S-Nitrosylation of Histone Deacetylase 2 by Neuronal Nitric Oxide Synthase as a Mechanism of Diastolic Dysfunction.

BACKGROUND: Although the clinical importance of heart failure with preserved ejection fraction has been extensively explored, most therapeutic regimens, including nitric oxide (NO) donors, lack therapeutic benefit. Although the clinical characteristics of heart failure with preserved ejection fraction are somewhat heterogeneous, diastolic dysfunction (DD) is one of the most important features. Here we report that neuronal NO synthase (nNOS) induces DD by S-nitrosylation of HDAC2 (histone deacetylase 2). METHODS: Two animal models of DD-SAUNA (SAlty drinking water/Unilateral Nephrectomy/Aldosterone) and mild transverse aortic constriction mice-as well as human heart samples from patients with left ventricular hypertrophy were used. Genetically modified mice that were either nNOS-ablated or HDAC2 S-nitrosylation-resistant were also challenged. N(ω)-propyl-L-arginine, an nNOS selective inhibitor, and dimethyl fumarate, an NRF2 (nuclear factor erythroid 2-related factor 2) inducer, were used. Molecular events were further checked in human left ventricle specimens. RESULTS: SAUNA or mild transverse aortic constriction stress impaired diastolic function and exercise tolerance without overt systolic failure. Among the posttranslational modifications tested, S-nitrosylation was most dramatically increased in both models. Utilizing heart samples from both mice and humans, we observed increases in nNOS expression and NO production. N(ω)-propyl-L-arginine alleviated the development of DD in vivo. Similarly, nNOS knockout mice were resistant to SAUNA stress. nNOS-induced S-nitrosylation of HDAC2 was relayed by transnitrosylation of GAPDH. HDAC2 S-nitrosylation was confirmed in both DD mouse and human left ventricular hypertrophy. S-nitrosylation of HDAC2 took place at C262 and C274. When DD was induced, HDAC2 S-nitrosylation was detected in wild-type mouse, but not in HDAC2 knock-in mouse heart that expressed HDAC2 C262A/C274A. In addition, HDAC2 C262A/C274A mice maintained normal diastolic function under DD stimuli. Gene delivery with adenovirus-associated virus 9 (AAV9)-NRF2, a putative denitrosylase of HDAC2, or pharmacological intervention by dimethyl fumarate successfully induced HDAC2 denitrosylation and mitigated DD in vivo. CONCLUSIONS: Our observations are the first to demonstrate a new mechanism underlying DD pathophysiology. Our results provide theoretical and experimental evidence to explain the ineffectiveness of conventional NO enhancement trials for improving DD with heart failure symptoms. More important, our results suggest that reduction of NO or denitrosylation of HDAC2 may provide a new therapeutic platform for the treatment of refractory heart failure with preserved ejection fraction.

Murmurs other than the early diastolic murmur in aortic dissection.

The purpose of this review is to draw attention to the presence and significance of murmurs other than the murmur of aortic regurgitation, in patients with aortic dissection. For that purpose, a literature search was conducted using Pubmed and Googlescholar. The search terms were "dissecting aneurysm of the aorta", "systolic murmurs", "ejection systolic murmurs", "holosystolic" murmurs, "continuous murmurs", and "Austin-Flint" murmur. Murmurs other than the murmur of aortic regurgitation, which were associated with aortic dissection, fell into the categories of systolic murmurs, some of which were holosystolic, and continuous murmurs, the latter attributable to fistulae between the dissecting aneurysm and the left atrium, right atrium, and the pulmonary artery, respectively. Mid-diastolic murmurs were also identified, and these typically occurred in association with both the systolic and the early diastolic murmurs. Among patients with systolic murmurs clinical features which enhanced the pre-test probability of aortic dissection included back pain, stroke, paraplegia, unilateral absence of pulses, interarm differences in blood pressure, hypertension, shock, bicuspid aortic valve, aortic coarctation, Turner's syndrome, and high D-dimer levels, respectively. In the absence of the murmur of aortic regurgitation timely diagnosis of aortic dissection could be expedited by increased attention to parameters which enhance pretest probability of aortic dissection. That logic would apply even if the only murmurs which were elicited were systolic murmurs.

Identifying cardiogenic shock in the emergency department.

INTRODUCTION: Cardiogenic shock is difficult to diagnose due to diverse presentations, overlap with other shock states (i.e. sepsis), poorly understood pathophysiology, complex and multifactorial causes, and varied hemodynamic parameters. Despite advances in interventions, mortality in patients with cardiogenic shock remains high. Emergency clinicians must be ready to recognize and start appropriate therapy for cardiogenic shock early. OBJECTIVE: This review will discuss the clinical evaluation and diagnosis of cardiogenic shock in the emergency department with a focus on the emergency clinician. DISCUSSION: The most common cause of cardiogenic shock is a myocardial infarction, though many causes exist. It is classically diagnosed by invasive hemodynamic measures, but the diagnosis can be made in the emergency department by clinical evaluation, diagnostic studies, and ultrasound. Early recognition and stabilization improve morbidity and mortality. This review will focus on identification of cardiogenic shock through clinical examination, laboratory studies, and point-of-care ultrasound. CONCLUSIONS: The emergency clinician should use the clinical examination, laboratory studies, electrocardiogram, and point-of-care ultrasound to aid in the identification of cardiogenic shock. Cardiogenic shock has the potential for significant morbidity and mortality if not recognized early.

Does Echocardiography Have a Role in the Cardiologist's Diagnosis of Innocent Murmurs in Childhood?

BACKGROUND: Innocent murmurs are common in childhood. Echocardiography may diagnose almost all congenital cardiac abnormalities. Earlier studies have suggested that it may be unnecessary when a clinical diagnosis of an innocent murmur is made by an experienced cardiologist. Yet, echocardiography is commonly performed despite such a diagnosis. Is that justifiable? METHODS: Patients referred to a paediatric cardiologist for evaluation of a murmur were assessed. If an innocent murmur was clinically diagnosed, an echocardiogram and an electrocardiogram were ordered when requested. The cardiologist completed a questionnaire documenting the reasons for the investigations and his degree of confidence in the clinical diagnosis. The parents and patients were informed of the diagnosis and the results of the investigations. RESULTS: In almost all 62 cases whose murmurs were clinically considered to be innocent, the referring doctor expected an echocardiogram to be performed. Following echocardiography, one patient was found to have a small muscular ventricular septal defect. On review, the murmur was consistent with that diagnosis. Three (3) others had abnormal echocardiograms namely congenitally corrected transposition of great arteries, partial anomalous right upper lobe pulmonary vein, and left ventricular non-compaction. All on review were still considered clinically to have innocent murmurs. CONCLUSIONS: Despite the competency of the cardiologist, echocardiography diagnosed important but relatively uncommon cardiac abnormalities with prognostic implications that would have been missed if only the clinical examination was performed. Over and above the referring doctor's expectations for an echocardiogram to be performed is the need for the cardiologist to provide a complete and definitive diagnosis.

Assessment of the Cardiovascular System in Horses During Prepurchase and Insurance Examinations.

Arrhythmias detected on prepurchase examination should be confirmed with an ECG. Exercising ECG determines if the arrhythmia is overdriven during exercise or is a safety concern. An echocardiogram is needed in all horses with a grade 3/6 or louder mid to late systolic, holosystolic, or pansystolic murmur or any holodiastolic decrescendo murmur to identify the cardiac abnormality and its hemodynamic impact. Most horses with arrhythmias and murmurs have a normal performance career and life expectancy and are insurable. Risks for sudden death and congestive heart failure associated with the common murmurs and arrhythmias are identified, because these horses cannot be insured.

An automatic segmentation method for heart sounds.

BACKGROUND: There are two major challenges in automated heart sound analysis: segmentation and classification. An efficient segmentation is capable of providing valuable diagnostic information of patients. In addition, it is crucial for some feature-extraction based classification methods. Therefore, the segmentation of heart sound is of significant value. METHODS: This paper presents an automatic heart sound segmentation method that combines the time-domain analysis, frequency-domain analysis and time-frequency-domain analysis. Employing this method, the boundaries of heart sound components are first located, and the components are then recognized. Finally, the heart sounds are divided into several segments on the basis of the results of boundary localization and component identification. RESULTS: In order to evaluate the performance of the proposed method, quantitative experiments are performed on an authoritative heart sound database. The experimental results show that the boundary localization has a sensitivity (Se) of 100%, a positive predictive value (PPV) of 99.3% and an accuracy (Acc) of 99.93%. Moreover, the Se, PPV and Acc of component identification reach 98.63, 99.86 and 98.49%, respectively. CONCLUSION: The proposed method shows reliable performance on the segmentation of heart sounds. Compared with previous works, this method can be applied to not only normal heart sounds, but also the sounds with S3, S4 and murmurs, thus greatly increasing the applied range.

Reversed Rivero-Carvallo's sign confirmed by blood flow analysis using cardiac magnetic resonance imaging in a patient with straight back syndrome.

An asymptomatic 45-year-old man was referred to our hospital for detailed evaluation of a systolic ejection murmur. The intensity of the murmur increased on deep expiration and decreased on deep inspiration, showing so-called reversed Rivero-Carvallo's sign. Using cardiac magnetic resonance imaging, we demonstrated a characteristic respiratory-induced change in peak flow velocity in the right ventricular outflow tract, which was the basic mechanism of the reversed Rivero-Carvallo's sign in a case with straight back syndrome. Concomitant anatomical changes in the entire heart in relation to the thoracic cage were also clarified.

Altered mitral inflow orifice in severe aortic regurgitation: real time three-dimensional echocardiographic findings.

We present the case of a young man with severe eccentric aortic regurgitation, obstructing mitral inflow and provoking an audible Austin Flint murmur at clinical examination. Two-dimensional color Doppler echocardiography depicts the remarkable mechanical interaction between aortic regurgitant jet and anterior mitral leaflet opening. Three-dimensional transesophageal echocardiography aids in understanding the geometric and hemodynamic consequences of the regurgitant jet and in the genesis of the Austin Flint murmur. This case accentuates the incremental value of three-dimensional echocardiography when evaluating valvular pathology, and offers more insight in the interaction between aortic regurgitant flow and mitral leaflet dynamics.

[Cardiac auscultation in children]. / L'auscultazione cardiaca nel bambino.

Cardiac auscultation permits to distinguish between the innocent heart murmurs and pathologic murmurs; characteristics of pathologic murmurs include a holosystolic or diastolic murmur, maximal murmur intensity at the upper left sternal border and increased intensity when the patient stands. Murmurs should be described by their timing in the cardiac cycle, intensity, shape, pitch, location, radiation, and response to dynamic maneuvers. When the medical history and physical examination support the diagnosis of innocent heart murmur, neither further investigation nor referal is indicated. On the contrary, echocardiography is recommended for patients with any other abnormal physical examination findings that increase the likelihood of structural heart disease. In this review we discuss the definition and classification of murmurs, how to evaluate it.

Identifying pediatric heart murmurs and distinguishing innocent from pathologic using deep learning.

OBJECTIVE: To develop a deep learning algorithm to perform multi-class classification of normal pediatric heart sounds, innocent murmurs, and pathologic murmurs. METHODS: We prospectively enrolled children under age 18 being evaluated by the Division of Pediatric Cardiology. Parents provided consent for a deidentified recording of their child's heart sounds with a digital stethoscope. Innocent murmurs were validated by a pediatric cardiologist and pathologic murmurs were validated by echocardiogram. To augment our collection of normal heart sounds, we utilized a public database of pediatric heart sound recordings (Oliveira, 2022). We propose two novel approaches for this audio classification task. We train a vision transformer on either Markov transition field or Gramian angular field image representations of the frequency spectrum. We benchmark our results against a ResNet-50 CNN trained on spectrogram images. RESULTS: Our final dataset consisted of 366 normal heart sounds, 175 innocent murmurs, and 216 pathologic murmurs. Innocent murmurs collected include Still's murmur, venous hum, and flow murmurs. Pathologic murmurs included ventricular septal defect, tetralogy of Fallot, aortic regurgitation, aortic stenosis, pulmonary stenosis, mitral regurgitation and stenosis, and tricuspid regurgitation. We find that the Vision Transformer consistently outperforms the ResNet-50 on all three image representations, and that the Gramian angular field is the superior image representation for pediatric heart sounds. We calculated a one-vs-rest multi-class ROC curve for each of the three classes. Our best model achieves an area under the curve (AUC) value of 0.92 ± 0.05, 0.83 ± 0.04, and 0.88 ± 0.04 for identifying normal heart sounds, innocent murmurs, and pathologic murmurs, respectively. CONCLUSION: We present two novel methods for pediatric heart sound classification, which outperforms the current standard of using a convolutional neural network trained on spectrogram images. To our knowledge, we are the first to demonstrate multi-class classification of pediatric murmurs. Multiclass output affords a more explainable and interpretable model, which can facilitate further model improvement in the downstream model development cycle and enhance clinician trust and therefore adoption.

Cardiac murmurs in children.

BACKGROUND: Approximately 50% of children experience a cardiac murmur at some point in their lives; <1% of these murmurs are attributed to congenital heart disease (CHD). Cardiac murmur might be the first clinical sign of a significant CHD in children. Despite careful routine medical examinations at birth, approximately 50% of CHD cases could remain unrecognised. OBJECTIVE: Cardiovascular symptoms and signs could be specific or non-specific in neonates and children with heart murmurs. Knowledge about red flags in history and physical examinations, and syndromic associations of common CHDs are important. Auscultatory skills to identify systolic, diastolic and continuous murmurs and heart sounds are essential. Differential diagnosis should be formulated based on the location of maximum intensity of murmurs. Younger infants and children with pathological murmurs and red-flag signs should be promptly referred to local paediatric cardiology services for further investigations. DISCUSSION: Significant skill and knowledge are required for the identification of critical murmurs and associated cardiovascular problems. This review provides a simplified comprehensive update on cardiac murmurs and associated conditions in neonates and children.

Asymptomatic pediatric pulmonic valve myxoma involving the right ventricular outflow tract: a case report and review of the literature.

Asymptomatic pediatric pulmonic valve myxoma involving the right ventricular out flow tract (RVOT) is very rare. The case is presented of 13-year-old asymptomatic boy who was referred to the cardiology clinic for evaluation of murmur, and was found to have a large mobile mass (3 x 2 cm) in the RVOT that protruded into the pulmonary artery across the pulmonary valve during systole, and relocated in the right ventricle in diastole. The patient underwent successful surgical excision of the tumor, which had a short stalk attached to the pulmonary valve. Macroscopic examination revealed a typical myxoma without any evidence of malignancy. This case elaborates the importance of early recognition and surgical excision of these tumors in order to prevent thromboembolic complications.

Inactive Lifestyles Among Young Children With Innocent Murmurs or Congenital Heart Disease, Regardless of Disease Severity or Treatment.

BACKGROUND: Sedentary lifestyle morbidities are common among children with congenital heart disease (CHD). Understanding the physical activity trajectory from early childhood could enhance timing and effectiveness of interventions. METHODS: We recruited 154 children (56% male) at 12 to 47 months of age for this prospective, longitudinal, observational study. Physical activity and sedentary behaviour (7-day accelerometry) and motor skill (Peabody Developmental Motor Scales-2) were assessed every 8 months until 5 years of age and then annually. Mixed-effect repeated measures regression models described outcome trajectories across study assessments. RESULTS: Children had innocent heart murmurs (n = 28), CHD with insignificant hemodynamics not requiring treatment (n = 47), CHD treated by catheterization or surgery without cardiopulmonary bypass (n = 31), or CHD treated surgically with bypass (n = 48). Motor skill was age appropriate (Peabody 49.0 ± 8.4), but participants had lower physical activity (143 ± 41 minutes per day) and higher sedentary time (598 ± 89 minutes per day) than healthy peers, starting at 18 months of age. Movement behaviours were not related to treatment group (P > 0.10), and physical activity was below the recommended 180 minutes per day. Over time, physical activity, sedentary time, and motor skills were primarily related to the baseline measure of each outcome (P < 0.001). CONCLUSIONS: Children with simple or complex CHD or innocent heart murmurs have increased risk for sedentary lifestyles. Their physical activity and sedentary behaviours are established before 2 years of age, persist until school age, and are unrelated to motor skills. These results emphasize the need for interventions targeting the youngest children seen in cardiac clinics, regardless of diagnoses of CHD or innocent murmur.

Evaluation of Cardiac Function Characteristics after Patent Ductus Arteriosus Closure in Children and Adults by Echocardiographic Data.

This study was to investigate the value of echocardiographic data in assessing changes in cardiac function before and after transcatheter closure in children and adult patients with patent ductus arteriosus (PDA). In this study, 150 patients with isolated PDA treated by cardiac catheterization and transcatheter closure were selected as the study sample. Real-time color Doppler echocardiography was used both after and after operation. The results showed that the left ventricle returned to normal in 75 patients one day after operation, with an average age of 10.95 ± 3.27 years; the left ventricle did not return to normal in 10 patients 360 days after operation, with an average age of 64.31 ± 7.05 years. Left ventricular end diastolic volume index (LVEDVI) and left ventricular end systolic volume index (LVESVI) of patients decreased significantly one day after operation and remained at 51.95 ± 9.55 mL/m2 and 20.36 ± 8.11 mL/m-2, respectively. In summary, echocardiographic data have a high reference value in assessing cardiac function characteristics in children and adult patients with PDA and are worthy of further promotion.

Digital Subtraction Phonocardiography (DSP) applied to the detection and characterization of heart murmurs.

BACKGROUND: During the cardiac cycle, the heart normally produces repeatable physiological sounds. However, under pathologic conditions, such as with heart valve stenosis or a ventricular septal defect, blood flow turbulence leads to the production of additional sounds, called murmurs. Murmurs are random in nature, while the underlying heart sounds are not (being deterministic). INNOVATION: We show that a new analytical technique, which we call Digital Subtraction Phonocardiography (DSP), can be used to separate the random murmur component of the phonocardiogram from the underlying deterministic heart sounds. METHODS: We digitally recorded the phonocardiogram from the anterior chest wall in 60 infants and adults using a high-speed USB interface and the program Gold Wave http://www.goldwave.com. The recordings included individuals with cardiac structural disease as well as recordings from normal individuals and from individuals with innocent heart murmurs. Digital Subtraction Analysis of the signal was performed using a custom computer program called Murmurgram. In essence, this program subtracts the recorded sound from two adjacent cardiac cycles to produce a difference signal, herein called a "murmurgram". Other software used included Spectrogram (Version 16), GoldWave (Version 5.55) as well as custom MATLAB code. RESULTS: Our preliminary data is presented as a series of eight cases. These cases show how advanced signal processing techniques can be used to separate heart sounds from murmurs. Note that these results are preliminary in that normal ranges for obtained test results have not yet been established. CONCLUSIONS: Cardiac murmurs can be separated from underlying deterministic heart sounds using DSP. DSP has the potential to become a reliable and economical new diagnostic approach to screening for structural heart disease. However, DSP must be further evaluated in a large series of patients with well-characterized pathology to determine its clinical potential.

Accuracy of cardiac auscultation in asymptomatic neonates with heart murmurs: comparison between pediatric trainees and neonatologists.

The aim of this study was to assess whether cardiac auscultation performed by pediatric trainees and neonatologists can reliably distinguish innocent from pathologic heart murmurs in asymptomatic neonates. From January 2008 to April 2009 the pediatric trainees of our institution were requested to refer all asymptomatic neonates with a murmur and classify the murmurs as "innocent," "pathologic," or "possibly pathologic." Prior to echocardiography, each neonate was evaluated by two experienced neonatologists. The echocardiographic studies of 169 neonates were analyzed. Abnormal cardiac anatomy was found in 55 neonates (32.6%). The overall ability of pediatric trainees in identifying congenital heart disease (CHD) was moderate [area under the curve (AUC) = 0.855] and significantly lower compared to neonatologists (AUC = 0.919, p = 0.007). However, at "lower" levels of clinical confidence (i.e., clinical diagnosis of possibly pathologic murmurs), pediatric trainees had good ability in excluding CHD (sensitivity 94.6%; negative likelihood ratio = 0.09). The ability of cardiac auscultation for diagnosing CHD in asymptomatic neonates is limited and dependent on the physician's experience and level of clinical confidence. Echocardiography should remain an option for all neonates with a possibly pathologic murmur.