Men have a higher risk of developing atrial fibrillation (AF) than women, though the reason for this is unknown. Here, we compared atrial electrical and structural properties in male and female mice and explored the contribution of sex hormones. Cellular electrophysiological studies revealed that action potential configuration, Na+ and K+ currents were similar in atrial myocytes from male and female mice (4–5 months). Immunofluorescence showed that male atrial myocytes had more lateralization of connexins 40 (63 ± 4%) and 43 (66 ± 4%) than females (Cx40: 45 ± 4%, p = 0.006; Cx43: 44 ± 4%, p = 0.002), with no difference in mRNA expression. Atrial mass was significantly higher in males. Atrial myocyte dimensions were also larger in males. Atrial fibrosis was low and similar between sexes. Orchiectomy (ORC) abolished sex differences in AF susceptibility (M: 65%; ORC: 38%, p = 0.050) by reducing connexin lateralization and myocyte dimensions. Ovariectomy (OVX) did not influence AF susceptibility (F: 42%; OVX: 33%). This study shows that prior to the development of age-related remodeling, male mice have more connexin lateralization and larger atria and atrial myocyte than females. Orchiectomy reduced AF susceptibility in males by decreasing connexin lateralization and atrial myocyte size, supporting a role for androgens. These sex differences in AF substrates may contribute to male predisposition to AF.
Background Elevated angiotensin II levels are thought to play an important role in atrial electrical and structural remodeling associated with atrial fibrillation. However, the mechanisms by which this remodeling occurs are still unclear. Accordingly, we explored the effects of angiotensin II on atrial remodeling using transgenic mice overexpressing angiotensin II type 1 receptor (AT1R) specifically in cardiomyocytes. Methods and Results Voltage‐clamp techniques, surface ECG, programmed electrical stimulations along with quantitative polymerase chain reaction, Western blot, and Picrosirius red staining were used to compare the atrial phenotype of AT1R mice and their controls at 50 days and 6 months. Atrial cell capacitance and fibrosis were increased only in AT1R mice at 6 months, indicating the presence of structural remodeling. Ca 2+ ( I CaL ) and K + currents were not altered by AT1R overexpression (AT1R at 50 days). However, I CaL density and Ca V 1.2 messenger RNA expression were reduced by structural remodeling (AT1R at 6 months). Conversely, Na + current ( I Na ) was reduced (−65%) by AT1R overexpression (AT1R at 50 days) and the presence of structural remodeling (AT1R at 6 months) yields no further effect. The reduced I Na density was not explained by lower Na V 1.5 expression but was rather associated with an increase in sarcolemmal protein kinase C alpha expression in the atria, suggesting that chronic AT1R activation reduced I Na through protein kinase C alpha activation. Furthermore, connexin 40 expression was reduced in AT1R mice at 50 days and 6 months. These changes were associated with delayed atrial conduction time, as evidenced by prolonged P‐wave duration. Conclusions Chronic AT1R activation leads to slower atrial conduction caused by reduced I Na density and connexin 40 expression.
Learning Objective: Recognize nonspecific and delayed presentations of malignant hyperthermia (MH). Case: A 22-year-old male was admitted with drug overdose. He was found to be afebrile and drowsy with shallow respirations in the ER and was intubated for airway protection. CXR showed a right lower lobe infiltrate. Five hours later in the MICU, he was noted to be flushed and tachycardic with a temperature of 104.8ЊC. Cultures were obtained; Tylenol and antibiotics administered with a cooling blanket applied later. A review of medications given in the ER revealed succinylcholine. A CPK level of 37,789 U/L, elevated urine myoglobin, and high fever suggested malignant hyperthermia with rhabdomyolysis. The patient became normothermic after two doses of dantrolene. He was counseled about MH on discharge. Discussion: MH is a rare genetic disorder due to the mutations of ryanodine receptor in skeletal muscles. It usually occurs after administration of inhaled anesthetics or depolarizing muscle relaxants. Clinical features include marked fever, muscle rigidity, metabolic acidosis, rhabdomyolysis and hemodynamic instability. Hyperthermia develops within minutes to hours following exposure to disease-inducing medications. Many of the early signs are nonspecific and can mimic those of other etiologies. In our case, delayed diagnosis of MH was due to not only late-onset hyperthermia, but also initial attribution of his fever to aspiration pneumonia. Treatment includes discontinuation of triggering agents, oxygenation and use of dantrolene along with cooling measures. This case demonstrates the variability of presentation and underscores the need for continuous monitoring whether in a surgical or medical setting.
Learning ObjectiveRecognize nonspecific and delayed presentations of malignant hyperthermia (MH).CaseA 22-year-old male was admitted with drug overdose. He was found to be afebrile and drowsy with shallow respirations in the ER and was intubated for airway protection. CXR showed a right lower lobe infiltrate. Five hours later in the MICU, he was noted to be flushed and tachycardic with a temperature of 104.8°C. Cultures were obtained; Tylenol and antibiotics administered with a cooling blanket applied later. A review of medications given in the ER revealed succinylcholine. A CPK level of 37,789 U/L, elevated urine myoglobin, and high fever suggested malignant hyperthermia with rhabdomyolysis. The patient became normothermic after two doses of dantrolene. He was counseled about MH on discharge.DiscussionMH is a rare genetic disorder due to the mutations of ryanodine receptor in skeletal muscles. It usually occurs after administration of inhaled anesthetics or depolarizing muscle relaxants. Clinical features include marked fever, muscle rigidity, metabolic acidosis, rhabdomyolysis and hemodynamic instability. Hyperthermia develops within minutes to hours following exposure to disease-inducing medications. Many of the early signs are nonspecific and can mimic those of other etiologies. In our case, delayed diagnosis of MH was due to not only late-onset hyperthermia, but also initial attribution of his fever to aspiration pneumonia. Treatment includes discontinuation of triggering agents, oxygenation and use of dantrolene along with cooling measures. This case demonstrates the variability of presentation and underscores the need for continuous monitoring whether in a surgical or medical setting.
Using a candidate-gene approach, we detected a variant of SCN5A, encoding the cardiac Na þ channel Nav1.5, by screening a family with cardiac arrhythmia resulting in frequent premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia. Arrhythmia mechanism involved ectopic foci originating from the His-Purkinje system. The same mutation, leading to the R222Q substitution, was present in two additional unrelated families with the same associated cardiac phenotype. Exercise or hydroquinidine dramatically decreased the number of PVCs. To evaluate the functional incidence of this substitution, whole-cell patch-clamp experiments were performed on transfected COS-7 cells. The activation and inactivation curves were negatively shifted in the presence of the mutation (V 1/2act , WT: À30.652.1 mV, n=9; heterozygous: À37.251.6 mV, n=9; p<0.05; V 1/2inact , WT: À79.650.7 mV, n=10; heterozygous: À82.251 mV, n=9; p<0.05) whereas the current density was unchanged. The use of depolarizing-voltage ramp confirmed the increase and negative shift of the TTX-sensitive window current (potential of g max , WT: À42.850.5 mV, n=12; homozygous: À58.651.1 mV, n=, p<0.001). WT and R222Q peak I Na were similarly half-reduced by 30 mM quinidine (p<0.001 vs control) as well as the window current (WT: from À1.8750.42 to À0.7450.16 pA/pF in quinidine, n=7; homozygous: À2.5450.41 to À1.1750.12 pA/pF in quinidine, n=6; p<0.001 vs. control). We carried out computer simulations in single-cell models of human Purkinje fibers and ventricle action potentials (AP). In heterozygous conditions, incomplete repolarization occurred in Purkinje cells only. We also built a multicellular model incorporating both cell models. In the heterozygous conditions, incomplete repolarization in the Purkinje fibers triggered premature APs propagating into the ventricle. This was normalized at higher pacing frequency or when quinidine was 'added'. From all these studies, the premature ventricular contractions are explained by the appearance of electrical abnormalities rather in Purkinje fibers than in ventricular cardiomyocytes.
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