An ABCC9 Missense Variant Is Associated with Sudden Cardiac Death and Dilated Cardiomyopathy in Juvenile Dogs.

Sudden cardiac death in the young (SCDY) is a devastating event that often has an underlying genetic basis. Manchester Terrier dogs offer a naturally occurring model of SCDY, with sudden death of puppies as the manifestation of an inherited dilated cardiomyopathy (DCM). We performed a genome-wide association study for SCDY/DCM in Manchester Terrier dogs and identified a susceptibility locus harboring the cardiac ATP-sensitive potassium channel gene ABCC9. Sanger sequencing revealed an ABCC9 p.R1186Q variant present in a homozygous state in all SCDY/DCM-affected dogs (n = 26). None of the controls genotyped (n = 398) were homozygous for the variant, but 69 were heterozygous carriers, consistent with autosomal recessive inheritance with complete penetrance (p = 4 × 10-42 for the association of homozygosity for ABCC9 p.R1186Q with SCDY/DCM). This variant exists at low frequency in human populations (rs776973456) with clinical significance previously deemed uncertain. The results of this study further the evidence that ABCC9 is a susceptibility gene for SCDY/DCM and highlight the potential application of dog models to predict the clinical significance of human variants.

Long-term outcome and troponin I concentrations in Great Danes screened for dilated cardiomyopathy: an observational retrospective epidemiological study.

INTRODUCTION: Dilated cardiomyopathy (DCM) is common in Great Danes (GDs) but screening for this condition can be challenging. We hypothesised that cardiac troponin-I (cTnI) concentration is elevated in GDs with DCM and/or ventricular arrhythmias (VAs), and is associated with reduced survival time in GDs. ANIMALS: One hundred and twenty-four client-owned GDs assigned echocardiographically as normal (n = 53), equivocal (n = 37), preclinical DCM (n = 21), or clinical DCM (n = 13). MATERIALS AND METHODS: A retrospective epidemiological study. Echocardiographic diagnosis, VAs, and contemporaneous cTnI concentrations were recorded. Diagnostic accuracy and cTnI cut-offs were determined with receiver operating characteristic analyses. Effects of the cTnI concentration and disease status on survival and cause of death were explored. RESULTS: Median cTnI was greater in clinical DCM (0.6 ng/mL [25th-75th percentiles: 0.41-1.71 ng/mL]) and GDs with VAs (0.5 ng/mL [0.27-0.80 ng/mL], P<0.001). Elevated cTnI detected these dogs with good accuracy (area under the curve: 0.78-0.85; cut-offs 0.199-0.34 ng/mL). Thirty-eight GDs (30.6%) suffered a cardiac death (CD); GDs suffering CD (0.25 ng/mL [0.21-0.53 ng/mL]) and specifically sudden cardiac death (SCD) (0.51 ng/mL [0.23-0.72 ng/mL]) had higher cTnI than GDs dying of other causes (0.20 ng/mL [0.14-0.35 ng/mL]; P<0.001). Elevated cTnI (>0.199 ng/mL) was associated with shorter long-term survival (1.25 years) and increased risk of SCD. Great Danes with VAs had shorter survival times (0.97 years). CONCLUSIONS: A cardiac troponin-I concentration is a useful adjunctive screening tool. Elevated cTnI is a negative prognostic indicator.

Prevalence of sudden cardiac death in dogs with atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is associated with increased risk of sudden cardiac death (SCD) in humans, independent of secondary risk factors such as thrombogenic disorders. In dogs, SCD is described in a number of heart diseases, but an association between AF and SCD is unreported. HYPOTHESIS: (a) A higher proportion of dogs with AF will experience SCD, and (b) SCD will be associated with complex ventricular arrhythmias. ANIMALS: One-hundred forty-two dogs with AF, and 127 dogs without AF. METHODS: Retrospective, multicenter, case-control study. Dogs included in the AF group were compared to a control group of dogs in sinus rhythm, matched for echocardiographic diagnosis. Descriptive statistics were used to identify proportions of each group suffering SCD, compared using chi-squared testing. Risk factors for SCD in dogs with AF were evaluated at the univariable and multivariable level using binary logistic regression. Significance was P < .05. RESULTS: A significantly higher proportion of dogs with AF suffered SCD than dogs in the control group (14.8% vs 5.5%; P = .01). Younger age at diagnosis, larger left atrial size, and a history of syncope all were independent predictors of SCD in dogs with AF (χ2 , 16.3; P = .04). CONCLUSIONS AND CLINICAL IMPORTANCE: Atrial fibrillation was associated with a higher prevalence of SCD in dogs. A history of syncope may be a useful predictor of SCD risk.

Heart rhythm characterization during sudden cardiac death in dogs.

INTRODUCTION/OBJECTIVES: Inherited or acquired arrhythmic disorders and cardiac disease have been associated with sudden cardiac death (SCD) in dogs. The electrical mechanism related to death in most of these cases is unknown. This retrospective study aimed to describe arrhythmic events in dogs that experienced SCD during Holter monitoring. ANIMALS, MATERIALS AND METHODS: Nineteen client-owned dogs that experienced SCD during Holter examination were included. Clinical records from a Holter service database were reviewed, and both the rhythm preceding death and the dominant rhythm causing SCD were analysed. Clinical data, Holter diaries and echocardiographic diagnosis were also evaluated. RESULTS: Structural heart disease was identified in 12/19 dogs (dilated cardiomyopathy in five dogs, arrhythmogenic right ventricular cardiomyopathy in four dogs, myxomatous mitral valve disease in two dogs, and suspected myocarditis in one dog), five of which had concurrent congestive heart failure. Sudden cardiac death was related to ventricular premature complexes or monomorphic ventricular tachycardia degenerating into ventricular fibrillation in 42% of dogs, polymorphic ventricular tachycardia, or torsade de pointes-like inducing ventricular fibrillation in 21%, and asystole or presumptive agonal pulseless electrical activity triggered by malignant bradyarrhythmias in 37%. CONCLUSIONS: The most common rhythm associated with SCD in our population of dogs was ventricular tachycardia leading to ventricular fibrillation, although bradyarrhythmia-related SCD, possibly related to inappropriate vagal reflexes, was also a notable cause.

Exercise-Associated Sudden Death in Finnish Standardbred and Coldblooded Trotters - A Case Series With Pedigree Analysis.

Exercise-associated sudden deaths (EASDs) are deaths occurring unexpectedly during or immediately after exercise. Sudden cardiac death (SCD) is one cause of EASD. Cardiac arrhythmias caused by genetic variants have been linked to SCD in humans. We hypothesize that genetic variants may be associated with SCD in animals, including horses. Genetic variants are transmitted to offspring and their frequency might increase within a family. Therefore, the frequency of such variants might increase with the inbreeding factor. Higher inbreeding could have a negative impact on racing performance. Pedigree data and career earnings from racehorses diagnosed with SCD between 2002 and 2017 were compared using non-parametric tests with 1) control horses that died due to catastrophic musculoskeletal injuries and 2) horses that raced during the same period without reported problems. Diagnosis of SCD was based on necropsy reports, including macroscopic and microscopic examinations. Death was registered in the study period for 61 horses. Eleven of these horses were excluded due to missing autopsy reports. In 25 cases, the diagnosis remained unknown and death was possibly caused by cardiac arrhythmia, in two cases cardiac disease was identified, in seven cases a rupture of a major vessel had occurred. In addition, 16 horses died or were euthanized due to severe musculoskeletal injuries. No significant differences in inbreeding coefficients or in career earnings were found between the groups or between horses with EASD compared with other horses racing during the same period. The study provides no evidence for increased inbreeding factor in Finnish racehorses with SCD.

Sudden cardiac death: A comparative review of humans, dogs and cats.

Sudden death is one of the most common causes of death in humans in Western countries. Approximately 85% of these cases are of cardiac origin. In dogs and cats, sudden cardiac death (SCD) also commonly occurs, but fewer pathophysiological and prevalence data are available. Both structural, primarily 'electrical' and ischemic heart diseases are known to cause SCD, many of which share similar underlying arrhythmogenic mechanisms between humans and companion animals. As for underlying genetics, numerous mutations on multiple loci have been related to SCD in humans, but only a few mutations associated with dilated cardiomyopathy and SCD have been identified in dogs, e.g. in the phospholamban and titin genes. Information published from human medicine can therefore inform future veterinary studies, but also dogs and cats could act as spontaneous models of SCD in humans. Further research in both fields is therefore warranted to better understand the pathophysiology, genetics, and prevention of SCD.

Sudden death in a dog with aortic coarctation.

A previously healthy, one-year-old, intact female Vizsla dog collapsed and experienced cardiopulmonary arrest after a stressful event. Postmortem examination identified juxtaductal aortic coarctation (AoCo) with complex morphology. Located in the isthmus aorta adjacent to the ligamentum arteriosum, the AoCo comprised a shelf-like structure caused by invagination of the aortic wall into the lumen. Just distally, a second region of aortic occlusion resulted from an obstructing aortic membrane that restricted blood flow into the descending aorta through a small, eccentric ostium. Plausibly, the AoCo contributed to high afterload which led to reduction of coronary blood flow, myocardial hypoxia, and sudden death during physical stress. Although AoCo is a well-recognized congenital defect in humans, it has been reported only rarely in animals. The present case details the gross and histologic features of a complex, juxtaductal AoCo in a dog who died suddenly after stress. These morphologic findings may be informative when contemplating diagnosis of this anomaly.

Adipositas Cordis in Two Cats with Sudden Death.

Adipositas cordis (AC) is a rare cardiomyopathy characterized by fatty infiltration of the myocardium without signs of tissue destruction or inflammation. Its diagnosis is challenging and requires histopathological examination. This study describes such cardiomyopathy in two cats that died suddenly. In both cases, anatomopathological examination showed gross lesions indicative of acute heart failure, associated with an increase in subepicardial fat, particularly in the right ventricle. Microscopically, there was an increased amount of subepicardial and intramyocardial adipose tissue in the right ventricular free wall, without signs of cellular degeneration, inflammatory infiltration, necrosis or fibrosis, confirmed by histochemical staining. AC is a rare cardiac pathology, but it should be taken into consideration in feline medicine when a sudden death occurs.

Ventricular arrhythmia and sudden cardiac death in young Leonbergers.

INTRODUCTION: To describe unexpected sudden cardiac death (SCD) in young Leonbergers (<3 years) and to review the circumstances before death and necropsy findings; to prospectively evaluate the presence of possible arrhythmias in young Leonbergers; and to examine pedigrees for determining potential modes of inheritance. ANIMALS: Postmortem evaluations included 21 Leonbergers. Clinical evaluation consisted of 46 apparently healthy Leonbergers with and without a close family history of SCD. MATERIALS AND METHODS: Necropsy reports were reviewed retrospectively. Prospective clinical evaluation included physical examination, 5-min electrocardiogram, 24-h Holter, echocardiography, and laboratory tests. Pedigree data were examined for mode of inheritance. RESULTS: Based on necropsy reports, SCD occurred at a median age of 12 months (range, 2.0-32.0 months) without any previous clinical signs and usually in rest. No evidence of structural cardiac disease was found; arrhythmia-related death was suspected. Clinical evaluation and 24-h Holter showed ventricular arrhythmia (VA) in 14 apparently healthy Leonbergers (median age, 18 months; range, 12-42 months). Severity of VA varied from infrequent couplets/triplets to frequent complexity (couplets, triplets, nonsustained ventricular tachycardias,VTs) characterized by polymorphology. During follow-up, two dogs with polymorphic VT died. Although breed specificity and high prevalence indicate a heritable disease, based on available pedigree data, the mode of inheritance could not be determined. CONCLUSIONS: Sudden cardiac death in young Leonbergers is associated with malignant VA characterized by complexity and polymorphic nature. Diagnosis is based on 24-h Holter monitoring. Pedigree analysis suggests that the arrhythmia is familial.

Structural and Physiological Imaging to Predict the Risk of Lethal Ventricular Arrhythmias and Sudden Death.

Identifying patients at risk of sudden cardiac death remains a major challenge in cardiovascular medicine. Advances in cardiovascular imaging have identified several anatomic and functional variables that can be quantified as continuous variables to predict the risk of developing lethal ventricular tachyarrhythmias in patients with depressed left ventricular (LV) systolic function. Some, such as LV mass, volume, and the dyssynchrony of contraction, can be derived from currently available echocardiographic and nuclear imaging modalities. Others require advanced cardiac imaging modalities with quantification of myocardial scar with gadolinium-enhanced cardiac magnetic resonance and myocardial sympathetic denervation using norepinephrine analogs and positron emission tomography or single-photon emission computed tomography offering the most promise. There is an immediate need to develop a sequential cost-effective approach that capitalizes on readily available clinical information complemented with advanced imaging modalities in selected patients to improve risk stratification for arrhythmic death beyond LV ejection fraction.

Sequence and expression analysis of cardiac ryanodine receptor 2 in broilers that died from sudden death syndrome.

Sudden death syndrome (SDS) is a stress-related disease in broilers with no diagnostic clinical or necropsy findings. SDS is associated with ventricular tachycardia (VT) and ventricular fibrillation (VF); however, its pathogenesis is not precisely described at the molecular level. Dysfunction of ryanodine receptor 2 (RYR2), that controls rapid release of Ca2+ from the sarcoplasmic reticulum (SR) into the cytosol during muscle contraction, has been associated with VT and sudden cardiac death (SCD) in human patients with structurally normal heart, but there is no report describing abnormalities in RYR2 in diseased broilers. In order to advance our knowledge on the molecular mechanisms predisposing broilers to fatal arrhythmia, the present study was conducted to determine the occurrence of possible mutations and changes in the expression level of the chicken RYR2 gene (chRYR2) in broilers that died from SDS. An increase in mRNA expression level and nine novel point mutations in chRYR2 were found in relation to SDS. In conclusion, susceptibility to lethal cardiac arrhythmia in SDS may be associated with specific changes in intracellular Ca2+ cycling components such as RYR2 due to mutation and dysregulation. Finding the probable association of SDS with gene defects can be applied to select for chickens with lower susceptibility to SDS and decrease the poultry industry losses due to SDS mortality. RESEARCH HIGHLIGHTS Investigation of the occurrence of possible mutations and changes in the expression level of chicken RYR2 gene (chRYR2) in broilers that died from SDS. Increase in the mRNA expression level of chRYR2 in relation to SDS. Nine novel point mutations in chRYR2 of broilers that died from SDS. Possible connection between susceptibility to lethal cardiac arrhythmia in SDS and changes in intracellular Ca2+ cycling machinery, such as RYR2, due to mutation and dysregulation.

Cardiac Pathology and Genomics of Sudden Death in Racehorses From New York and Maryland Racetracks.

Postmortem evaluation of racehorses has focused primarily on musculoskeletal injuries; however, horses also die suddenly on the track (sudden death [SD]). Although cardiac conditions are frequently suspected as a cause of death, SD racehorses are often autopsy negative; however, previous studies have been limited due to inconsistent or insufficient cardiac sampling and lack of controls. SD in New York (NY) and Maryland (MD) racehorses was evaluated in an observational case vs control study comparing clinical information, postmortem evaluation including cardiac dissection, and cardiac conduction system histopathology. In the study period, there were 40 cases of SD. In NY, SD occurred in 12% (37/316) of submissions, and 36 (11%) cases of SD were exercise associated (EASD); 3 EASD cases occurred in MD. In NY/MD EASD cases with histologic examination of the heart, 11 of 36 (31%) had significant lesions, including mesenteric artery rupture (1), axial trauma (2), systemic inflammation (2), pulmonary hemorrhage (1), and cardiac disease (5). Mild myocardial fibrosis, mild inflammation, coronary arteriosclerosis, and variation in cardiac nodal connective tissue were present in both SD cases and controls and thus were not considered to be causes of SD. While not excluding a genetic basis for SD, analysis of the genotypes (GGP Equine 70 K Array) of cases and controls did not reveal significant differences in allele frequencies at any locus. Most SD racehorses were autopsy negative; further research using standardized protocols and controls is needed to understand the underlying causes of SD, which is crucial to protecting the viability of racing.

A QIL1 Variant Associated with Ventricular Arrhythmias and Sudden Cardiac Death in the Juvenile Rhodesian Ridgeback Dog.

The QIl1 gene produces a component of the Mitochondrial Contact Site and Cristae Organizing System that forms and stabilizes mitochondrial cristae junctions and is important in cellular energy production. We previously reported a family of Rhodesian Ridgebacks with cardiac arrhythmias and sudden cardiac death. Here, we performed whole genome sequencing on a trio from the family. Variant calling was performed using a standardized bioinformatics approach. Variants were filtered against variants from 247 dogs of 43 different breeds. High impact variants were validated against additional affected and unaffected dogs. A single missense G/A variant in the QIL1 gene was associated with the cardiac arrhythmia (p < 0.0001). The variant was predicted to change the amino acid from conserved Glycine to Serine and to be deleterious. Ultrastructural analysis of the biceps femoris muscle from an affected dog revealed hyperplastic mitochondria, cristae rearrangement, electron dense inclusions and lipid bodies. We identified a variant in the Q1l1 gene resulting in a mitochondrial cardiomyopathy characterized by cristae abnormalities and cardiac arrhythmias in a canine model. This natural animal model of mitochondrial cardiomyopathy provides a large animal model with which to study the development and progression of disease as well as genotypic phenotypic relationships.

A missense variant in the titin gene in Doberman pinscher dogs with familial dilated cardiomyopathy and sudden cardiac death.

The dog provides a large animal model of familial dilated cardiomyopathy for the study of important aspects of this common familial cardiovascular disease. We have previously demonstrated a form of canine dilated cardiomyopathy in the Doberman pinscher breed that is inherited as an autosomal dominant trait and is associated with a splice site variant in the pyruvate dehydrogenase kinase 4 (PDK4) gene, however, genetic heterogeneity exists in this species as well and not all affected dogs have the PDK4 variant. Whole genome sequencing of a family of Doberman pinchers with dilated cardiomyopathy and sudden cardiac death without the PDK4 variant was performed. A pathologic missense variant in the titin gene located in an immunoglobulin-like domain in the I-band spanning region of the molecule was identified and was highly associated with the disease (p < 0.0001). We demonstrate here the identification of a variant in the titin gene highly associated with the disease in this spontaneous canine model of dilated cardiomyopathy. This large animal model of familial dilated cardiomyopathy shares many similarities with the human disease including mode of inheritance, clinical presentation, genetic heterogeneity and a pathologic variant in the titin gene. The dog is an excellent model to improve our understanding of the genotypic phenotypic relationships, penetrance, expression and the pathophysiology of variants in the titin gene.

Genetic analyses in a bonobo (Pan paniscus) with arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a disorder that may lead to sudden death and can affect humans and other primates. In 2012, the alpha male bonobo of the Milwaukee County Zoo died suddenly and histologic evaluation found features of ARVC. This study sought to discover a possible genetic cause for ARVC in this individual. We sequenced our subject's DNA to search for deleterious variants in genes involved in cardiovascular disorders. Variants found were annotated according to the human genome, following currently available classification used for human diseases. Sequencing from the DNA of an unrelated unaffected bonobo was also used for prediction of pathogenicity. Twenty-four variants of uncertain clinical significance (VUSs) but no pathogenic variants were found in the proband studied. Further familial, functional, and bonobo population studies are needed to determine if any of the VUSs or a combination of the VUSs found may be associated with the clinical findings. Future genotype-phenotype establishment will be beneficial for the appropriate care of the captive zoo bonobo population world-wide as well as conservation of the bobono species in its native habitat.

Sudden cardiac death in a dog during Holter recording-R on T phenomenon.

A 6-year-old castrated male Golden Retriever was diagnosed with severe subaortic stenosis with severe left atrial enlargement and high heart rate due to atrial fibrillation. Treatment with digoxin and diltiazem to control ventricular response rate was initiated. Ambulatory electrocardiographic monitoring (Holter monitoring) was performed at the beginning of treatment and was repeated to evaluate the patient's response to drug therapy. Drug dose adjustments were made based on response to therapy as assessed by Holter monitoring. The dog experienced sudden death at home 19 days after beginning treatment while wearing the Holter monitor. Analysis of the Holter recording revealed marked increase in number and complexity of ventricular arrhythmias. A ventricular premature complex occurring on a T wave (R on T) was noted preceding the polymorphic ventricular tachycardia. This arrhythmia immediately degenerated into ventricular fibrillation followed by asystole. This case report describes the arrhythmia that preceded cardiac arrest and reviews the risk factors that could have potentiated the fatal arrhythmia in this dog.

Unexpected Cardiac Death During Anaesthesia of a Young Rabbit Associated with Fibro-fatty Replacement of the Right Ventricular Myocardium.

A 6-month-old female pet rabbit was presented for routine ovariectomy. The pre-anaesthetic evaluation was unremarkable and no anaesthetic complications occurred during the procedure. However, at the end of the surgery, the rabbit suddenly showed acute bradycardia and cardiac death. Necropsy examination revealed marked dilation of the right ventricle, associated with diffuse thinning of the right ventricular free wall. Gross and histopathological findings were suggestive of a congenital dilated cardiomyopathy characterized by fibro-fatty replacement of the right ventricular myocardium. Similar myocardial lesions have not been previously described in rabbits, although they have been documented in myocardial diseases of man, dogs, cats, cattle, horses and chimpanzees.