Atrial Tissue Of Patients Research Articles

Ivabradine in Heart Failure: To SHIFT or Not to SHIFT

Despite advances in treatment during the past two decades, long-term prognosis of heart failure (HF) still is poor in patients at advanced stages. Antiadrenergic therapy has demonstrated consistent morbidity and mortality benefits, which often are linked to its ability to facilitate reversal in cardiac remodeling. Although a direct association between heart rate (HR) and cardiovascular (CV) outcomes in patients with HF has been observed [1, 2], there is debate regarding the importance of HR reduction as a contributor to the beneficial effects of antiadrenergic therapy [3–6]. A recent meta-analysis found a significant association between the degrees of HR reduction and the impact of antiadrenergic therapy in survival of patients with HF, whereas the dose of antiadrenergic therapy achieved was not correlated [7]. However, in the real world, β-blocker uptitration in response to persistently elevated HR can be associated with increased risk of adverse reactions [8, 9], and such limitations of antiadrenergic therapy have prompted the interest of looking into alternative treatment strategies to lower HR. Ivabradine is a selective inhibitor of the pacemaker I “funny” (If) channel, which is responsible for the autonomic capacity of the sinoatrial node. If channels are upregulated in atrial tissue of patients with atrial fibrillation or atrial flutter and they also are present in ventricular myocytes of patients with HF [10]. Ivabradine works by reducing its diastolic depolarization slope, thereby decreasing HR via direct sinus node inhibition without direct effects on myocardial contractility and intracardiac conduction. In the BEAUTIFUL (Morbidity–Mortality Evaluation of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease and Left Ventricular Systolic Dysfunction) study, patients with high baseline HR had an increase in serious CV events including death (34%), hospital admission secondary to congestive HF (53%), acute myocardial infarction (46%), or revascularization procedure (38%) [11]. In a subset of patients with baseline HR of 70 bpm and left ventricular ejection fraction (LVEF) less than 40%, ivabradine was associated with a 36% decrease in hospital admissions secondary to fatal and nonfatal myocardial infarction and a 30% decrease in coronary revascularization [11].

Clinical Determinants of ckit-Positive Cardiac Cell Yield in Coronary Disease

Recent animal studies and clinical trials have reported the scope of heart-resident ckit-positive stem cells in regenerating infarcted myocardium. The determinants of successful isolation of such cells are unknown. The objective of this study was to determine the influence of risk factors for coronary artery disease and disease severity on the successful isolation of ckit-positive cells from right atrial tissue of patients with coronary artery disease. The findings suggest that coronary artery disease and cardiac remodeling in chronic ischemia may not affect the yield of ckit-positive cells from atrial tissue, but a significant negative correlation between the age of the patient and the number of migrated ckit-positive cells was observed. This suggests that in older patients, stem cell isolation from cardiac biopsies may not succeed, and such cells may not be available for cell therapy.

Selective segmental ostial ablation and circumferential pulmonary veins ablation. Results of an individualized strategy to cure refractory atrial fibrillation

Previous studies have analyzed the efficacy of atrial fibrillation (AF) ablation in series of consecutive patients or comparing methods in a randomized way, without taking account individual patient characteristics. The purpose of this study was to evaluate the results of a strategy based on selecting the ablation method according to patient clinical features in drug-refractory paroxysmal or persistent AF. Patients with left atrial diameter < or =40 mm and runs of atrial tachycardia of more than ten beats during Holter recording were selected for selective segmental ostial ablation (SSOA) in order to disconnect only those pulmonary veins with electrical potentials. The remaining patients underwent circumferential pulmonary veins ablation (CPVA) to modify left atrial substrate by extensive linear lesions. A group of 131 consecutive patients were included. Mean follow-up was 21.5 +/- 15.2 months. In paroxysmal AF, 44 and 55 patients were selected for SSOA and CPVA, respectively, and the efficacy of the procedure was similar in the two groups (77 vs 74%; log-rank test p = NS). In persistent AF, 6 and 26 patients underwent SSOA and CPVA, respectively, and greater efficacy was observed in the second group (17 vs 65%; log-rank test p = 0.004). Selecting the ablation method according to patient characteristics achieved good results and reduced the overall amount of ablated atrial tissue in patients with paroxysmal AF. However, in persistent AF the SSOA technique showed very limited efficacy despite the previous patient selection and a CPVA-like procedure may be the appropriate choice in all cases.

2062 Extracellular matrix proteins in left atrial tissue of patients with atrial fibrillation of different causes

2062 Extracellular matrix proteins in left atrial tissue of patients with atrial fibrillation of different causes

2717 Different expression of angiotensin-II-receptors in left atrial tissue of patients with atrial fibrillation of different causes

2717 Different expression of angiotensin-II-receptors in left atrial tissue of patients with atrial fibrillation of different causes

Vagal neurostimulation in patients with coronary artery disease

We tested the hypotheses that (1) progression of coronary artery disease (CAD) increases sympathetic inflow to the heart, thus impairing cardiac blood supply, and (2) reduced sympathetic tone improves cardiac microcirculation and ameliorates severity of anginal symptoms. Electrical irritation of the nerve auricularis—a sensitive ramus of the vagus nerve—provides a central sympatholytic action. Using this technique, we studied the effects of vagal neurostimulation (VNS) on hemodynamics, the content of atrial noradrenergic nerves and the microcirculatory bed of CAD patients. VNS was performed in the preoperative period of CAD patients with severe angina pectoris. The comparison groups consisted of untreated patients with CAD or Wolff–Parkinson–White syndrome. Atrial tissue of patients with this syndrome ( n=6); with effort angina ( n=14); with angina at rest ( n=10); and with severe angina treated with VNS ( n=8) contained the following volume percentages of noradrenergic nerves: 1.7±0.1%, 1.3±0.3%, 0.5±0.1% ( p<0.05 vs. the other groups) and 1.3±0.2%, respectively. In these groups, cardiac microcirculatory vessels (diameter, 10–20 μm) had the following densities: 2.7±0.2%, 3.4±0.2%, 2.0±0.4% ( p<0.05 vs. the other groups) and 3.3±0.3%, respectively. VNS treatment abolished angina at rest, decreased heart rate and blood pressure. It improved left ventricular ejection fraction from 50±1.5% to 58±1.0% ( p<0.05), also changing left ventricular diastolic filling. The ratio of time velocity integrals of the early ( E i) to late ( A i) waves increased from 1.07±0.12 to 1.65±0.17 after VNS ( p<0.05). In electrocardiograms of VNS-treated patients, QRS- and QT-duration were shortened, the PQ-interval did not change, but T-wave configuration improved. In the postoperative period, heart failure occurred in 90% of the control group, vs. 12% in patients treated with VNS ( p<0.05). We conclude that CAD is characterized by overactivity of sympathetic cardiac tone. Vagal stimulation reduced sympathetic inflow to the heart, seemingly via an inhibition of norepinephrine release from sympathetic nerves. VNS' sympatholytic/vagotonic action dilated cardiac microcirculatory vessels and improved left ventricular contractility in patients with severe CAD.

Up-regulation of inositol 1,4,5 trisphosphate receptor expression in atrial tissue in patients with chronic atrial fibrillation

OBJECTIVESWe examined whether patients with atrial fibrillation (AF) have alterations in atrial inositol 1,4,5 trisphosphate receptors (IP3 receptors).BACKGROUNDAbnormal intracellular Ca2+homeostasis occurs in chronic AF. The intracellular Ca2+concentration is regulated by ryanodine and IP3 receptors. We recently reported alterations in ryanodine receptors in atrial tissue from patients in chronic AF.METHODSWe analyzed IP3 receptor expression in the right atrial myocardium from 13 patients with mitral valvular disease (MVD) with AF (MVD/AF), five patients with MVD who had normal sinus rhythm (MVD/NSR) and eight control patients with NSR (tissue obtained during coronary artery bypass surgery). Hemodynamic and echocardiographic data were obtained preoperatively, and an immunohistochemical study was performed on atrial tissue.RESULTSThe relative expression level of IP3 receptor protein was significantly greater in MVD/AF (0.75 ± 0.26) than it was in MVD/NSR (0.42 ± 0.13, p < 0.01), and both were significantly above control (0.14 ± 0.08). The relative expression level of IP3 receptor messenger RNA was significantly greater in the MVD/AF group (0.028 ± 0.008) than it was in the control group (0.015 ± 0.004, p < 0.01), but patients with MVD/AF did not differ from patients with MVD/NSR (0.020 ± 0.006). The relative expression levels of IP3 receptor protein and messenger RNA were higher in patients with left atrial dimension ≥40 mm, pulmonary capillary wedge pressure ≥10 mm Hg and right atrial pressure ≥5 mm Hg. Inositol 1,4,5 trisphosphate receptors were over-expressed in the cytosol and at the nuclear envelope of atrial myocytes in MVD.CONCLUSIONSSince chronic mechanical overload of the atrial myocardium increased IP3 receptor expression, especially in patients with chronic AF, up-regulation of IP3 receptors may be important in modulating intracellular Ca2+homeostasis and initiating or perpetuating AF.

No variation in Hsp70 mRNA level during cardiac surgery in pediatric patients evaluated by semiquantitative RT-PCR.

We evaluated mRNA expression of the heat shock protein gene, Hsp70-1, by means of a semiquantitative RT-PCR in atrial tissue specimens from pediatric patients collected before and after cardiopulmonary bypass surgery for congenital heart diseases, to see whether surgical stress may affect the expression level of this mRNA. We studied thirty nine pediatric patients (aged 3 months to 15 years) undergoing surgical correction of congenital heart malformation. Twenty-one patients were affected by the tetralogy of Fallot, two by combined atrioventricular septal defects, six by ventricular septal defect, three by atrial septal defect, two by atrioventricular canal defect, two by pulmonary valve stenosis, one by mitral insufficiency, and one by double-outlet right ventricle. Our results showed no significant changes in the Hsp70-1 mRNA expression in atrial tissue of patients before and after cross-clamping (the mean relative expression after cross-clamping was 1.0+/-0.6 compared to the baseline value). Furthermore, no significant correlations were observed between cross-clamping time and temperature, cardiopulmonary bypass time and mRNA variation. Our study suggests that, during cardioplegia, myocardial tissue does not have an appropriate adaptive response to surgical stress.

Atrial L-type Ca2+-channel, beta-adrenorecptor, and 5-hydroxytryptamine type 4 receptor mRNAs in human atrial fibrillation.

Molecular and electrical remodeling of ion channels determining action potential duration has been proposed as a major mechanism in chronic atrial fibrillation. We investigated the mRNA expression of the cardiac L-type Ca2+-channel subunits alpha1c, alpha2/delta1, beta1a, and beta1b/c in atrial tissue of patients with chronic atrial fibrillation compared to patients in sinus rhythm. In addition, the mRNA expression of the 5-hydroxytryptamine type 4-, beta1-, and beta2-adrenergic receptors, which are known to stimulate the L-type Ca2+-current in human atrium, was analyzed and the effect of chronic beta-blocker treatment on the mRNA expression of these receptors and of the L-type Ca2+-channel subunits was assessed. Total RNA was isolated from right atrial appendages of patients in sinus rhythm and of patients with chronic atrial fibrillation. Then, semiquantitative RT-PCR using 18S RNA as the "housekeeping gene" was performed. In patients with chronic atrial fibrillation, there were only mild reductions in mRNA expression of the alpha1c-subunit (-15.5 %, p = 0.13), and of the beta1-subunit isoforms a and c (-13.3 %, p = 0.14 and -16.6%, p = 0.18, respectively). However, mRNA expression of the alpha2/delta1-subunit (-31.5 %, p < 0.01) and of the beta1-subunit isoform b (-39.9 %, p < 0.0005) was significantly reduced in patients with chronic AF. Taken together, the mRNA expression of the beta1-subunit isoforms b and c, which are splice variants, was significantly down-regulated by 26.5 % (p < 0.05) in these patients. The analysis of the beta1c/beta1b ratio resulted in a significant shift by 39.2 % (p < 0.0001) in favor of beta1c in patients with chronic atrial fibrillation. In the AF patients, the abundance of the 5-HT4-receptor transcript was significantly reduced by 36 % (p < 0.05). The beta-adrenoreceptor transcription was unchanged. In both SR and AF patients, chronic beta-blocker treatment did neither significantly effect the mRNA expression of the L-type Ca2+-channel subunits, the beta-adrenoreceptor subtypes 1 and 2, nor that of the 5-HT4-receptor. Our data show that chronic AF is associated with a decrease in the atrial mRNA amount of auxiliary subunits of the L-type Ca2+-channel and of the 5-HT4-receptor. This supports the hypothesis that the observed alterations in mRNA transcription in AF patients may lead to a decrease in the availability of functional L-type Ca2+-channels and 5-HT4-receptors and/or reduce L-type Ca2+-current amplitude and density, thus, promoting and stabilizing the arrhythmia.

Unstable angina activates myocardial heat shock protein 72, endothelial nitric oxide synthase, and transcription factors NFkappaB and AP-1.

Unstable angina may improve the clinical outcome of acute myocardial infarction, but increases the morbidity and mortality of open heart surgery. We hypothetized that unstable angina influences the myocardium, and investigated the expression of the inducible heat shock protein 72 (HSP72), constitutive HSP73, and endothelial nitric oxide synthase (eNOS), and activation of the transcription factors NFkappaB and AP-1 in cardiac tissue. Biopsies were taken from the right atrium of 15 patients with unstable and 15 with stable angina undergoing coronary artery bypass grafting. Immunoblotting with monoclonal antibodies against HSP72, HSP73, and eNOS were performed on protein extracts, while nuclear proteins were assessed by electromobility shift assay. When calculating the optical density of the bands, patients with unstable angina had more than twice as much HSP72 and eNOS as stable patients (P<0.005), while HSP73 was similar in both groups. Nuclear translocation of NFkappaB and AP-1 was found in patients with anginal pain shortly before surgery, but not in stable patients or in patients without symptoms for 4 days or more prior to surgery. HSP72 and eNOS, which may be associated with cardioprotection in ischemic preconditioning, are increased in atrial tissue of patients with unstable angina. Activation of NFkappaB and AP-1, which regulate a battery of inflammatory genes, was found in hearts of unstable patients. NFkappaB activation may induce a myocardial proinflammatory state, possibly making the unstable myocardium more susceptible to the inflammation induced by open heart surgery.

Up-regulation of inositol 1 ,4,5-trisphosphate receptor (IP3R) in the atrial tissue of patients with chronic atrial fibrillation

Up-regulation of inositol 1 ,4,5-trisphosphate receptor (IP3R) in the atrial tissue of patients with chronic atrial fibrillation

Alterations in cardiac sarcoplasmic reticulum Ca2+regulatory proteins in the atrial tissue of patients with chronic atrial fibrillation

OBJECTIVESOur purpose was to determine whether atrial fibrillation (AF) patients have alterations in sarcoplasmic reticulum (SR) Ca2+regulatory proteins in the atrial myocardium.BACKGROUNDClinically, AF is the most frequently encountered arrhythmia. Recent studies indicate that an inability to maintain intracellular Ca2+homeostasis with a consequent increase in membrane-triggered activity could be the primary initiating factor in some circumstances, and that cytosolic Ca2+abnormalities are an important mediator of sustained AF.METHODSWe measured the maximum number of [3H]ryanodine binding sites (Bmax) and the expression levels of ryanodine receptor (RyR) mRNA and calcium-adenosine triphosphatase (Ca2+-ATPase) mRNA in atrial myocardial tissue from 13 patients with AF due to mitral valvular disease (MVD) and 9 patients with normal sinus rhythm (NSR).RESULTSIn AF patients, 1) Bmax was significantly lower in each atrium (0.21 ± 0.03 pmol/mg [right], 0.16 ± 0.04 pmol/mg [left]) than in the right atrium (0.26 ± 0.08 pmol/mg) of NSR patients; 2) Bmax was significantly lower in the left atrium than in the right atrium; 3) Bmax in the left atrium was significantly lower at higher levels of pulmonary capillary wedge pressure; 4) the expression level of RyR mRNA was significantly lower in both the left (1.24 × 10−2± 1.28 × 10−2) and right (1.70 × 10−2± 1.78 × 10−2) atrium than in the right atrium of NSR patients (6.11 × 10−2± 2.79 × 10−2); and 5) the expression level of Ca2+-ATPase mRNA was significantly lower in both the left (5.67 × 10−2± 4.01 × 10−2) and right (7.71 × 10−2± 3.56 × 10−2) atrium than in the right atrium (12.60 × 10−2± 3.92 × 10−2) of NSR patients.CONCLUSIONSThese results provide the first direct evidence of abnormalities in the Ca2+regulatory proteins of the atrial myocardium in chronic AF patients. Conceivably, such abnormalities may be involved in the initiation and/or perpetuation of AF.

Gene expression of the natriuretic peptide system in atrial tissue of patients with paroxysmal and persistent atrial fibrillation.

Circulating cardiac natriuretic peptides play an important role in maintaining volume homeostasis, especially during conditions affecting hemodynamics. During atrial fibrillation (AF), levels of plasma atrial natriuretic peptide (ANP) becomes elevated. The aim of this study was to gather information about gene expression of the natriuretic peptide system on the atrial level in patients with AF. Right atrial appendages of 36 patients with either paroxysmal or persistent AF were compared with 36 case matched controls in sinus rhythm for mRNA expression of pro- atrial natriuretic peptide (pro-ANP), pro-brain natriuretic peptide (pro-BNP), and their natriuretic peptide receptor type-A (NPR-A). We investigated patients without (n = 36) and with (n = 36) valvular disease. Persistent AF was associated with higher mRNA expression of pro-BNP (+66%, P = 0.04, in patients without valvular disease, and +69%, P < 0.01, in patients with valvular disease) and lower mRNA expression of NPR-A (-58%, P = 0.02, in patients without valvular disease, and -62 %, P < 0.01, in patients with valvular disease). The mRNA content of pro-ANP was only increased in patients with valvular disease (+12%, P = 0.03). No changes were observed in patients with paroxysmal AF. This study demonstrates that persistent, but not paroxysmal, AF induces alterations in gene expression of pro-BNP and NPR-A on the atrial level. Although AF generally is associated with an increase of plasma ANP level, a change in mRNA content of pro-ANP is only observed in the presence of concomitant valvular disease and is of minor magnitude.

Radiofrequency ablation of atrial flutter. Efficacy of an anatomically guided approach.

Previous reports have shown that radiofrequency ablation can terminate atrial flutter and prevent recurrences. However, different methods have been used, and the current experience remains limited. The objective of the present study was to determine the efficacy of radiofrequency ablation of atrial tissue in patients with atrial flutter using an anatomically guided approach. We treated 22 patients aged 30 to 73 years. Atrial flutter was recurrent for a mean of 5 years despite the administration of multiple antiarrhythmic drugs. Radiofrequency current was directed to the atrial isthmus between the inferior vena cava and the tricuspid ring, regardless of the morphology of local electrograms. Radiofrequency energy was applied during typical atrial flutter in 12 patients, atypical atrial flutter in 2 patients, and successively both forms in 8 patients. In 19 patients, atrial flutter abruptly terminated. In 3 patients, atrial flutter persisted despite 37, 48, and 25 applications, respectively. Atrial recordings demonstrated that atrial flutter termination occurred as a consequence of conduction block at the site of radiofrequency energy application, regardless of the type of atrial flutter. The number of applications before termination ranged from 1 to 82 (mean, 32). Atrial flutter could no longer be induced in every case. There were no complications. During a 13-month mean follow-up, atrial flutter recurred in only 2 of the 19 patients who had a successful ablation. Four patients experienced chronic atrial fibrillation, and 2 of them returned to sinus rhythm with antiarrhythmic therapy. Radiofrequency ablation of atrial flutter using anatomic guidance is feasible and effective. Further experience is needed to delineate its role as an alternative approach to the management of refractory atrial flutter.

Calcium-Antagonist Receptors in the Atrial Tissue of Patients with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is characterized by a nondilated, hypertrophied left ventricle in the absence of any overt cause. A possible role of adrenergic innervation or of cellular calcium regulation is suggested by the presence of hyperdynamic left ventricular function and by the clinical and symptomatic improvement seen in patients treated with beta-receptor antagonists or calcium antagonists. Therefore, we measured the density of calcium-antagonist receptors and beta-adrenoceptors in the atrial myocardium of 16 patients with hypertrophic cardiomyopathy and 19 patients with various other cardiac disorders. For comparison, we also measured the number of voltage-sensitive sodium channels. Calcium-antagonist binding sites, measured as the amount of dihydropyridine bound to atrial tissue, were increased by 33 percent in patients with hypertrophic cardiomyopathy (mean [+/- SD], 397 +/- 104 fmol per milligram of protein in patients with hypertrophic cardiomyopathy, as compared with 299 +/- 108 in patients with other cardiac disorders; P less than 0.01). The densities of saxitoxin-binding sites on voltage-sensitive sodium channels and beta-adrenoceptors were the same in the two groups, although the density of beta-adrenoceptors was higher in atrial samples from patients receiving beta-receptor antagonists (165 +/- 86 fmol per milligram of protein [patients receiving beta-blockers] vs. 85 +/- 60 [patients not receiving beta-blockers]; P less than 0.04). The increase in the number of calcium-antagonist receptors in hypertrophic cardiomyopathy suggests that abnormal calcium fluxes through voltage-sensitive calcium channels may play a pathophysiologic part in the disease.

Demonstration of prostaglandin E 2 and F 2α in atrial tissue of patients with heart disease

Demonstration of prostaglandin E 2 and F 2α in atrial tissue of patients with heart disease