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Prophylactic Surgical Left Atrial Appendage Closure in Bioprosthetic Aortic Valve Replacement: Short-Term Outcomes of Randomized Controlled LAA-CLOSURE Trial.

BACKGROUND: Surgical closure of the left atrial appendage (LAA) reduces stroke risk in patients with atrial fibrillation (AF) undergoing cardiac surgery. We evaluated the safety and efficacy of prophylactic LAA closure during bioprosthetic surgical aortic valve replacement in patients without prior AF. METHODS: In this investigator-initiated, academic, randomized, open-label, multicenter LAA-CLOSURE (Left Atrial Appendage CLOSURE for the Prevention of Thromboembolisms in Patients Undergoing Aortic Bioprosthesis Surgery) trial, 921 patients without prior AF undergoing bioprosthetic surgical aortic valve replacement with or without concomitant surgery were randomized and 904 patients included in the modified intention-to-treat analysis (prophylactic LAA closure, n=445; or usual care, n=459). Median age was 73 years (interquartile range, 69-76), 34.8% were women, and 49% had concomitant coronary artery disease. The primary end point was a composite of cardiovascular death, stroke, or systemic embolism at 30 days. RESULTS: The primary end point occurred in 10 of 434 (2.2%) patients in the LAA closure group and 14 of 452 (3.1%) patients in the control group; however, the treatment effect changed direction at ≈7 days. In the time-split Cox regression model, hazard ratios were 2.4 (95% CI, 0.62-9.4; P=0.20) between 0 and 7 days and 0.29 (95% CI, 0.080-1.0; P=0.056) between 7 and 30 days. No closure-related serious complications or differences in bleeding were observed. Postoperative AF occurred in 205 of 445 (46.1%) versus 184 of 459 (40.1%) patients (relative risk, 1.1 [95% CI, 0.99-1.3]; P=0.07), and AF at discharge in 40 of 445 (9.2%) versus 34 of 459 (7.7%) patients (relative risk, 1.2 [95% CI, 0.77-1.8]; P=0.44), in the closure and control groups, respectively. CONCLUSIONS: Prophylactic LAA closure during bioprosthetic surgical aortic valve replacement was safe and did not increase bleeding. REGISTRATION: URL: clinicaltrials.gov; Unique Identifier: NCT02321137.

Aged

The significance of the left atrial appendage in rheumatic heart disease.

The possible diagnostic value of an enlarged left atrial appendage (LAA) on the posterior-anterior or right anterior oblique chest film as a means of implicating a rheumatic etiology for mitral valve disease in children was investigated. Chest films were examined without prior knowledge of clinical or laboratory data, and the results were later correlated with this information in 113 children and adolescents. The clinical and laboratory data included application of the modified Jones criteria for the diagnosis of acute rheumatic fever, streptococcal antibody titers and clinical and cardiac catheterization findings. In children with mitral valve disease, our data suggest that as enlarged LAA, especially in the presence of pulmonary venous obstruction, is characteristic of rheumatic heart disease. This finding appears to be particularly useful, in conjunction with streptococcal antibody studies, in distinguishing rheumatic from nonrheumatic patients with mitral insufficiency.

Cardiomegaly

Integrative multi-omics reveals a fibroblast-centered, ZFHX3-prioritized regulatory framework linking sick sinus syndrome and atrial fibrillation.

OBJECTIVE: To define shared genetic and multi-scale mechanisms underlying comorbidity between sick sinus syndrome (SSS) and atrial fibrillation (AF). METHODS: We integrated genome-wide association study (GWAS) summary statistics for SSS and AF with Genotype-Tissue Expression (GTEx) expression and splicing quantitative trait loci (eQTL/sQTL), atrial single-cell and spatial transcriptomics, and epigenomics. We identified trait-relevant tissues and pathways, prioritized shared cell types, quantified genome-wide and local genetic sharing, detected joint loci by cross-trait meta-analysis, and linked loci to regulatory programs via colocalization and cell-prioritized co-expression networks. RESULTS: Both traits showed strongest enrichment in cardiac tissue, especially Heart Atrial Appendage. Fibroblasts from the left atrial appendage were consistently prioritized as the key shared cell population. SSS and AF displayed significant positive genome-wide genetic correlation, with multiple locally shared regions, including six major loci. Cross-trait meta-analysis identified eight joint-phenotype SNPs implicating four susceptibility genes. ZFHX3 was the leading tissue-cell-gene candidate, acting as a hub in fibroblast co-expression modules and colocalizing with cardiac regulatory signals. CONCLUSION: Shared liability for SSS and AF is highly tissue- and cell-specific, converging on regulatory networks in atrial appendage fibroblasts, with ZFHX3 serving as a central mechanistic and biomarker node.

Humans

Preliminary experience with the helifix electrode for transvenous atrial implantation.

A Helifix electrode was inserted transvenously in the right atrial appendage for temporary atrial stimulation in three patients. The low stimulation threshold as well as the excellent stability of the electrode encouraged us to proceed to permanent implantation of this lead in thirteen patients. The lead was introduced through the saphenous vein in twelve patients and through the cephalic vein in one patient. Five patients had sinoatrial dysfunction and five had bradycardia-tachycardia syndrome; they received atrial demand pacemakers. Two patients had atrioventricular block and received atrial synchronous ventricular pacemarkers. Our last patient had restrictive cardiomyopathy, heart failure and a drug-refractory atrial arrhythmia. She received a dual-chamber sequential pacing device. Atrial electrode displacement occurred in one patient soon after implantation. The lead was promptly repositioned without difficulty. Partial sensing of spontaneous P waves was observed in two patients. One recovered spontaneously, the second after substituting a pulse generator with a higher input sensitivity. Our clinical experience during the period from November 1977 to January 1979 has shown that the Helifix electrode is suitable for transvenous atrial implantation.

Adult

Atrial programmed pacing.

Early experience with a J-shaped lead inserted transvenously into the right atrial appendage is reviewed in thirty-one patients. Fifteen patients are still being followed with satisfactory atrial programmed pacing for five to ten years. A dislodgement rate of twenty percent led to the development of the "tined" J lead in the hope that better fixation would be achieved. Experimental data has shown the new lead to be stable with evidence in both animal and man of firm fixation of the lead in the appendage. The lead has been inserted in twenty patients. Of these, fifteen are still being followed with satisfactory atrial programmed pacing. There has been no case of dislodgement of the lead in a follow-up period of two years and eight months.

Aged

Comparison of contractile performance of canine atrial and ventricular muscles.

This study compared the contractile performance of a canine right atrial trabecula with that of a macroscopically indistinguishable trabecula isolated from the right ventricular apex. The heart was removed from nine mongrel puppies weighing 6-8 kg and placed in Krebs-Ringer's bicarbonate solution. The bathing solution contained only 1.25 mmoles of Ca2+ and was bubbled with a 95% O2-5% CO2 gas mixture. Each atrial trabecula was specially selected from the right atrial appendage. Histologically, these trabeculae showed a remarkable longitudinal orientation of the fibers. At Lmax (the length of the muscle at which developed tension was maximum) under identical conditions of temperature, rate of stimulation, ionic milieu, pH, and O2 and CO2 supply, right atrial trabeculae achieved the same developed and total tensions but in a much shorter time than did ventricular trabeculae. In both muscle groups the maximum developed tension averaged about 2.5 g/mm2. Since Lo (expressed as a fraction of Lmax) was less in atrial muscle than it was in ventribular muscle, we concluded that atrial muscle can be stretched considerably more than can ventricular muscle before optimum length is reached. At any given initial muscle length, the maximum of tension rise for atrial trabeculae amounted to at least twice that for ventricular trabeculae. At any given load up to 1.5 g/mm2, the maximum velocity of shortening of an atrial trabecula was about three to four times that of a ventricular trabecula. These results collectively indicate that the contractile performance of the right atrial muscle is in many respects superior to that of the right ventricle, at least under the conditions of these experiments.

Animals

Isolated ventricular inversion with double inlet left ventricle.

2 patients with viscero-atrial situs solitus, isolated ventricular inversion (IVI) and double inlet right-sided morphologic left ventricle are presented. Isolated ventricular inversion is a rare cardiac anomaly characterized by ventricular inversion, subpulmonary conus, and ventriculo-arterial concordance. Their angiocardiographic and pathologic features are presented, and the morphologic findings of the 9 patients in the literature with isolated ventricular inversion are reviewed. Of the 11 known patients with isolated ventricular inversion, levocardia was present in 10 and dextrocardia in 1; viscero-atrial situs solitus in 9 and inversus in 2; L-ventricular loop in 9 and D-loop in 2. The atrial septum was intact in 4. An intact ventricular septum was noted in only 2 patients while in 3, more than one ventricular septal defects were present, and 2 patients exhibited morphologic single ventricle. A solitary ventricular septal defect was noted in the remainder. Significant tricuspid valve abnormalities, including atresia, stenosis or hypoplasia with supravalvular fibrous ring were found in 7 patients. In 2 of these, both with significant obstruction at the tricuspid valve, both atrioventricular valves emptied into the morphologic left ventricle--thus isolated ventricular inversion with double inlet left ventricle. Pulmonary outflow tract obstruction was evident in only 3 patients. Total anomalous pulmonary venous return occurred twice and right juxtaposition of the atrial appendages once. Thus, while the patient with isolated ventricular iversion may present with clinical and hemodynamic features characteristic of classical transposition physiology the high frequency of significant associated anomalies would complicate this. Finally, the anomaly must be differentiated from the levo-transposition, isolated atrial inversion, and the anatomically corrected malpositions.

Adult

Long-term results of permanent atrioventricular sequential demand pacing.

Pervenous atrioventricular sequential demand pacemakers (AVSDPs) were implanted in 18 patients using an atrial electrode positioned in the right atrial appendage and a ventricular electrode positioned at the apex of the right ventricle. The indications included 13 patients with the sick sinus syndrome (72%), five of whom had the tachycardia-bradycardia syndrome, three with paroxysmal supraventricular tachycardia, one with cardiomyopathy and one with carotid sinus syncope. The follow-up ranged from 6 to 38 months, with a mean of 19.4 months (a total of 350 pacing months). Seventeen patients (94%) are asymptomatic. One patient had persistent episodes of paroxysmal supraventricular tachycardia. In the remaining patients with tachyarrhythmia, pacing alone (three patients) or in combination with antiarrhythmic drugs (four patients) controlled the tachyarrhythmia. There was one displacement of the atrial electrode (5.5%). Extrusion of the pacer occurred in three patients. It is concluded from this experience that AV sequential pacing is an effective technique and may be useful in patients with sick sinus syndrome, in patients with tachyarrhythmia and/or patients with poor myocardial function. However, continued research is needed to prolong battery life and to reduce the size of the pacemaker.

Aged

Adenosine-induced release of cyclic adenosine 3',5'-monophosphate from the left ventricle in the anaesthetized intact dog.

1. The influence of adenosine on the release of cyclic adenosine 3',5'-monophosphate (cyclic AMP) from the heart was examined in twenty-two anaesthetized intact dogs. The animals were pre-treated with propranolol and vagotomized. The rate of nucleotide release from the left ventricle was determined as the product of the left ventricular myocardial plasma flow and the coronary veno-arterial difference in plasma nucleotide concentration. 2. Adenosine was infused into the left ventricle during three successive 15 min periods at rates of 25, 50 and 100 n-mole/kg. min, respectively. The mean blood pressure in the ascending aorta was prevented from falling by inflating a balloon placed into the thoracic aorta. The measurements were performed before the infusion and at the 10th min of each infusion period. The values given are means +/- S.E. 3. During the 45 min infusion of adenosine at increasing rate, the cyclic AMP concentration in arterial plasma increased from 7.0 +/- 0.3 to 14.0 +/- 0.9 p-mole/ml. The nucleotide was released from the left ventricle at rates increasing from 48.2 +/- 7.1 to 206.5 +/- 56.2 p-mole/100 g. min while the left ventricular myocardial blood flow increased from 127 +/- 6 to 399 +/- 33 ml./100 g.min. The oxygen consumption of the left ventricle was not modified. 4. When adenosine was infused at a rate of 100 n-mol/kg.min, the thorax was opened and the apex of the heart and the left atrial appendage were removed for nucleotide assay. The cardiac cyclic AMP concentration did not differ from that observed in control dogs. 5. The results suggest that cyclic AMP is likely to be involved in the membrane and cellular events underlying the relaxant effect of adenosine on the coronary smooth muscle. The lack of change in cardiac cyclic AMP concentration, as determined by whole tissue extractions, is consistent with a study by others showing that, under normoxic conditions, cyclic AMP is released from a small, compartmentalized fraction of the cyclic AMP content of the heart. The elevation of the plasma nucleotide concentration could result from adenosine effects on various cell systems or organs, in addition to the observed release from the heart.

Adenosine

Malignant obstruction of the superior vena cava and its palliation: report of four cases.

Four cases of obstruction of the superior vena cava caused by inoperable bronchogenic carcinoma are presented in which the signs and symptoms were disabling. Palliation was achieved by placing a 10 mm. Dacron prosthetic bypass graft between the left innominate vein and the right atrial appendage, resulting in prompt relief. All patients were given warfarin for anticoagulation and subsequently deep x-ray therapy and diuretics were added. There was no operative or hospital death or morbidity. Two of the patients died of distant metastases at 14 and 6 months, respectively, postoperatively. The other two are alive and well at 11 and 5 months after the operation. Venous obstruction has not recurred to date in any of the four patients. A relevant review of the literature has been made.

Blood Vessel Prosthesis

Studies of auricular catecholamines by fluorescence histochemistry in various heart diseases of man.

A comparative histochemical and clinical study concerning the state of the intrinsic adrenergic innervation of the human atrial myocardium was carried out, using the glyoxylic acid-induced fluorescence histochemical method. Specimens from the right auricular appendage were obtained during open-heart surgery from patients suffering from 1. ischaemic heart disease (IHD), 2. atrial septal defect of the secundum type (ASD), and 3. left-sided univalvular or multivalvular heart disease (VHD) with or without congestive heart failure (CHF) experienced prior to surgery. In the IHD group the densities of both the perivascular and the "free" myocardial adrenergic nerve net were greater than in the ASD group and especially in the VHD/CHF group. Secondly, the intensity of fluorescence of the adrenergic structures was generally higher in the IHD group than that in the VDH/CHF group. Further, the average size of the varicosities, the number of varicosities per given length of axon, and the proportional share of the large varicosities were greater in the IHD group than in the ASD and VHD/CHF groups. The difference between the IHD and ASD groups was not great but was obvious in any case. In some patients with VHD/CHF fluorescing axons were observed only occasionally, and the tiny varicosities exhibited a hardly discernible fluorescence. Thus the amount of noradrenaline (NA) in the adrenergic fibres in the IHD group seems to be higher than in the ASD and especially VHD/CHF groups. The level of NA in the IHD group is assumed to constitute a contributory factor in both intracellular metabolic changes and the systemic changes typical of myocardial ischaemia and infarction. In one patient with IHD and in six patients with VHD/CHF with significantly higher heart volume (mean+/-SD) compared with the rest of the patients (P less than 0.001), huge local axonal accumulations of NA in the form of "droplet fibres" were found. These enlarged, bulging adrenergic axons are assumed to be a consequence of mechanical trauma with stretching or disruption of the axons due to myodegenerative processes. It is further assumed that these "droplet fibres" are relatively common in those patients with diseased myocardium. They may constitute an extra contributory factor to the tendency to arrhythmiility of non-atuomatic tissue.

Adult

The chemical nature of human atrial specific granules.

The nature of human auricular specific granules was assessed by a variety of cytochemical and histochemical methods. The specific granules were found to be argentaphobic when ultrathin sections of Araldite-embedded auricular appendages were stained according to the periodic acid-thiocarbohydrazide-silver proteinate technique of Thiery. The entire core of these granules was moderately positive after ultrathin sections of glutaraldehyde-fixed, glycol methacrylate (GMA)-embedded auricles were stained with phosphotungstic acid (PTA) at a low pH. A similar reaction was shown by the cell coat, residual bodies (C-granules), lysosomes, Z-discs as well as by a very small portion of the Golgi complex. Analogous results were obtained in semithin sections of GMA-embedded auricles stained by the periodic acid-Schiff (PAS) technique. Incubation of ultrathin sections (fixed in glutaraldehyde and embedded in GMA) with proteolytic enzymes (pronase, pepsin, trypsin, or alpha-chymotrypsin) elicited selective digestion of atrial specific granules and Z-bands and, to a much lesser degree, of the cell coat. It is concluded that human auricular specific granules, as in rat atrial cardiocytes, are composed mostly of proteins. In addition, these granules may contain complex carbohydrates.

Chemical Phenomena