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Malignant hyperthermia susceptibility (MHS) is an autosomal dominant pharmacogenetic disorder that manifests as a hypermetabolic state when carriers are exposed to halogenated volatile anesthetics or depolarizing muscle relaxants. In animals, heat stress intolerance is also observed. MHS is linked to over 40 variants in RYR1 that are classified as pathogenic for diagnostic purposes. More recently, a few rare variants linked to the MHS phenotype have been reported in CACNA1S, which encodes the voltage-activated Ca2+ channel CaV1.1 that conformationally couples to RyR1 in skeletal muscle. Here, we describe a knock-in mouse line that expresses one of these putative variants, CaV1.1-R174W. Heterozygous (HET) and homozygous (HOM) CaV1.1-R174W mice survive to adulthood without overt phenotype but fail to trigger with fulminant malignant hyperthermia when exposed to halothane or moderate heat stress. All three genotypes (WT, HET, and HOM) express similar levels of CaV1.1 by quantitative PCR, Western blot, [3H]PN200-110 receptor binding and immobilization-resistant charge movement densities in flexor digitorum brevis fibers. Although HOM fibers have negligible CaV1.1 current amplitudes, HET fibers have similar amplitudes to WT, suggesting a preferential accumulation of the CaV1.1-WT protein at triad junctions in HET animals. Never-the-less both HET and HOM have slightly elevated resting free Ca2+ and Na+ measured with double barreled microelectrode in vastus lateralis that is disproportional to upregulation of transient receptor potential canonical (TRPC) 3 and TRPC6 in skeletal muscle. CaV1.1-R174W and upregulation of TRPC3/6 alone are insufficient to trigger fulminant malignant hyperthermia response to halothane and/or heat stress in HET and HOM mice.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Malignant hyperthermia is a metabolic myopathy, whose carrier patients have a different response than the general population in the presence of a triggering agent such as volatile analgesics and depolarizing muscle relaxants. Its incidence varies between 1:10,000 to 1:250,000 anesthesias. Their current mortality using etiological treatment is 5%. Malignant hyperthermia crisis manifests with tachycardia, hypercapnia, masseter and generalized muscle rigidity, hyperthermia accompanied by acidosis, hyperkalemia, rhabdomyolysis, hypox-emia, acute renal failure, cardiac arrhythmias, heart failure, cardiorespiratory failure, and death. Variants in the skeletal muscle ryanodine receptor have been identified as the cause of more than 70% of cases of malignant hyperthermia through the RYR1 gene located on chro-mosome 19 (19q13.1). The gold standard test to make an adequate diagnosis is the halothane-caffeine contracture test, not yet available in Ecuador. Prompt treatment with dantrolene sodium has markedly decreased the mortality rate associated with this rare but fatal disease., La hipertermia maligna es una miopatía metabólica, cuyos pacientes portadores tienen una respuesta diferente a la población general ante la presencia de un agente desencadenante como a los analgésicos volátiles y relajantes musculares despolarizantes. Su incidencia varía entre 1:10.000 a 1: 250.000 anestesias. Su mortalidad actual usando el tratamiento etiológico es de 5%. La crisis de hipertermia maligna se manifiesta con taquicardia, hipercapnia, rigidez de los músculos maseteros y generalizada, hipertermia que se acompaña de acidosis, hiperkalemia, rabdomiólisis, hipoxemia, insuficiencia renal aguda, arritmias cardiacas, falla cardiaca, para cardiorrespiratorio y muerte. Se han identificado variantes en el receptor de rianodina del músculo esquelético como causantes de más del 70% de los casos de hipertermia maligna a través del gen RYR1 localizado en el cromosoma 19 (19q13.1). La prueba estándar de oro para realizar un diagnostico adecuado es la prueba de contractura de halotano-cafeína hasta el momento no disponible en Ecuador. El tratamiento oportuno con dantroleno sódico ha disminuido notablemente la tasa de mortalidad asociada a esta rara pero fatal enfermedad.

Purpose: Malignant hyperthermia is a rare crisis associated with anesthesia that boasts an 80%fatality rate if left untreated. The purpose of this doctorate of nursing practice project was to evaluate impact of multimodal training and protocol availability on malignant hyperthermia management. Ultimately, the goal was to demonstrate improved provider competence to strengthen the recommendation for standardized malignant hyperthermia policy within the hospital. With this change, lives could be saved. Background: Malignant hyperthermia is a life-threatening response to triggering pharmacological agents. Triggering agents include all the contemporary anesthetic gasses used in the United States in addition to succinylcholine – a drug used to induce paralysis during induction of anesthesia. The pathology of malignant hyperthermia is a hypermetabolic state which confers electrolyte disturbances, rapid hyperthermia, cardiac dysrhythmias, muscle rigidity, hypertension and tachypnea. Methods: This quality improvement project started with optional use of a protocol, developed by Malignant Hyperthermia Association of the United States, during a live simulation training. Following the 20-minute simulation, eight anesthesia providers were debriefed and a short educational PowerPoint was presented. Finally, participants answered 15 survey questions to establish efficacy of the purported training session. Results: Results of the survey overwhelmingly support the use of a protocol for managing malignant hyperthermia. All (100%) providers had seen malignant hyperthermia in practice. Additionally, all providers agreed that, at minimum, annual training for all operating room staff would be valuable. All chose to use the optional protocol during practice simulation and subsequently agreed it was useful. All reported that they would choose to utilize the protocol if faced with this crisis in practice. And all felt more confident with recognition of malignant hyperthermia, dantrolene adm

Purpose: The focus of the quality improvement (QI) project was to improve provider preparedness for malignant hyperthermia (MH) by increasing exposure and experience through biannual education.Background: Malignant hyperthermia (MH) is a rare hypermetabolic medical emergency that will result in significant morbidity and mortality if left untreated. MH is caused by a mutation in the ryanodine receptor (RYR1). When the defected RYR1 is exposed to triggering agents, it causes a continuous release of calcium from the sarcoplasmic reticulum leading to sustained contraction of the muscle. Methods: A descriptive design was used for this QI project in Mesa, Arizona. A post-intervention survey assessed the level of knowledge retained after biannual education, perception of preparedness, usefulness of an MH flowchart, and benefit of biannual education. MH PowerPoint education and stimulated scenario was provided prior to the QI project in March 2021. A second education session was delivered in person at the facility using the same PowerPoint presentation on November 8, 2021. The sample size included 20 participants. Data was collected through a post-intervention survey accessed through a QR code provided and through paper copies. Results: The QI project found that participants agreed that biannual education was beneficial. The key findings also included correct identification of trigger agents and MH treatment, location of MH carts and flowchart, and increased MH management confidence. Conclusion: The QI project found that participants agreed that biannual MH education was beneficial and improved confidence, which helps provider’s to be better prepared for an MH emergency. Participants found the MH Development Tool useful, and it was laminated and placed in the MH cart to be utilized during an MH crisis.

Background: Patients at risk of malignant hyperthermia need trigger-free anesthesia. Therefore, anesthesia machines prepared for safe use in predisposed patients should be free of volatile anesthetics. The washout time depends on the composition of rubber and plastic in the anesthesia machine. Therefore, new anesthesia machines should be evaluated regarding the safe preparation for trigger-free anesthesia. This study investigates wash out procedures of volatile anesthetics for two new anesthetic workstations: Dräger Atlan A350 and General Electric Healthcare (GE) Carestation 650 and compare it with preparation using activated charcoal filters (ACF). Methods: A Dräger Atlan and a Carestation 650 were contaminated with 4% sevoflurane for 90 min. The machines were decontaminated with method (M1): using ACF, method 2 (M2): a wash out method that included exchange of internal parts, breathing circuits and soda lime canister followed by ventilating a test lung using a preliminary protocol provided by Dräger or method 3 (M3): a universal wash out instruction of GE, method 4 (M4): M3 plus exchange of breathing system and bellows. Decontamination was followed by a simulated trigger-free ventilation. All experiments were repeated with 8% desflurane contaminated machines. Volatile anesthetics were detected with a closed gas loop high-resolution ion mobility spectrometer with gas chromatographic pre-separation attached to the bacterial filter of the breathing circuits. Primary outcome was time until < 5 ppm of volatile anesthetics and total preparation time. Results: Time to < 5 ppm for the Atlan was 17 min (desflurane) and 50 min (sevoflurane), wash out continued for a total of 60 min according to protocol resulting in a total preparation time of 96-122 min. The Carestation needed 66 min (desflurane) and 24 min (sevoflurane) which could be abbreviated to 24 min (desflurane) if breathing system and bellows were changed. Total preparation time was 30-73 min. When using active ch

Malignant hyperthermia (MH) is a potentially fatal, autosomal dominant, metabolic disorder triggered in susceptible individuals upon exposure to volatile anaesthetics. Following the onset of an MH episode, a patient will enter a hypermetabolic state, displaying the symptoms of intense muscle contraction, metabolic acidosis, increased oxygen consumption. Prolonged episodes can result in rhabdomyolysis. If left untreated, MH can manifest as an increase in body temperature and death by cardiac arrest. MH is diagnosed by the invasive in vitro contracture test, which requires a muscle tissue biopsy. DNA screening has been implemented and is commonly used to diagnose a genetic predisposition to MH; however, the test is currently limited to fifty variants confirmed to be pathogenic out of approximately 350 variants linked to the disorder. DNA-based tests are limited because of the technical difficulties associated with functional analysis. Thus, additional variants must be functionally characterised. The structural implications of MH-linked variants potentially leading to the onset of MH are not yet well defined. Potential structural changes induced by pathogenic variants have been modelled in silico, where variants were mapped to the rabbit RyR1 structure characterised by cryo electron microscopy. However, this does not confirm the role the variants play in the structural and functional alteration of the channel. To address, this a functionally significant region of RyR1 was cloned for recombinant expression in E. coli. The RyR1 region was shown to be soluble and efforts were made to purify the protein. However, the protein could not be purified to an extent acceptable for either biochemical analysis or crystallisation trials or for subsequent X-ray crystallography. A number of pathogenic variants were instead modelled in silico to provide some insights into their potential pathogenic functional role. The viability of a new cell-based system for the functional characteris

Malignant hyperthermia (MH) is characterized by induction of skeletal muscle hyperthermia in response to a dysregulated increase in myoplasmic calcium. Although altered energetics play a central role in MH, MH-susceptible humans and mouse models are often described as having no phenotype until exposure to a triggering agent. The purpose of this study was to determine the influence of the R163C ryanodine receptor 1 mutation, a common MH mutation in humans, on energy expenditure, and voluntary wheel running in mice. Energy expenditure was measured by indirect respiration calorimetry in wild-type (WT) and heterozygous R163C (HET) mice over a range of ambient temperatures. Energy expenditure adjusted for body weight or lean mass was increased (P < .05) in male, but not female, HET mice housed at 22°C or when housed at 28°C with a running wheel. In female mice, voluntary wheel running was decreased (P < .05) in the HET vs WT animals when analyzed across ambient temperatures. The thermoneutral zone was also widened in both male and female HET mice. The results of the study show that the R163C mutations alters energetics even at temperatures that do not typically induce MH.

Ryanodine receptor (RYR) mutations confer stress-triggered malignant hyperthermia (MH) susceptibility. Dietary caffeine (CAF) is the most commonly consumed psychoactive compound by humans. CAF-triggered Ca2+ release and its influences on skeletal muscle contractility are widely used as experimental tools to study RYR function/dysfunction and diagnose MH susceptibility. We hypothesize that dietary CAF achieving blood levels measured in human plasma exacerbates the penetrance of RYR1 MH susceptibility mutations triggered by gaseous anesthetic, affecting both central and peripheral adverse responses. Heterozygous R163C-RYR1 (HET) MH susceptible mice are used to investigate the influences of dietary CAF on both peripheral and central responses before and after induction of halothane (HAL) maintenance anesthesia under experimental conditions that maintain normal core body temperature. HET mice receiving CAF (plasma CAF 893 ng/ml) have significantly shorter times to respiratory arrest compared with wild type, without altering blood chemistry or displaying hyperthermia or muscle rigor. Intraperitoneal bolus dantrolene before HAL prolongs time to respiratory arrest. A pilot electrographic study using subcutaneous electrodes reveals that dietary CAF does not alter baseline electroencephalogram (EEG) total power, but significantly shortens delay to isoelectric EEG, which precedes respiratory and cardiac arrest. CAF ± HAL are studied on RYR1 single-channel currents and HET myotubes to define molecular mechanisms of gene-by-environment synergism. Strong pharmacological synergism between CAF and HAL is demonstrated in both single-channel and myotube preparations. Central and peripheral nervous systems mediate adverse responses to HAL in a HET model of MH susceptibility exposed to dietary CAF, a modifiable lifestyle factor that may mitigate risks of acute and chronic diseases associated with RYR1 mutations. SIGNIFICANCE STATEMENT: Dietary caffeine at a human-relevant dose synergi

La hemorragia postparto es considerada una emergencia obstétrica y es una de las cinco principales causas de mortalidad materna a nivel mundial. La mortalidad depende tanto de la salud general de la mujer embarazada así como de los recursos para su tratamiento agudo. La incidencia depende de los criterios utilizados para su diagnóstico. La determinación de la causa e intervención temprana son de gran importancia ya que la mayoría de las muertes por sangrado postparto ocurren dentro de las primeras cuatro horas del puerperio y el monitoreo cercano es indispensable para evaluar y conocer la agresividad de la intervención que se dará a cada paciente., Postpartum hemorrhage is considered an obstetric emergency and is one of the five leading causes of maternal mortality worldwide. Mortality depends on both the general health of pregnant women and the resources for their acute treatment. The incidence will depend on the criteria used for its diagnosis. Detecting the main cause and having an early intervention is important since the majority of deaths from postpartum bleeding occur within the first four hours of the puerperium. Also, a close monitoring is essential to assess and know the aggressiveness of the intervention that will be given to each patient

Chlorantraniliprole (CP) and flubendiamide (FD) are widely used in agriculture globally to control lepidopteran pests. Both insecticides target ryanodine receptors (RyRs) and promote Ca2+ leak from sarcoplasmic reticulum (SR) within insect skeletal muscle yet are purportedly devoid of activity toward mammalian RyR1 and muscle. RyRs are ion channels that regulate intracellular Ca2+ release from SR during physiological excitation-contraction coupling. Mutations in RYR1 genes confer malignant hyperthermia susceptibility (MHS), a potentially lethal pharmacogenetic disorder in humans and animals. Compared with vehicle control, CP (10 µM) triggers a 65-fold higher rate of Ca2+ efflux from Ca2+-loaded mammalian WT-RyR1 SR vesicles, whereas FD (10 µM) produces negligible influence on Ca2+ leak. We, therefore, compared whether CP or FD differentially influence patterns of high-affinity [3H]ryanodine ([3H]Ry) binding to RyR1 isolated from muscle SR membranes prepared from adult C57BL/6J mice expressing WT, homozygous C-terminal MHS mutation T4826I, or heterozygous N-terminal MHS mutation R163C. Basal [3H]Ry binding differed among genotypes with rank order T4826I ≫R163C∼WT, regardless of [Ca2+] in the assay medium. Both CP and FD (0.01-100 µM) elicited concentration-dependent increase in [3H]Ry binding, although CP showed greater efficacy regardless of genotype or [Ca2+]. Exposure to CP (500 mg/kg; p.o) failed to shift intolerance to heat stress (38°C) characteristic of R163C and T4826I MHS mice, nor cause lethality in WT mice. Although nM-µM of either diamide is capable of differentially altering WT and MHS RyR1 conformation in vitro, human RyR1 mutations within putative diamide N- and C-terminal interaction domains do not alter heat stress intolerance (HSI) in vivo.

Malignant hyperthermia (MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum (SR), leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1 ( RYR1) and CACNA1S have been identified in approximately 50% to 86% and 1% of MH-susceptible (MHS) individuals, respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm, hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.

Chlorantraniliprole (CP) and flubendiamide (FD) are widely used in agriculture globally to control lepidopteran pests. Both insecticides target ryanodine receptors (RyRs) and promote Ca2+ leak from sarcoplasmic reticulum (SR) within insect skeletal muscle yet are purportedly devoid of activity toward mammalian RyR1 and muscle. RyRs are ion channels that regulate intracellular Ca2+ release from SR during physiological excitation-contraction coupling. Mutations in RYR1 genes confer malignant hyperthermia susceptibility (MHS), a potentially lethal pharmacogenetic disorder in humans and animals. Compared with vehicle control, CP (10 µM) triggers a 65-fold higher rate of Ca2+ efflux from Ca2+-loaded mammalian WT-RyR1 SR vesicles, whereas FD (10 µM) produces negligible influence on Ca2+ leak. We, therefore, compared whether CP or FD differentially influence patterns of high-affinity [3H]ryanodine ([3H]Ry) binding to RyR1 isolated from muscle SR membranes prepared from adult C57BL/6J mice expressing WT, homozygous C-terminal MHS mutation T4826I, or heterozygous N-terminal MHS mutation R163C. Basal [3H]Ry binding differed among genotypes with rank order T4826I ≫R163C∼WT, regardless of [Ca2+] in the assay medium. Both CP and FD (0.01-100 µM) elicited concentration-dependent increase in [3H]Ry binding, although CP showed greater efficacy regardless of genotype or [Ca2+]. Exposure to CP (500 mg/kg; p.o) failed to shift intolerance to heat stress (38°C) characteristic of R163C and T4826I MHS mice, nor cause lethality in WT mice. Although nM-µM of either diamide is capable of differentially altering WT and MHS RyR1 conformation in vitro, human RyR1 mutations within putative diamide N- and C-terminal interaction domains do not alter heat stress intolerance (HSI) in vivo.

Malignant hyperthermia (MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum (SR), leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1 ( RYR1) and CACNA1S have been identified in approximately 50% to 86% and 1% of MH-susceptible (MHS) individuals, respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm, hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.

Malignant hyperthermia (MH) is an uncommon pharmacogenetic disorder that is asymptomatic until triggered by volatile anaesthetics or depolarising muscle relaxants. Exposure to such a trigger can result in a potentially fatal hypermetabolic crisis in an MH-susceptible individual. With prior diagnosis, MH episodes can be avoided by using alternative anaesthesia. Diagnostic testing requires a morbidly invasive muscle biopsy for those considered at risk based on family history. Linkage of MH-susceptibility to variants in the skeletal muscle calcium release channel ryanodine receptor 1 (RyR₁) has provided an opportunity for DNA testing as an alternative to the muscle biopsy. DNA-based diagnosis is severely limited by the number of diagnostic mutations identified—only 50 mutations have been established as MH-causative from over 300 genetic variants associated with the disorder. Moreover, DNA testing may only diagnose an individual as MH-susceptible; a negative DNA test is insufficient under current guidelines for a negative MH diagnosis. The purpose of this study was to develop molecular tools to investigate the hypothesis that RyR₁ variants associated with MH-susceptibility cause dysregulation of calcium release from intracellular stores. Two experimental approaches were followed with the objective of expanding the capabilities of DNA-based diagnosis for MH. The first technique was the generation of mammalian cell lines stably expressing recombinant RyR₁ variants by use of the Flp-In™ T-REx™ system from Invitrogen, followed by functional analysis. Four of five genetic variants associated with MH or myopathy had altered sensitivities to an RyR₁ agonist and therefore meet the criteria for use as diagnostic variants for MH-susceptibility. The second molecular technique explored was gene editing, with the aim of showing that a single nucleotide change was both necessary and sufficient to cause MH-susceptibility. This was developed by introducing a well-characterised MH-causa

Malignant hyperthermia (MH) is a rare and life-threatening pharmacogenetic disorder triggered by volatile anesthetics, the depolarizing muscle relaxant succinylcholine, and rarely by strenuous exercise or environmental heat. The exact prevalence of MH is unknown, and it varies from 1:16 000 in Denmark to 1:100 000 in New York State. The underlying mechanism of MH is excessive calcium release from the sarcoplasmic reticulum (SR), leading to uncontrolled skeletal muscle hyper-metabolism. Genetic mutations in ryanodine receptor type 1 ( RYR1) and CACNA1S have been identified in approximately 50% to 86% and 1% of MH-susceptible (MHS) individuals, respectively. Classic clinical symptoms of MH include hypercarbia, sinus tachycardia, masseter spasm, hyperthermia, acidosis, muscle rigidity, hyperkalemia, myoglobinuria, and etc. There are two types of testing for MH: a genetic test and a contracture test. Contracture testing is still being considered as the gold standard for MH diagnosis. Dantrolene is the only available drug approved for the treatment of MH through suppressing the calcium release from SR. Since clinical symptoms of MH are highly variable, it can be difficult to establish a diagnosis of MH. Nevertheless, prompt diagnosis and treatments are crucial to avoid a fatal outcome. Therefore, it is very important for anesthesiologists to raise awareness and understand the characteristics of MH. This review summarizes epidemiology, clinical symptoms, diagnosis and treatments of MH and any new developments.

Background: The autosomal dominant inherited trait of malignant hyperthermia (MH) may result in a fatal metabolic crisis triggered by volatile anaesthetics and/or succinylcholine. Immediate diagnosis and goal-directed therapy reduce the mortality of an acute MH event to less than 5%. In order to reach this goal, national and international recommendations, standard operating procedures (SOPs) and guidelines were published. Aim: In a German national survey among anaesthesiologists, the current study investigated the awareness level of SOPs and guidelines for preparedness and treatment of an acute MH-crisis. Material and Methods: An online questionnaire including questions about demography and personal experiences with MH was posted to all members of the German Society of Anaesthesiology and Intensive Care Medicine (DGAI). Other questions were concerned with the existence of SOPs and guidelines for preparedness and treatment of an acute MH crisis in hospital or outpatient settings, as well as the individual rating of German and European guidelines. The questionnaire was active from the 2nd of September until the 30th of September 2015. Results: 1,673 members of the DGAI participated in the study. 94.5% of the participants stated that they used volatile anaesthetics and/or succinylcholine. 34.0% had witnessed one or more clinical MH episodes, and 44.9% had experienced at least one or more cases in which MH had been suspected. As regards the use of volatile anaesthetics 84.6% of the heads of anaesthesiological departments and 77.1% of self-employed anaesthesiologists working in in private practices stated that they hold available SOPs/guidelines on MH. 66.7% of the participants believed that the DGAI guidelines are adequate, whereas 22.0% preferred the guidelines released by the EMHG. However, 14.3% were not aware of DGAI or EMHG guidelines. Discussion: National and international anaesthesiological societies recommend that SOPs/guidelines for the prevention, recogniti

Malignant hyperthermia is a potentially fatal disorder of skeletal muscle manifesting as a rise in body temperature in response inhalational anaesthetics and muscle relaxants. Further clinical signs include muscle rigidity and increased oxygen consumption. The increased metabolism is induced by alterations to Ca2+ homeostasis resulting from the dysregulation of the sarcoplasmic reticulum protein the ryanodine receptor type 1 (RyR1). A large proportion of known malignant hyperthermia linked genetic variants reside within the gene encoding the type 1 ryanodine receptor, RYR1. Malignant hyperthermia can be diagnosed by in vitro contracture testing of biopsied muscle tissue. The use of DNA diagnostic testing is advantageous, however it is limited to only 35 of the proposed 400 RYR1 linked variants known to be associated with malignant hyperthermia. The research described in this thesis reports the functional characterisation of two RYR1 variants linked to malignant hyperthermia, c.641C>T and c.7042_7044delCAG resulting in the amino acid changes p.T214M and p.ΔE2348. The ability of each variant to release Ca2+ in response to a stimulus was examined in a heterologous system. The variant p.ΔE2348 was shown to be hyperactive in response to agonists indicating the variant is the cause of malignant hyperthermia, while the p.T214M variant does not appear to have an effect ryanodine receptor function. To understand the relationship between RyR1 function and any structural alterations induced by the p.T214M and p.ΔE2348 variants, the domain housing each variant was cloned for bacterial expression. Subsequent purification and structural characterisation could be used to explain the role each variant plays with respect to the onset of MH. The RyR1 N-­terminal domain, amino acids 1-­558, and helical domain, amino acids 2091-­2525, were expressed in E. coli and partially purified. The domains were shown to be soluble and stable following expression.

Modern anaesthetic techniques have resulted in the clinical presentation of malignant hyperthermia to be more often indolent and/or insidious than truly fulminant, as previously known in the anaesthetic community. We present four recently referred cases to illustrate this point: one late-onset case, two patients with slowly progressive hypercapnia as the sole sign and a fourth patient with postoperative myalgias and elevated creatine kinase. We also discuss the reasons for the shift in typical clinical presentation. The more insidious character of malignant hyperthermia is most likely due to the lower triggering potency of modern volatile anaesthetics, the mitigating effects of several intravenous drugs (neuromuscular blocking agents, alpha 2 adrenergic receptor agonists, beta-adrenergic blockade) or techniques (neuraxial anaesthesia) and the routine use of end-tidal CO2 monitoring leading to the early withdrawal of triggering drugs. Awareness among anaesthetists of this change in presentation is important since the clinical diagnosis is often more doubtful and, if corroborative evidence is not sought, the diagnosis may be delayed or missed altogether.

This study was designed to identify human mutation that caused Exertional and/or environmental heat stroke (EHS) and exertional rhabdomyolysis (ER) and to develop new interventions to prevent EHS and ER. We identified RyR1 mutations as a major cause of exertional rhabdomyolysis. 82% of the individuals that were enrolled in the study that had a family history of MH were positive for disease-associated mutations in the RYR1 gene, while 10.5% of index cases enrolled for a history of unexplained or recurrent ER were positive for disease-associated mutations in the RYR1 gene. All of these cases were CHCT positive. Although AICAR was not effective in preventing isoflurane or heat induced episodes in hyper-metabolic response in pigs homozygous for an RyR1 mutation, AICAR was effective in preventing heat-induced hyper-metabolic responses in the heterozygous mouse model of malignant hyperthermia., The original document contains color images.

Malignant hyperthermia (MH) is potentially fatal pharmacogenetic disorder of skeletal muscle caused by intracellular Ca(2+) dysregulation. NCX is a bidirectional transporter that effluxes (forward mode) or influxes (reverse mode) Ca(2+) depending on cellular activity. Resting intracellular calcium ([Ca(2+)]r) and sodium ([Na(+)]r) concentrations are elevated in MH susceptible (MHS) swine and murine muscles compared with their normal (MHN) counterparts, although the contribution of NCX is unclear. Lowering [Na(+)]e elevates [Ca(2+)]r in both MHN and MHS swine muscle fibers and it is prevented by removal of extracellular Ca(2+) or reduced by t-tubule disruption, in both genotypes. KB-R7943, a nonselective NCX3 blocker, reduced [Ca(2+)]r in both swine and murine MHN and MHS muscle fibers at rest and decreased the magnitude of the elevation of [Ca(2+)]r observed in MHS fibers after exposure to halothane. YM-244769, a high affinity reverse mode NCX3 blocker, reduces [Ca(2+)]r in MHS muscle fibers and decreases the amplitude of [Ca(2+)]r rise triggered by halothane, but had no effect on [Ca(2+)]r in MHN muscle. In addition, YM-244769 reduced the peak and area under the curve of the Ca(2+) transient elicited by high [K(+)]e and increased its rate of decay in MHS muscle fibers. siRNA knockdown of NCX3 in MHS myotubes reduced [Ca(2+)]r and the Ca(2+) transient area induced by high [K(+)]e. These results demonstrate a functional NCX3 in skeletal muscle whose activity is enhanced in MHS. Moreover reverse mode NCX3 contributes to the Ca(2+) transients associated with K(+)-induced depolarization and the halothane-triggered MH episode in MHS muscle fibers.

Rippling muscle disease (RMD) is a benign disorder affecting striated muscle.Malignant hyperthermia (MH) susceptibility is a potentially lethal disorder in which otherwise healthy individuals can develop an extreme hypermetabolism and muscle rigidity/rhabdomyolysis during anesthesia with potent inhalational agents and/or succinylcholine. Disturbed calcium homeostasis has been suggested as the cause of RMD symptoms. Uncontrolled increase in intracellular calcium concentration starts a MH reaction. Purpose To investigate if there is a relation between RMD and MH susceptibility in a family with both RMD and MH susceptibility. Materials and methods Ten members of a family segregating RMD had, prior to RMD diagnosis, been investigated for MH susceptibility. Results from MH and RMD investigations and anesthesia outcomes were cross-referenced and evaluated to find connections or phenotype variations predicted by in vitro contracture test results. Results There was no relation between RMD and MH susceptibility. There were no adverse anesthesia reactions recorded in this family. Conclusions RMD and MH susceptibility did not co-segregate. RMD patients should probably not be considered at risk for MH reactions.

Cognitive aids are prompts designed to help users complete a task or series of tasks. They may take the form of posters, flowcharts, checklists, or even mnemonics. It has been suggested that the use of cognitive aids improves performance and patient outcomes during anesthetic emergencies; however, a systematic assessment of the evidence is lacking. The aim of this literature review was to determine (1) whether cognitive aids improve performance of individuals and teams and (2) whether recommendations can be made for future cognitive aid design, testing, and implementation. Medical, nursing, and psychology databases were searched using broad criteria to find cognitive aids that have been reported in the literature for use in anesthetic emergencies. The reference lists of the articles selected for review were also screened to identify additional studies. Selected articles that described the evaluation of cognitive aids used in anesthetic emergencies were reviewed to determine how the content of the aid was derived, how the design was evaluated, and the success of the aid in improving technical and team performance. The search yielded 22 cognitive aids developed to support clinicians during anesthetic emergencies that had been evaluated in 23 studies. Ten studies using simulation suggested that technical performance improves with the use of cognitive aids in some anesthetic emergencies such as malignant hyperthermia, cardiopulmonary resuscitation, and airway management. However, in 3 of the simulator-based evaluations, participants had either no improvement or took longer to diagnose and treat and made more incorrect diagnoses. Four studies investigated the effect of the aids on teamwork with differing conclusions. One study suggested improved participants' coordination patterns and one found aids improved their decision-making scores, but 2 other studies indicated that there was no improvement and even provided evidence of reduced levels of team communication when tea

Malignant hyperthermia (MH) is an autosomal dominant pharmacogenetic disorder of skeletal muscle triggered by volatile halogenated anaesthetics. Susceptible individuals can exhibit symptoms including tachycardia, high temperature, hypoxia, hypermetabolism and skeletal muscle rigidity. There are usually no symptoms of MH in normal day to day life although “awake” episodes have been reported as a result of extreme exercise in MH-susceptible subjects. Genetic variants have been associated with the skeletal muscle ryanodine receptor gene (RYR1) in 50-70 % of susceptible patients. At the molecular level susceptible patients are thought to have an increased sensitivity to RYR1 agonists in skeletal muscle compared to non-affected patients that results in disregulated skeletal muscle Ca2+ homeostasis. In 2000 a novel RYR1-mutation, c.G7354T (p.R2452W), associated with MH, was identified in a New Zealand (NZ) family. Subsequently the same mutation was identified in a separate NZ family and has also been reported in the United Kingdom. To date this mutation had not been shown to be causative of MH. Therefore, the aim of this study was to carry out functional analyses to test whether the R2452W mutant receptor alters Ca2+ release compared to wildtype. For this study Ca2+ release assays were carried out in three different cell types: B-lymphoblastoid cells, myotubes and HEK293 cells transfected with full-length human RYR1 cDNA. Cells were exposed to the RYR1-specific agonist 4-chloro-m-cresol, which stimulates Ca2+ release through the receptor while the increase in cytosolic Ca2+ was detected using a membrane-permeable fluorophore. Cells expressing R2452W mutant RYR1 showed altered Ca2+ release from the sarco(endo)plasmic reticulum suggesting a hypersensitive channel. In order to study structure/function relationships of the R2452W mutation within the RYR1 protein, as well as the 3D structure of a central RYR1 domain (amino acid 2144-2489), a region encompassing this substituti

Thesis (Ph.D.)--University of Rochester. School of Medicine & Dentistry. Dept. of Pharmacology and Physiology, 2010., The type 1 isoform of the ryanodine receptor (RyR1) controls the release of Ca2+ from the sarcoplasmic reticulum (SR) during skeletal muscle excitation-contraction (EC) coupling. Mutations in the RYR1 gene cause several rare inherited skeletal muscle disorders including malignant hyperthermia (MH) and central core disease (CCD). In the human population, two RyR1 mutations, I4898T (IT) and Y522S (YS), result in CCD and MH with cores, respectively. The IT mutation is proposed to result in gating/Ca2+ permeation defects while the YS mutation is hypothesized to increase Ca2+ leak. Providing a comprehensive comparison of the proposed pathogenic mechanisms in skeletal muscle of IT and YS knock-in mice is the central goal of this thesis. Myotubes homozygous for the IT mutation (IT/IT) completely lack 4-chloro-m-cresol (4-CMC) and electrically-evoked Ca2+ release, despite exhibiting normal SR Ca2+ content. Interestingly, as in IT/IT myotubes, EC coupling is absent in YS/YS myotubes, though this phenotype results from severe SR Ca2+ leak and SR Ca2+ store depletion rather than a defect in Ca2+ permeation as seen for the IT mutation. Heterozygous IT (IT/+) and YS (YS/+) mice were crossed to generate compound heterozygous mice (YS/IT) in order to evaluate potential rescue of RyR1 activity due to functional RyR1 complementation. The foundation of this hypothesis is the opposing mechanistic defects for the IT and YS mutations (reduced Ca2+ permeation vs increased Ca2+ leak, respectively). Results from compound heterozygous YS/IT myotubes demonstrate a partial rescue of both electrically-evoked (21.4% rescue) and 4-CMC-induced (42.5% rescue) Ca2+ release compared to IT/IT myotubes. Whole cell voltage clamp experiments confirmed that depolarization-induced Ca2+ release is partially rescued in YS/IT myotubes versus both IT/IT and YS/YS myotubes (F/Fmax WT: 3.29 ± 0.10; IT/IT: 0.28 ± 0.03; YS/YS 0.69 ± 0.10; YS/IT: 1.26 ± 0.14) and that the presence of the dominant YS mutation is s

A thesis submitted for the degree of Doctor of Medicine, Monash University, 2012 Contents: Chapter 1 Why medical history is relevant to a doctorate of medicine Chapter 2 General introduction: My involvement in the history of anaesthesia Chapter 3 Early anaesthetic delivery - simple wire masks Murray's chloroform mask Esmarch's mask The Schimmelbusch mask Kocher's mask Bellamy Gardner's ether mask Chapter 4 Early airway management in anaesthesia Clearing the airway - tongue forceps Clearing the airway - mouth gags, wedges and openers Clearing the airway - the development of the pharyngeal airway Clearing the airway - the cuffed pharyngeal airway Chapter 5 Measuring anaesthetic gas delivery - the development of flow meters Gwathmey's water sight feed The Coxeter Boyle gas anaesthesia apparatus The water depression flowmeter Maximilian Neu and the first anaesthetic rotameter Dry flowmeters The rotameter Chapter 6 Intravenous anaesthesia - the development of equipment and drugs Intravenous equipment - early syringes Intravenous equipment - the ongoing development of the syringe Early blood transfusion equipment Intravenous equipment - infusions Intravenous cannulae Modem developments - plastic cannulae and the Court butterfly needle Early intravenous anaesthesia The history of intravenous anaesthesia: the barbiturates. Part 1 The history of intravenous anaesthesia: the barbiturates. Part 2 The history of intravenous anaesthesia: the barbiturates. Part 3 Intravenous anaesthesia: steroids Induction agents: Avertin Intravenous induction agents: benzodiazepines Intravenous induction agents: ketamine Intravenous induction agents: propanidid Intravenous induction agents: etomidate Intravenous induction agents: propofol Intravenous induction agents: opioids Chapter 7 Local anaesthesia - the development of equipment and drugs Local anaesthesia - before cocaine Local anaesthesia - the early history of cocaine Local anaesthesia - Freud, Koller and cocaine Local anaesthesia - earl

A thesis submitted for the degree of Doctor of Medicine, Monash University, 2012 Contents: Chapter 1 Why medical history is relevant to a doctorate of medicine Chapter 2 General introduction: My involvement in the history of anaesthesia Chapter 3 Early anaesthetic delivery - simple wire masks Murray's chloroform mask Esmarch's mask The Schimmelbusch mask Kocher's mask Bellamy Gardner's ether mask Chapter 4 Early airway management in anaesthesia Clearing the airway - tongue forceps Clearing the airway - mouth gags, wedges and openers Clearing the airway - the development of the pharyngeal airway Clearing the airway - the cuffed pharyngeal airway Chapter 5 Measuring anaesthetic gas delivery - the development of flow meters Gwathmey's water sight feed The Coxeter Boyle gas anaesthesia apparatus The water depression flowmeter Maximilian Neu and the first anaesthetic rotameter Dry flowmeters The rotameter Chapter 6 Intravenous anaesthesia - the development of equipment and drugs Intravenous equipment - early syringes Intravenous equipment - the ongoing development of the syringe Early blood transfusion equipment Intravenous equipment - infusions Intravenous cannulae Modem developments - plastic cannulae and the Court butterfly needle Early intravenous anaesthesia The history of intravenous anaesthesia: the barbiturates. Part 1 The history of intravenous anaesthesia: the barbiturates. Part 2 The history of intravenous anaesthesia: the barbiturates. Part 3 Intravenous anaesthesia: steroids Induction agents: Avertin Intravenous induction agents: benzodiazepines Intravenous induction agents: ketamine Intravenous induction agents: propanidid Intravenous induction agents: etomidate Intravenous induction agents: propofol Intravenous induction agents: opioids Chapter 7 Local anaesthesia - the development of equipment and drugs Local anaesthesia - before cocaine Local anaesthesia - the early history of cocaine Local anaesthesia - Freud, Koller and cocaine Local anaesthesia - earl

Bidirectional communication between the 1,4-dihydropyridine receptor (DHPR) in the plasma membrane and the type 1 ryanodine receptor (RYR1) in the sarcoplasmic reticulum (SR) is responsible for both skeletal-type excitation-contraction coupling (voltage-gated Ca(2+) release from the SR) and increased amplitude of L-type Ca(2+) current via the DHPR. Because the DHPR and RYR1 are functionally coupled, mutations in RYR1 that are linked to malignant hyperthermia (MH) may affect DHPR activity. For this reason, we investigated whether cultured myotubes originating from mice carrying an MH-linked mutation in RYR1 (R163C) had altered voltage-gated Ca(2+) release from the SR, membrane-bound charge movement, and/or L-type Ca(2+) current. In myotubes homozygous (Hom) for the R163C mutation, voltage-gated Ca(2+) release from the SR was substantially reduced and shifted ( approximately 10 mV) to more hyperpolarizing potentials compared with wild-type (WT) myotubes. Intramembrane charge movements of both Hom and heterozygous (Het) myotubes displayed hyperpolarizing shifts similar to that observed in voltage-gated SR Ca(2+) release. The current-voltage relationships for L-type currents in both Hom and Het myotubes were also shifted to more hyperpolarizing potentials ( approximately 7 and 5 mV, respectively). Compared with WT myotubes, Het and Hom myotubes both displayed a greater sensitivity to the L-type channel agonist +/-Bay K 8644 (10 microM). In general, L-type currents in WT, Het, and Hom myotubes inactivated modestly after 30-s prepulses to -50, -10, 0, 10, 20, and 30 mV. However, L-type currents in Hom myotubes displayed a hyperpolarizing shift in inactivation relative to L-type currents in either WT or Het myotubes. Our present results indicate that mutations in RYR1 can alter DHPR activity and raise the possibility that this altered DHPR function may contribute to MH episodes.

Bidirectional signaling between the sarcolemmal L-type Ca(2+) channel (1,4-dihydropyridine receptor [DHPR]) and the sarcoplasmic reticulum (SR) Ca(2+) release channel (type 1 ryanodine receptor [RYR1]) of skeletal muscle is essential for excitation-contraction coupling (ECC) and is a well-understood prototype of conformational coupling. Mutations in either channel alter coupling fidelity and with an added pharmacologic stimulus or stress can trigger malignant hyperthermia (MH). In this study, we measured the response of wild-type (WT), heterozygous (Het), or homozygous (Hom) RYR1-R163C knock-in mouse myotubes to maintained K(+) depolarization. The new findings are: (a) For all three genotypes, Ca(2+) transients decay during prolonged depolarization, and this decay is not a consequence of SR depletion or RYR1 inactivation. (b) The R163C mutation retards the decay rate with a rank order WT > Het > Hom. (c) The removal of external Ca(2+) or the addition of Ca(2+) entry blockers (nifedipine, SKF96365, and Ni(2+)) enhanced the rate of decay in all genotypes. (d) When Ca(2+) entry is blocked, the decay rates are slower for Hom and Het than WT, indicating that the rate of inactivation of ECC is affected by the R163C mutation and is genotype dependent (WT > Het > Hom). (e) Reduced ECC inactivation in Het and Hom myotubes was shown directly using two identical K(+) depolarizations separated by varying time intervals. These data suggest that conformational changes induced by the R163C MH mutation alter the retrograde signal that is sent from RYR1 to the DHPR, delaying the inactivation of the DHPR voltage sensor.