Increase in sudden death from coronary artery disease in young adults.

BACKGROUND: Sudden cardiac death (SCD) is the most common cause of death in adults aged <65 years, making it a major public health problem. A growing incidence in coronary artery disease (CAD) in young individuals has been predicted in developed countries, which could in turn be associated with an increase in SCD in this population. The aim of the study was to assess the prevalence of CAD among autopsies of young individuals (<40 years) who had sudden death (SD). METHODS: We selected all the autopsies referred to the Montreal Heart Institute and Maisonneuve-Rosemont Hospital from January 2002 to December 2006 that corresponded to individuals <40 years old who had died suddenly. For each decedent, the following data were collected: cause of death, autopsy findings, available clinical history, toxicological findings, and cardiovascular risk factors. RESULTS: From a total of 1,260 autopsies, 243 fulfilled the inclusion criteria. Coronary artery disease was the main cause of SCD from age 20 years, representing the 37% of deaths in the group of 21 to 30 years old, and up to 80% of deaths in the group of 31 to 40 years old. Among individuals who died of CAD, 3-vessel disease was observed in 39.7% of cases. Moreover, among the whole population <40 years old, at least 1 significant coronary lesion was observed in 39.5% of cases, irrespective to the cause of death. In the multivariable analysis, an increased BMI (hazard ratio 1.1 for each kg/m(2), 95% CI 1.01-1.1) and hypercholesterolemia (hazard ratio 2.4, 95% CI 1.7-333.3) showed to be the modifiable factors related to an increased risk of SD from CAD. CONCLUSIONS: In our population, CAD was the main cause of SD from age 20 years. These data bring into question whether present prevention strategies are sufficient and reinforce the need to extend prevention to younger ages.

Genetic fate mapping identifies second heart field progenitor cells as a source of adipocytes in arrhythmogenic right ventricular cardiomyopathy.

The phenotypic hallmark of arrhythmogenic right ventricular cardiomyopathy, a genetic disease of desmosomal proteins, is fibroadipocytic replacement of the right ventricle. Cellular origin of excess adipocytes, the responsible mechanism(s) and the basis for predominant involvement of the right ventricle are unknown. We generated 3 sets of lineage tracer mice regulated by cardiac lineage promoters alpha-myosin heavy chain (alphaMyHC), Nkx2.5, or Mef2C. We conditionally expressed the reporter enhanced yellow fluorescent protein while concomitantly deleting the desmosomal protein desmoplakin in cardiac myocyte lineages using the Cre-LoxP technique. Lineage tracer mice showed excess fibroadiposis and increased numbers of adipocytes in the hearts. Few adipocytes in the hearts of alphaMyHC-regulated lineage tracer mice, but the majority of adipocytes in the hearts of Nkx2.5- and Mef2C-regulated lineage tracer mice, expressed enhanced yellow fluorescent protein. In addition, rare cells coexpressed adipogenic transcription factors and the second heart field markers Isl1 and Mef2C in the lineage tracer mouse hearts and in human myocardium from patients with arrhythmogenic right ventricular cardiomyopathy. To delineate the responsible mechanism, we generated transgenic mice expressing desmosomal protein plakoglobin in myocyte lineages. Transgene plakoglobin translocated to nucleus, detected by immunoblotting and immunofluorescence staining and coimmunoprecipitated with Tcf7l2, a canonical Wnt signaling transcription factor. Expression levels of canonical Wnt/Tcf7l2 targets bone morphogenetic protein 7 and Wnt5b, which promote adipogenesis, were increased and expression level of connective tissue growth factor, an inhibitor of adipogenesis, was decreased. We conclude adipocytes in arrhythmogenic right ventricular cardiomyopathy originate from the second heart field cardiac progenitors, which switch to an adipogenic fate because of suppressed canonical Wnt signaling by nuclear plakoglobin.

Heart rate reduction by ivabradine reduces diastolic dysfunction and cardiac fibrosis.

OBJECTIVES: To determine if heart rate (HR) reduction with ivabradine (IVA), a selective inhibitor of the pacemaker I(f) current, prevents cardiac dysfunction associated with dyslipidemia. METHODS: New Zealand White rabbits received either a standard diet, a 0.5% cholesterol-enriched diet only (CD), or a 0.5% CD with IVA (17 mg/kg/day) for 12 weeks. HR, left ventricular (LV) systolic function, diastolic function and LV regional myocardial performance index (MPI) were studied using echocardiography. Histological analysis included cardiac interstitial fibrosis and collagen type I fibers. Plasma levels of angiotensin II and aldosterone were quantified by immunoassays. RESULTS: IVA reduced HR by approximately 11%. IVA improved MPI and attenuated LV diastolic dysfunction (DD) (92% mild and 8% moderate DD with IVA vs. 54% mild and 46% moderate DD in CD group). IVA also reduced atrial fibrosis (p = 0.027), ventricular fibrosis (p = 0.0002) and ventricular collagen type I (p = 0.0042). IVA decreased plasma angiotensin II levels (p = 0.042), and both angiotensin II and aldosterone levels were correlated with HR (p = 0.038 and 0.008). CONCLUSION: Selective HR reduction with IVA reduces DD and cardiac fibrosis in hypercholesterolemic rabbits. These beneficial effects of IVA support testing pure HR reduction in patients with diastolic heart failure.

The rat heart contains a neural stem cell population; role in sympathetic sprouting and angiogenesis.

Nestin-expressing cells were identified in the normal rat heart characterized by a small cell body and numerous processes and following an ischemic insult migrated to the infarct region. The present study was undertaken to identify the phenotype, origin and biological role of nestin-expressing cells during reparative fibrosis. A neural stem cell phenotype was identified based on musashi-1 expression, growth as a neurosphere, and differentiation to a neuronal cell. Using the Wnt1-cre; Z/EG transgenic mouse model, which expresses EGFP in embryologically-derived neural crest cells, the reporter signal was detected in nestin-expressing cells residing in the heart. In infarcted human hearts, nestin-expressing cells were detected in the viable myocardium and the scar and morphologically analogous to the population identified in the rat heart. Following either an ischemic insult or the acute administration of 6-hydroxydopamine, sympathetic sprouting was dependent on the physical association of neurofilament-M immunoreactive fibres with nestin-positive processes emanating from neural stem cells. To specifically study the biological role of the subpopulation in the infarct region, neural stem cells were isolated from the scar, fluorescently labelled and transplanted in the heart of 3-day post-MI rats. Injected scar-derived neural stem cells migrated to the infarct region and were used as a substrate for de novo blood vessel formation. These data have demonstrated that the heart contains a resident population of neural stem cells derived from the neural crest and participate in reparative fibrosis. Their manipulation could provide an alternative approach to ameliorate the healing process following ischemic injury.

Omega-3 polyunsaturated fatty acids prevent atrial fibrillation associated with heart failure but not atrial tachycardia remodeling.

BACKGROUND: There is epidemiological evidence that omega-3 polyunsaturated fatty acids (PUFAs) reduce the risk of atrial fibrillation (AF), but clinical data are conflicting. The present study assessed the effects of PUFA on AF in experimental models. METHODS AND RESULTS: We studied the effects of oral PUFA supplements in 2 experimental AF paradigms: electrical remodeling induced by atrial tachypacing (400 bpm for 1 week) and congestive heart failure-associated structural remodeling induced by ventricular tachypacing (240 bpm for 2 weeks). PUFA pretreatment did not directly change atrial effective refractory period (128+/-6 [mean+/-SEM] versus 127+/-2 ms; all effective refractory periods at 300-ms cycle lengths) or burst pacing-induced AF duration (5+/-4 versus 34+/-18 seconds). Atrial tachypacing dogs had shorter refractory periods (73+/-6 ms) and greater AF duration (1185+/-300 seconds) than shams (119+/-5 ms and 20+/-11 seconds; P<0.01 for each). PUFAs did not significantly alter atrial tachypacing effects on refractory periods (77+/-8 ms) or AF duration (1128+/-412 seconds). PUFAs suppressed ventricular tachypacing-induced increases in AF duration (952+/-221 versus 318+/-249 seconds; P<0.05) and attenuated congestive heart failure-related atrial fibrosis (from 19.2+/-1.1% to 5.8+/-1.0%; P<0.001) and conduction abnormalities. PUFAs also attenuated ventricular tachypacing-induced hemodynamic dysfunction (eg, left ventricular end-diastolic and left atrial pressure from 12.2+/-0.5 and 11.4+/-0.6 mm Hg, respectively, to 6.4+/-0.5 and 7.0+/-0.8 mm Hg; P<0.01) and phosphorylation of mitogen-activated protein kinases (extracellular-signal related and P38 kinase). CONCLUSIONS: PUFAs suppress congestive heart failure-induced atrial structural remodeling and AF promotion but do not affect atrial tachycardia-induced electrical remodeling. The beneficial effects of PUFAs on structural remodeling, possibly related to prevention of mitogen-activated protein kinase activation, may contribute to their clinical anti-AF potential.

The pharmacological response of ischemia-related atrial fibrillation in dogs: evidence for substrate-specific efficacy.

OBJECTIVE: Acute atrial ischemia produces a substrate for atrial fibrillation (AF) maintenance, but the response of this substrate to antiarrhythmic-drugs has not been defined. The present study assessed the effects of class 1-4 antiarrhythmic-drugs on the electrophysiological consequences of acute atrial ischemia, and compared effects in ischemic AF with those in vagal AF. METHODS AND RESULTS: Isolated atrial ischemia was created by ligating a right coronary artery branch perfusing the right atrial free wall. Experiments were performed in dogs treated with loading and maintenance doses of flecainide (class 1; n=5), nadolol (class 2, n=7), dofetilide (class 3, n=5), or diltiazem (class 4, n=7) prior to coronary artery occlusion. Dogs subjected to coronary occlusion without pre-treatment (n=10) served as controls. Coronary artery occlusion substantially increased AF duration, e.g. from 7+/-4 s (pre-ischemic baseline) to 876+/-245 s at 3 h of ischemia, and caused substantial ischemic zone conduction slowing. Diltiazem and nadolol prevented AF promotion (AF durations 12+/-8 s and 4+/-1 s at 3 h of ischemia respectively; each p<0.001 vs control) and suppressed ischemic conduction slowing. Flecainide and dofetilide failed to prevent ischemia-induced AF promotion (e.g. AF duration at 3-hour ischemia 779+/-417 and 801+/-414 respectively, p=NS vs control) and failed to alter ischemia-induced conduction slowing. A different pattern of response occurred with vagal AF: flecainide was highly effective in reducing vagal AF duration; dofetilide, diltiazem, and nadolol were ineffective. CONCLUSIONS: Beta-blockade and Ca(2+) antagonism suppress the arrhythmic consequences of acute atrial ischemia, whereas Na(+) channel or K(+)-channel block are ineffective. These results are relevant to understanding the effects of different classes of antiarrhythmic-drugs on AF occurring in coronary disease patients.

Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) is a common cause of atrial fibrillation (AF). Oxidative stress and inflammation (profibrotic) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha, antifibrotic) factors may be involved in CHF-related remodeling. We evaluated the effects of simvastatin (antioxidant, anti-inflammatory) and fenofibrate (PPAR-alpha activator) on CHF-related atrial remodeling. METHODS AND RESULTS: Dogs were subjected to 2-week ventricular tachypacing (VTP) in the absence and presence of simvastatin (20 or 80 mg/day) or fenofibrate. Induced AF duration (DAF) was increased by VTP from 36+/-14 (non-paced controls) to 1005+/-257 s (p<0.01). Simvastatin prevented VTP-induced DAF increases (147+/-37 and 84+/-37 s at 20 and 80 mg/day, respectively), but fenofibrate did not (1018+/-352 s). Simvastatin also attenuated CHF-induced conduction abnormalities (heterogeneity-index reduced from 1.5+/-0.1 to 1.1+/-0.1 and 1.0+/-0.1 at 20 and 80 mg/day, p<0.01) and atrial fibrosis (from 19.4+/-1.3% to 10.8+/-0.8% and 9.9+/-0.8% at 20 and 80 mg/day, p<0.01), while fenofibrate did not. Simvastatin (but not fenofibrate) also attenuated VTP-induced left-ventricular nitric-oxide synthase and nitrotyrosine increases, along with hemodynamic dysfunction. Atrial fibroblast proliferation increased with 24-h fetal bovine serum (FBS) stimulation from 654+/-153 to 7264+/-1636 DPM (p<0.001). Simvastatin, but not fenofibrate, suppressed fibroblast proliferation (664+/-192 DPM, p<0.001). Simvastatin also significantly attenuated transforming growth factor-beta1-stimulated alpha-smooth muscle actin (alpha-SMA) expression (indicating myofibroblast differentiation) from 1.3+/-0.1 to 1.0+/-0.1 times baseline (p<0.05). CONCLUSIONS: CHF-induced atrial structural remodeling and AF promotion are attenuated by simvastatin, but not fenofibrate. Statin-induced inhibition of profibrotic atrial fibroblast responses and attenuation of left-ventricular dysfunction may contribute to preventing the CHF-induced fibrotic AF substrate.

Atrial tachycardia remodeling of pulmonary vein cardiomyocytes: comparison with left atrium and potential relation to arrhythmogenesis.

BACKGROUND: The pulmonary veins (PVs) are important in the pathophysiology of atrial fibrillation (AF), as is atrial tachycardia (AT) remodeling. The relative importance of AT remodeling in PVs versus other atrial sites is unknown. The present study assessed AT-induced cellular changes in PVs versus left atrium (LA) and their relationship to arrhythmogenesis. METHODS AND RESULTS: We studied ionic currents (single-cell patch clamp) and action potentials (APs; coronary-perfused multicellular preparations) in the PVs and LA free wall of dogs after 7-day AT pacing (400 bpm), as well as in nonpaced control dogs. In controls, rapid (I(Kr)) and slow (I(Ks)) delayed-rectifier currents were larger in PVs; transient-outward (I(to)), inward-rectifier (I(K1)), and L-type Ca2+ (I(Ca)) currents and AP duration were smaller. AT remodeling reduced I(Ca) and I(to), left I(Kr) and I(Ks) unchanged, and increased I(K1) in both LA and PV. AT reduced action potential duration in both LA and PV. LA-PV AP differences became smaller in AT than in control dogs. Premature extrastimuli induced atrial tachyarrhythmias at 4.5+/-2.8% (mean+/-SEM) sites in 6 control multicellular preparations compared with 64.2+/-7.3% sites in 9 AT-remodeled preparations (P<0.001). Resection of all PVs failed to alter atrial tachyarrhythmia inducibility in AT-remodeled preparations (67.5+/-13.1%). PV resection did not significantly change tachyarrhythmia duration (mean 3.9 seconds per heart, range 0.7 to 15.7 seconds before resection; mean 7.0 seconds per heart, range 0.9 to 36.0 seconds after resection) or cycle length (120+/-6 ms before resection, 115+/-8 ms after resection). CONCLUSIONS: AT produces qualitatively similar ionic remodeling in LA and PVs but reduces PV-LA AP differences. PVs are not essential for AT-induced atrial tachyarrhythmia promotion in this model, which may relate to the failure of PV isolation to prevent AF in some patient populations.

Successful explantation of a left ventricular assist device following acute fulminant myocarditis.

A left ventricular (LV) assist device was implanted in a 53-year-old woman in cardiogenic shock secondary to fulminant myocarditis. LV function recovered to normal after one week of support from an LV assist device. The device was explanted and the patient is showing a good outcome with a normalized LV function.

Consequences of atrial tachycardia-induced remodeling depend on the preexisting atrial substrate.

BACKGROUND: All animal studies of atrial tachycardia (AT) remodeling to date have been performed in normal hearts, but clinical atrial fibrillation (AF) often occurs in the setting of heart disease. This study evaluated the effects of a pathological AF substrate on AT-induced remodeling. METHODS AND RESULTS: Fourteen control dogs, 12 AT-only dogs (400 bpm for 1 week), 14 congestive heart failure (CHF) dogs (CHF only, ventricular tachypacing, 220 to 240 bpm for 5 weeks), and 13 CHF+AT dogs (ventricular tachypacing-induced CHF, 1 week of AT superimposed on the last week of ventricular tachypacing) were studied for evaluation of AT effects in normal hearts (AT-only versus control dogs) and CHF hearts (CHF+AT versus CHF-only dogs). In normal hearts, AT strongly decreased the effective refractory period (ERP) and abolished ERP rate adaptation, whereas conduction velocity was unaltered. In CHF dogs, AT reduced ERP to a significantly lesser extent, did not alter ERP rate adaptation, and reduced conduction velocity. AT alone increased atrial vulnerability to extrastimuli and prolonged AF. In the presence of CHF, AT had no clear effect on atrial vulnerability but increased the prevalence of prolonged AF. CONCLUSIONS: The electrophysiological effects of AT are different in hearts with a CHF-induced pathological substrate for AF than in normal hearts. These findings have potentially important implications for understanding how AF occurring in diseased hearts begets AF.

Dynamic nature of atrial fibrillation substrate during development and reversal of heart failure in dogs.

BACKGROUND: Clinical atrial fibrillation (AF) often results from pathologies that cause atrial structural remodeling. The reversibility of arrhythmogenic structural remodeling on removal of the underlying stimulus has not been studied systematically. METHODS AND RESULTS: Chronically instrumented dogs were subjected to 4 to 6 weeks of ventricular tachypacing (VTP; 220 to 240 bpm) to induce congestive heart failure (CHF), followed by a 5-week recovery period leading to hemodynamic normalization at 5-week recovery (Wk5(rec)). The duration of burst pacing-induced AF under ketamine/diazepam/isoflurane anesthesia increased progressively during VTP and recovered toward baseline during the recovery period, paralleling changes in atrial dimensions. However, even at full recovery, sustained AF could still be induced under relatively vagotonic morphine/chloralose anesthesia. Wk5(rec) dogs showed no recovery of CHF-induced atrial fibrosis (3.1+/-0.3% for controls versus 10.7+/-1.0% for CHF and 12.0+/-0.8% for Wk5(rec) dogs) or local conduction abnormalities (conduction heterogeneity index 1.8+/-0.1 in controls versus 2.3+/-0.1 in CHF and 2.2+/-0.2 in Wk5(rec) dogs). One week of atrial tachypacing failed to affect the right atrial effective refractory period significantly in CHF dogs but caused highly significant effective refractory period reductions and atrial vulnerability increases in Wk5(rec) dogs. CONCLUSIONS: Reversal of CHF is followed by normalized atrial function and decreased duration of AF; however, fibrosis and conduction abnormalities are not reversible, and a substrate that can support prolonged AF remains. Early intervention to prevent fixed structural abnormalities may be important in patients with conditions that predispose to the arrhythmia.

Atrial ischemia promotes atrial fibrillation in dogs.

BACKGROUND: Coronary artery disease is a significant risk factor for atrial fibrillation (AF), but the basis for this association is incompletely understood. The present study evaluated the hypothesis that atrial ischemia can create a substrate for AF maintenance. METHODS AND RESULTS: Atrial ischemia was induced by occlusion of an atrial arterial branch that did not provide blood flow to the ventricles. Atrial-arterial occlusion increased the duration of AF induced by burst pacing from 57+/-32 seconds (control) to 803+/-214 seconds (P<0.001) after 0.5 hour of occlusion and to 887+/-209 seconds (P<0.001) after 3 hours of occlusion. Prolonged AF (>20 minutes) was induced in 0 of 16 dogs (0%) under control conditions, 7 of 16 (44%, P<0.01) at 0.5 to 3 hours, and 5 of 13 (38%, P<0.01) 3 to 5 hours after occlusion. Atrial conduction was slowed substantially within the ischemic zone: eg, conduction delay was 8+/-1 ms at a cycle length of 200 ms, control, versus 22+/-5 ms (P<0.01) after 0.5 hours and 27+/-5 ms (P<0.001) after 3 hours of ischemia. Refractoriness was initially unaffected but was prolonged 5 hours after occlusion. Phase-delay analysis and high-density mapping confirmed severe conduction slowing in the ischemic zone. Histological examination confirmed the location of ischemic regions and revealed extensive ischemia-induced necrosis at sites of conduction delay. CONCLUSIONS: Experimental atrial ischemia creates a substrate for AF maintenance, apparently by causing local conduction slowing that promotes reentry. These results suggest that atrial ischemia may significantly promote AF, and may be relevant to AF mechanisms in association with coronary artery disease.

Dissociation between ionic remodeling and ability to sustain atrial fibrillation during recovery from experimental congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) downregulates atrial transient outward (I(to)), slow delayed rectifier (I(Ks)), and L-type Ca(2+) (I(Ca,L)) currents and upregulates Na(+)-Ca(2+) exchange current (I(NCX)) (ionic remodeling) and causes atrial fibrosis (structural remodeling). The relative importance of ionic versus structural remodeling in CHF-related atrial fibrillation (AF) is controversial. METHODS AND RESULTS: We measured hemodynamic and echocardiographic parameters, mean duration of burst pacing-induced AF (DAF), and atrial-myocyte ionic currents in dogs with CHF induced by 2-week ventricular tachypacing (240 bpm), CHF dogs allowed to recover without pacing for 4 weeks (REC), and unpaced controls. Left ventricular ejection fraction averaged 58.6+/-1.2% (control), 36.2+/-2.3% (CHF, P<0.01), and 57.9+/-1.6% (REC), indicating full hemodynamic recovery. Similarly, left atrial pressures were 2.2+/-0.3 (control), 13.1+/-1.5 (CHF), and 2.4+/-0.4 (REC) mm Hg. CHF reduced I(to) density by approximately 65% (P<0.01), decreased I(Ca,L) density by approximately 50% (P<0.01), and diminished I(Ks) density by approximately 40% (P<0.01) while increasing I(NCX) density by approximately 110% (P<0.05). In REC, all ionic current densities returned to control values. DAF increased in CHF (1132+/-207 versus 14.3+/-8.8 seconds, control) and remained increased with REC (1014+/-252 seconds). Atrial fibrous tissue content also increased in CHF (2.1+/-0.2% for control versus 10.2+/-0.7% for CHF, P<0.01), with no recovery observed in REC (9.4+/-0.8%, P<0.01 versus control, P=NS versus CHF). CONCLUSIONS: With reversal of CHF, there is complete recovery of ionic remodeling, but the prolonged-AF substrate and structural remodeling remain. This suggests that structural, not ionic, remodeling is the primary contributor to AF maintenance in experimental CHF.

Beta-radiation for the creation of linear lesions in the canine atrium.

BACKGROUND: Creating linear lesions is important for the treatment of arrhythmias such as atrial flutter and fibrillation. Making these lesions with standard radiofrequency catheters can be difficult and may result in charring and thrombosis. The purpose of this study was to evaluate beta-radiation as a novel energy source for creating linear myocardial lesions. METHODS AND RESULTS: Eight dogs with intact conduction across the cavotricuspid isthmus were studied. The isthmus was irradiated (25 to 50 Gy) with strontium/yttrium-90 delivered via a deflectable 7F catheter (Novoste Corporation). There were no immediate effects, but bidirectional conduction block developed during follow-up studies in 7 of 8 dogs. The dog without conduction block received 25 Gy. After the animals were euthanized, histology revealed transmural, linear areas of fibrosis without any thrombus. CONCLUSIONS: Beta-radiation can safely and effectively create linear lesions that are contiguous and nonthrombogenic. This energy source may become an interesting adjunct to radiofrequency for the treatment of atrial flutter and fibrillation.

Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure.

BACKGROUND: Congestive heart failure (CHF) causes arrhythmogenic remodeling in both atria and ventricles, but differences between atrial and ventricular remodeling in CHF have not been well characterized. METHODS AND RESULTS: We examined atrial and ventricular tissues from dogs with CHF induced by ventricular tachypacing (220-240/min) for 0 (control) or 24 h, or 1, 2 or 5 weeks. Histopathology was used to assess apoptosis, fibrosis, white blood cell infiltration and cell death, ELISA to measure angiotensin-II concentration and Western blot to evaluate protein expression. Ventricular tachypacing-induced CHF was associated with substantially more fibrosis in left atrium (maximum 10 +/- 1% at 5 weeks) than in left ventricle (0.4 +/- 0.1% at 5 weeks, P < 0.01 versus left atrium). Tissue angiotensin-II concentration increased to steady state in atrial tissue at 24 h but increased more slowly in left ventricle, with a maximum that was significantly higher in atrium than ventricle. Ventricular tachypacing caused tissue apoptosis, inflammatory cell infiltration and cell death, with maximum changes in left atrium being faster, transient and larger than in left ventricle. Mitogen activated protein kinase activation was rapid (within 24 h) in left atrium, but smaller and slower (p38, c-Jun N-terminal kinase) or non-significant (extracellular signal-related kinase) in left ventricle. The 25-kDa activated form of transforming growth factor-beta1, a particularly important profibrotic mediator in atrium, increased significantly in left atrium, from 2.6 +/- 0.6 (control) to 9.2 +/- 1.7 (24 h) and 8.1 +/- 1.8 optical density units (1 week), but was not significantly changed in ventricle. CONCLUSIONS: There are qualitative and quantitative differences in atrial versus ventricular remodeling in experimental ventricular tachypacing-induced CHF, with potentially important consequences for understanding underlying mechanisms and developing new therapeutic approaches.

Evolution of the atrial fibrillation substrate in experimental congestive heart failure: angiotensin-dependent and -independent pathways.

OBJECTIVE: Augmented atrial apoptosis, angiotensin II expression, and related signalling pathway activation have been shown in clinical atrial fibrillation (AF), but their significance is poorly understood. This study evaluated temporal relationships between changes in atrial histopathology, selected signalling mediators, and AF promotion, as well as effects of angiotensin-converting enzyme (ACE) inhibition, in a canine model of congestive heart failure (CHF). METHODS: Dogs were subjected to ventricular tachypacing (VTP) for varying periods up to 5 weeks. Apoptosis was assessed by terminal dUTP nick-end labelling (TUNEL) and DNA fragmentation. Protein expression was determined by Western blot, angiotensin II concentration by ELISA (tissue) and radioimmunoassay (plasma), and caspase-3 activity by enzymatic assay. Histopathological analyses were used to quantify fibrosis, inflammation, and cell death. RESULTS: Significant apoptosis developed 24 h after VTP onset and persisted for 1 week, returning to baseline thereafter. Apoptosis was preceded by increases in tissue (but not plasma) angiotensin II concentration; enhanced expression of phosphorylated mitogen-activated protein (MAP) kinases p38, JNK, and ERK; and augmented ratios of the proapoptotic protein Bax to the antiapoptotic protein Bcl-2. Increased cell death, leukocyte infiltration, and caspase-3 activity occurred at the time of peak apoptosis. Apoptosis was followed by interstitial fibrosis, which peaked at 5 weeks. ACE inhibition (enalapril) prevented increases in tissue angiotensin II concentration, phosphorylated ERK expression, Bax/Bcl-2 ratio, and cellular apoptosis, but did not affect total cell death, leukocyte infiltration, JNK or p38 activation, and reduced but did not eliminate tissue fibrosis. CONCLUSIONS: AF-promoting atrial structural remodeling in experimental CHF involves angiotensin II-dependent and angiotensin II-independent pathways. Significant apoptosis occurs, but prevention of apoptosis by ACE inhibition only partially prevents atrial structural remodeling.

Lung structural remodeling and pulmonary hypertension after myocardial infarction: complete reversal with irbesartan.

OBJECTIVES: The severity of pulmonary hypertension associated with heart failure carries a poor prognosis. The lungs are very sensitive to the constrictive and proliferative effects of angiotensin-II and could represent a preferential target for this peptide. METHODS: Rats with large myocardial infarcts or sham surgery received the angiotensin-II receptor antagonist irbesartan (40 mg/kg/day) or vehicle for 2 or 8 weeks (n=5 to 8 for each group). Hemodynamic and morphometric measurements were obtained followed by immunohistochemistry, immunofluorescence analysis and electron microscopic characterization of lung sections. RESULTS: The infarct groups developed progressive pulmonary hypertension and right ventricular hypertrophy with elevated left ventricular filling pressures (all P<0.01). Despite similar infarct size, filling pressures were lower (P<0.01) while pulmonary hypertension and right ventricular hypertrophy were completely normalized by irbesartan. Isolated lungs pressure-flow relationships were identical at 2 weeks. At 8 weeks it was steepest and shifted upward in the infarct group (P<0.001), and completely normalized by irbesartan. Lung weight doubled after infarct with no evidence of pulmonary edema and was also normalized by irbesartan. Important lungs structural remodeling evidenced by collagen and reticulin deposition, thickening of the alveolar septa and proliferation of cells with ultrastructural characteristics of myofibroblasts (pericytes) were identified after infarct. CONCLUSIONS: After large myocardial infarct there is important pulmonary structural remodeling in which myofibroblasts (pericytes) proliferation may play an important role. This initially protective mechanism against high filling pressures could eventually contribute to the development of pulmonary hypertension and right ventricular hypertrophy. Future studies are needed to determine if angiotensin-II directly modulates pulmonary remodeling after myocardial infarct.

Ionic current abnormalities associated with prolonged action potentials in cardiomyocytes from diseased human right ventricles.

OBJECTIVES: This study was designed to determine whether ionic currents in right ventricular myocytes from explanted human transplant recipient hearts are related to right ventricular histopathology and function. BACKGROUND: Cardiac action potential duration (APD) is prolonged in ventricular tissues/cells from patients with heart failure, but the ionic mechanisms are not well documented. METHODS: Membrane currents and transmembrane action potentials in myocytes from right ventricular epicardium of explanted human hearts were recorded using whole-cell patch clamp technique. Data from cells from right ventricles with severe histologic and functional abnormalities (abnormal histology group [AH]) and from right ventricles with preserved histology and function (relatively normal histology group [RNH]) were compared. RESULTS: We found that APD at 50% (APD(50)) and 90% repolarization (APD(90)) were significantly longer in AH cells than in RNH cells. Early afterdepolarizations (EADs) were observed in 20% of AH cells and none of the RNH cells. Inwardly rectifying K(+) current (I(K1)) was decreased (both inward and outward components). Both transient outward K(+) current (I(to1)) and slowly delayed rectifier K(+) current (I(Ks)) were down-regulated in AH cells. L-type Ca(2+) (I(Ca.L)) was not altered in AH cells. CONCLUSIONS: I(K1), I(to1), and I(Ks) are down-regulated in AH cells of human heart failure. This down-regulation contributes to APD prolongation that favors the occurrence of arrhythmogenic EADs and suggests a link between human cardiac histopathologic/functional abnormalities and arrhythmogenic ionic remodeling.

Incidence and outcome of radial artery infections following cardiac surgery.

BACKGROUND: Radial artery infections secondary to catheterization for blood pressure monitoring are rare but potentially serious complications. The objective of the study was to evaluate the incidence, the risk factors and the evolution of radial artery infections following cardiac surgery. METHODS: A retrospective review of 8300 patients undergoing cardiac surgery between 1998 and 2002 at the Montreal Heart Institute (MHI) was undertaken. All patients with superficial radial artery infections, infected radial artery pseudoaneurysms, and arterial catheter-related bacteremia were considered using prospective global surveillance of all nosocomial infections over the study period by an infection control nurse. RESULTS: Thirteen patients with radial infections were encountered (0.2%) with bacteremia occurring in 9 patients (0.15%). Five patients developed infected radial artery pseudoaneurysms (0.05%) and 5 patients developed subsequent sternal wound infections. Two patients died in their early postoperative evolution. Mean patient age was 67 years old and mean duration of cannulation was 5.8 days. Only 1 patient had diabetes. Seven of 13 patients were positive for Staphylococcus aureus (54%). All patients had undergone cardiopulmonary bypass (CPB) for various procedures. All superficial infections responded well to antibiotic therapy. Early surgical intervention is essential in cases of infected radial artery pseudoaneurysms. CONCLUSIONS: The postoperative state and cardiopulmonary bypass put patients at risk for infectious complications. Strict systematic changing of arterial lines on a timely basis is unwarranted in our opinion. A high suspicion index, aggressive surgical treatment of bacterial arteritis and appropriate intravenous antibiotics are essential to improve the prognosis.

Surgical radiofrequency ablation induces coronary endothelial dysfunction in porcine coronary arteries.

OBJECTIVES: Surgical radiofrequency ablation is increasingly used during open heart surgery for the treatment of chronic atrial fibrillation. The purpose of this study was to determine the effects of application of radiofrequency on coronary endothelial function and structure and establish the relationship between coronary lesions and distance of radiofrequency application. METHODS: Six Landrace swine (25.9+/-2.0 kg) were included in the study. With the heart kept beating, three epicardial radiofrequency lesions (20 W, 20 s duration, 60 degrees C) 2 cm in length each, were created 1, 5 and 10 mm away from the left anterior descending and the right coronary arteries. The circumflex artery served as control. Coronary rings were placed in organ chambers. After contraction to KCl and prostaglandin F2alpha, endothelium-dependent relaxations to bradykinin were studied. Gomori trichrome and hematoxylin-eosin safran staining were used for histological evaluation. RESULTS: Exposure to radiofrequency 1 mm from the coronary arteries caused a significant decrease in endothelium-independent contractions to KCl and endothelium-dependent relaxations to bradykinin compared to controls (P<0.05). No significant decrease of endothelium-dependent relaxations occurred for rings exposed to radiofrequency at a distance of 5 and 10 mm, compared to controls. Histological examination showed endothelial disruption and medial smooth muscle cells at different stages of necrosis up to 5 mm from the radiofrequency application site. CONCLUSIONS: Radiofrequency may induce coronary endothelial functional and morphological damages when applied less than 5 mm from the artery. Caution must be exerted during left atrial radiofrequency application due to the proximity of the circumflex artery.