSMC) phenotypic plasticity has a critical role in the pathophysiology of arterial remodeling in essential hypertension. MicroRNAs are emerging as potential biomarkers and therapeutic targets in cardiovascular disease. We assessed the expression levels of the microRNAs miR-143, miR-145, miR-21, miR-133 and miR-1, which are implicated in VSMC phenotypic modulation, in 60 patients with essential hypertension and 29 healthy individuals. All patients underwent 24-h ambulatory blood pressure (BP) monitoring. MicroRNA levels in peripheral blood mononuclear cells were quantified by real-time reverse transcription polymerase chain reaction. Hypertensive patients showed lower miR-143 (2.20±0.25 versus 4.19±0.57, P<0.001), miR-145 (13.51±1.73 versus 22.38±3.31, P=0.010) and miR-133 (8.15±1.32 versus 37.03±8.18, P<0.001) and higher miR-21 (3.08±0.32 versus 2.06±0.31, P=0.048) and miR-1 (33.94±5.19 versus 12.35±2.13 P=0.006) expression levels compared with controls. In hypertensive patients, we observed correlations of miR-143 (r=−0.380, P=0.003), miR-145 (r=−0.405, P=0.001), miR-21 (r=−0.486, P<0.001) and miR-133 (r=0.479, P<0.001) expression levels with 24-h diastolic BP. Furthermore, we observed correlations of miR-21 (r=−0.291, P=0.024), miR-1 (r=−0.312, P=0.015) and miR-133 (r=0.310, P=0.016) levels with the dipping status. Associations of miR-143 (r=−0.292, P=0.025), miR-145 (r=−0.399, P=0.002), miR-21 (r=−0.343, P=0.008) and miR-133 (r=0.370, P=0.004) levels with 24-h mean pulse pressure were also found. Our data provide important evidence that VSMC-modulating microRNAs are closely related to essential hypertension in humans and they may represent potential therapeutic targets in essential hypertension.

Amiodarone, Sotalol, or Propafenone in Atrial Fibrillation: Which Is Preferred to Maintain Normal Sinus Rhythm?

This randomized study compared the efficacy and safety of amiodarone, propafenone and sotalol in the prevention of atrial fibrillation. Methods: The population consisted of 214 consecutive patients (mean age 64 ± 8 years, 106 men) with recurrent symptomatic atrial fibrillation. After restoration of sinus rhythm, patients were randomized to amiodarone (200 mg/day), propafenone (450 mg/day) or sotalol (320 ± 20 mg/day). Follow‐up evaluations were conducted at 1, 2, 4 and 6 months, and at 3‐month intervals thereafter. The proportion of patients developing recurrent atrial fibrillation and/or experiencing unacceptable adverse effects was measured in the three groups by the Kaplan‐Meier method. Results: Recurrent atrial fibrillation occurred in 25 of the 75 patients treated with amiodarone compared to 51 of the 75 patients treated with sotalol and 24 of the 64 patients treated with propafenone. Fourteen patients treated with amiodarone, five with sotalol, and one with propafenone experienced adverse effects while in sinus rhythm, necessitating discontinuation of treatment (P < 0.001 for amiodarone and propafenone vs sotalol). The difference between amiodarone and propafenone was statistically nonsignificant when all events were included in the analysis. However, if the analysis was limited to recurrent atrial fibrillation events, amiodarone was more effective than propafenone (P < 0.05). Conclusions: Amiodarone and propafenone were superior to sotalol in maintaining long‐term normal sinus rhythm in patients with atrial fibrillation. Amiodarone tended to be superior to propafenone, though its long‐term efficacy was limited by adverse side effects.

Intravenous Propafenone Versus Intravenous Amiodarone in the Management of Atrial Fibrillation of Recent Onset: A Placebo-Controlled Study

The efficacy and safety of intravenous propafenone, amiodarone, or placebo were compared in the treatment of atrial fibrillation (AF) of recent onset (duration ≤ 48 hours). Methods: 143 patients (77 men, mean age 63 ± 12 years) were studied, of whom 46 received propafenone (2 mg/kg over 15 minutes followed by 10 mg/kg over the next 24 hours), 48 received amiodarone (300 mg intravenously over 1 hour, followed by 20 mg/kg over the next 24 hours, plus 1,800 mg/day orally, in 3 divided doses), and 49 received placebo (the equivalent amount of saline IV over 24 hours). Digoxin was administered to all patients who had not previously received it. Results: Conversion to normal sinus rhythm occurred in 36 of 46 patients (78.2%) receiving propafenone, in 40 of 48 patients (83.3%) receiving amiodarone, and in 27 of the 49 (55.10%) controls (P < 0.02, drug vs placebo, between drugs NS). The mean time to conversion was 2 ± 3 hours for propafenone, 7 ± 5 hours for amiodarone, and 13 ± 9 for placebo (P < 0.05). Patients who converted had smaller atria than those who did not (diameter: 42.7 ± 5 vs 47.2 ± 7 mm, P < 0.001 for all). Treatment was discontinued in one patient in the amiodarone group because of an allergic reaction and in two patients in the propafenone group because of excessive QRS widening. No side effects were observed in the placebo group. Conclusions: Both drugs tested intravenously were equally effective and safe for the rapid conversion of recent‐onset atrial fibrillation to sinus rhythm. However, propafenone offered the advantage of more rapid conversion than amiodarone.

Spectral analysis of heart rate variability during tilt-table testing in patients with vasovagal syncope.

Spectral analysis of heart rate variability was used to assess changes in autonomic function in 44 patients with vasovagal syndrome and 20 normal controls before and during postural tilt and to attempt to relate such changes to specific types of haemodynamic response to tilt. Frequency domain measurements of the high (HF) and low (LF) frequency bands and the ratio LF/HF were derived from Holter recordings, computed by Fast Fourier Analysis for 4 min intervals immediately before tilt testing, immediately after tilting and just before the end of the test. In the syncopal patients the mean values of LF and HF decreased significantly in response to tilting, while the LF/HF ratio remained constant. All parameters showed a statistically significant increase just before the onset of syncope. In the control group there was an increase in the LF and LF/HF ratio and a decrease in the HF immediately after tilting. The three subgroups of patients had similar patterns of changes in autonomic activity. The results of this study show that syncopal patients have a different pattern of response to the tilting test. The pathological mechanism leading to vasovagal syncope appears to be independent of the specific type of haemodynamic response to tilt testing.

Cardioprotective Effects of a Selective B2 Receptor Agonist of Bradykinin Post-Acute Myocardial Infarct

BACKGROUND The cardioprotective benefits of bradykinin are attributable to activation of its B(2) receptor (B(2)R)-mediated actions and abolished by B(2)R antagonists. The current experiments evaluated the cardioprotective potential of a potent, long-acting B(2)R-selective agonist peptide analogue of bradykinin, the compound NG291. METHODS We compared the extent of cardiac tissue damage and remodeling and expression pattern of selected genes in mice submitted to acute myocardial infarct (MI) and treated for 1 week with either NG291 [Hyp(3),Thi(5),(N)Chg(7),Thi(8)]-bradykinin or with saline delivered via osmotic minipump. RESULTS Active treatment resulted in better ejection fraction (EF) 69 +/- 1% vs. 61 +/- 3.1% (P = 0.01), (vs. 85 +/- 1.3% in sham-operated controls), fractional shortening (FS) 38 +/- 4% vs. 32 +/- 8% (NS) (vs. 53 +/- 1.2 in sham-operated controls), and fewer markers of myocyte apoptosis (TUNEL-positive nuclei 4.9 +/- 1.1% vs. 9.7 +/- 0.03%, P = 0.03). Systolic blood pressure (SBP) at end point was normal at 110 +/- 4.2 in actively treated mice, but tended to be lower at 104 +/- 4.7 mm Hg in saline controls with decreased cardiac systolic capacity. Expression patterns of selected genes to factors related to tissue injury, inflammation, and metabolism (i.e., the B(1)R, B(2)R, endothelial nitric oxide synthase (eNOS), TNF-alpha, cardiomyopathy-associated 3 (Cmya3), and pyruvate dehydrogenase kinase isoenzyme 4 (PDK4)) showed that acute MI induced significant upregulation of these genes, and active treatment prevented or attenuated this upregulation, whereas the B(2)R agonist itself produced no difference in the myocardium of sham-operated mice. CONCLUSIONS Treatment with a selective B(2)R agonist initiated at the time of induction of acute MI in mice had a beneficial effect on cardiac function, tissue remodeling, and inflammation-related tissue gene expression, which may explain its structural and functional benefits.

Autonomic Nervous System Activity Before and During Episodes of Myocardial Ischemia in Patients with Stable Coronary Artery Disease During Daily Life

Spectral analysis of heart rate variability (HR V) was used to assess changes in the autonomic nervous system (ANS) 10 minutes before, during, and 10 minutes after 110 ischemic episodes (IEs) in 38 patients (25 men, age 61 ± 10 years) with stable coronary artery disease. In 26 of 77 diurnal IEs (07:00–22:59) there were no changes in the spectral indexes (LF and HF) during the study period. In the remainder there was an increase in the LF:HF ratio due to HF withdrawal that started before the onset of the IE. AII 33 nocturnal episodes also showed an increase in the LF:HF ratio, which was due not only to HF withdrawal, but also to a simultaneous increase in LF. Although it is not the only cause, the ANS plays a significant role in triggering IEs during daily life in patients with stable coronary artery disease. The common factor in all such episodes is a gradual withdrawal of parasympathetic tone.

Cardioprotective properties of bradykinin: role of the B 2 receptor

Following the introduction of angiotensin-converting enzyme (ACE) inhibitors in the treatment of hypertension and ischemic heart disease, there has been increasing interest in the bradykinin-mediated aspects of ACE inhibition. Several preclinical and clinical studies have been conducted using genetically engineered animals or pharmacological agonists and antagonists of the two receptors of bradykinin, B1R and B2R. The results have mostly indicated that the B1R, whose expression is induced by tissue damage, seem to have mostly noxious effects, whereas the constitutively expressed B2R, when activated, exert mostly beneficial actions. Accumulating evidence in the recent literature suggests that the B2R have an important role in the process of ischemic post-conditioning that limits the ischemia/reperfusion injury of the myocardium. In this article, we describe a series of experiments conducted on mice submitted to acute myocardial infarct and treated either with ACE inhibition (which produces potentiation of bradykinin resulting in non-selective B1R and B2R activation) or with a potent and highly selective B2R agonist. These data suggest that this latter pharmacological approach offers functional and structural benefits and is therefore a promising cardioprotective therapeutic modality against acute ischemic events.

Early cardiac gene transcript levels in peripheral blood mononuclear cells in patients with untreated essential hypertension.

Objectives To assess the expression of early cardiac genes, implicated in the hypertrophic growth response of the adult heart, in peripheral blood mononuclear cells in patients with essential hypertension and its relationship to ambulatory blood pressure monitoring (ABPM) parameters and to echocardiographic left ventricular mass. Methods Twenty-four-hour ABPM, echocardiography and blood sampling were performed in 62 untreated participants with essential hypertension. Blood samples from 38 healthy individuals were included for comparison. Peripheral blood mononuclear cells (PBMCs) were isolated and gene transcript levels were determined by quantitative real-time reverse transcription PCR. Results Myocardin (3.92±0.68 versus 2.09 ± 0.67, P < 0.001), GATA4 (3.48 ± 0.68 versus 0.32 ± 0.08, P < 0.001) and Nkx2.5 (208.91 ± 35.01 versus 129.75 ± 49.70, P < 0.001) were upregulated in hypertensive patients compared with controls. In hypertensive patients, transcript levels of myocardin (r = 0.698, P < 0.001) and GATA4 (r = 0.374, P = 0.003) showed significant positive correlations with 24-h systolic blood pressure (BP) as well as with mean BP, (r = 0.626, P < 0.001) and (r = 0.340, P = 0.007), respectively. A significant positive correlation between myocardin and 24-h pulse pressure (r = 0.467, P < 0.001) was also observed. Myocardin (r = −0.606, P < 0.001) and GATA4 (r = −0.453, P < 0.001) transcript levels also showed significant negative correlations with the mean 24-h dipping status. Additionally, myocardin (r = 0.341, P = 0.007), GATA4 (r = 0.337, P = 0.007) and Nkx2.5 (r = 0.325, P = 0.010) transcript levels showed significant positive correlations with left ventricular mass index. Conclusion Myocardin and GATA4 transcript levels correlate significantly with 24-h ABPM parameters, rendering them potential candidate biomarkers in hypertension. Early cardiac gene transcript levels in PBMCs of hypertensive patients are associated with left ventricular mass and may reflect activation of the hypertrophic response gene network in these patients.