Jugular Venous Response for Risk Stratification in Heart Failure.

BACKGROUND:  The response of jugular venous pressure (JVP) to increased preload with inspiration has been recognized as a method of stratifying risk in the management of heart failure (HF). Whether the JVP response to inspiration may be more effective than other simple approaches in this setting remains unclear. METHODS:  This study enrolled 79 patients with stable HF. JVP was assessed from the right internal jugular vein in the sitting position and was considered high if visible above the right clavicle at rest. JVP responses to inspiration, the five-repetition sit-to-stand test (5-STS), and squatting were also evaluated. The primary outcome was a composite of all-cause death and hospitalization for worsening HF. RESULTS:  JVP assessment after 5-STS and during squatting was not conducted in two and 14 HF patients, respectively, due to physical limitations. During a mean follow-up of 837 days, the primary outcome was associated with a high JVP at rest (hazard ratio, 2.47; 95% confidence interval [CI], 1.09 to 5.60; P <0.05), with inspiration (hazard ratio, 2.53; 95% CI, 1.17 to 5.46; P <0.05), after 5-STS (hazard ratio, 2.61; 95% CI, 1.23 to 5.97; P <0.05), and during squatting (hazard ratio, 2.40; 95% CI, 1.03 to 6.06; P <0.05). Among patients without a high JVP at rest, the specificity of the primary outcome at one year was greater for the JVP response to inspiration (89%) and squatting (92%) than for the response to 5-STS (80%). CONCLUSIONS:  JVP response to increased preload with inspiration may be a simple and practical method for risk assessment in patients with stable HF.

A Case of Sinus Venosus Atrial Septal Defect: Physical Examination as a Diagnostic Clue.

An atrial septal defect (ASD) may be detected later in life due to its asymptomatic status. We report a case of superior sinus venosus ASD, a rare type of ASD, in which bedside physical examination was useful for the diagnosis. A 72-year-old male was referred to cardiology during the treatment of a cerebral infarction. On examination, a right ventricular heave, a split-second heart sound with an increased pulmonary component, and a systolic ejection murmur in the pulmonary region were noted. Transthoracic echocardiography showed a systolic pulmonary artery pressure of 50 mmHg with right heart enlargement, but there was no shunt flow. Because an agitated saline contrast study was positive, transesophageal echocardiography was performed and demonstrated direct flow between the left atrium and superior vena cava. Our report highlights the importance of considering ASD, such as sinus venosus type, even in the absence of transthoracic echocardiographic findings suggestive of this condition, when patients present with a bedside physical examination consistent with ASD.

Infective Endocarditis Caused by Staphylococcus lugdunensis.

Staphylococcus lugdunensis, a minor species of coagulase-negative staphylococci, has attracted attention because of its formidable pathogenicity. We present a case of infective endocarditis (IE) caused by S. lugdunensis in a 72-year-old woman with a history of breast cancer and metastases who presented with fever. Two of two blood culture bottles were positive for gram-positive cocci. Transesophageal echocardiography revealed vegetation attached to the right cusp of the aortic valve and an abscess in the annulus, which was less evident on transthoracic echocardiography. This case underscores the importance of considering S. lugdunensis as a potential cause of IE.

Takotsubo cardiomyopathy induced by acute coronary syndrome: A case report.

Takotsubo cardiomyopathy (TC) can be provoked by various triggers. It should be differentiated from acute coronary syndrome (ACS). Herein, we report a case of TC triggered by ACS. An 80-year-old woman was referred to the emergency room because of prolonged chest pain and ST-segment elevations. Echocardiography demonstrated left ventricular apical ballooning, findings suggestive of TC rather than ACS. Emergency coronary angiography revealed severe stenosis of the first diagonal branch of the left anterior descending coronary artery with distal flow delay. Recanalization of the diagonal branch was achieved by stent implantation and her chest pain was resolved. Cardiac magnetic resonance imaging showed increased signal intensities in the apex and the inner layer of the anterior wall on fat-suppressed, T2-weighted imaging. The present case highlights the importance of recognizing TC in relation to ACS not only as a differential diagnosis but also as a possibly concomitant condition unless clinical features fit one diagnosis. Learning objective: Takotsubo cardiomyopathy can be provoked by various conditions and differentiated from acute coronary syndrome based on the presence or absence of coronary artery stenosis. Our case highlights the importance of acknowledging that takotsubo cardiomyopathy may be induced by acute coronary syndrome.

A Case of Docetaxel-Induced Left Ventricular Outflow Tract Obstruction.

Docetaxel, a taxoid chemotherapy agent, may induce fluid retention. We present a case of metastatic breast cancer in which high output caused by docetaxel-induced fluid retention resulted in heart failure due to left ventricular outflow tract (LVOT) obstruction. A 58-year-old woman presented with exertional dyspnea and anasarca. The jugular venous pressure was elevated, and the carotid pulse was pulsus bisferiens with a spike-and-dome configuration. On auscultation, a mid-late systolic murmur that did not radiate to the neck but increased with the Valsalva maneuver was noted. Echocardiography revealed a left ventricular ejection fraction of 63% with systolic anterior motion (SAM) of the mitral valve, resulting in LVOT obstruction with a resting pressure gradient of 64 mmHg and moderate to severe mitral regurgitation. Treatment with carvedilol, trichlormethiazide, and an increased dose of furosemide gradually improved her symptoms, physical findings, and echocardiographic abnormalities. This case highlights the importance of recognizing high-output heart failure along with LVOT obstruction in patients scheduled to receive docetaxel.

Unusual Change in Murmurs in a Case of Mitral Valve Prolapse.

Mitral valve prolapse (MVP) has changeable auscultatory features regarding the onset and amplitude with physiologic and pharmacologic maneuvers. We report a case of MVP in which not only the onset and amplitude of systolic murmurs but also the endpoint of systolic murmurs were dynamically altered according to preload. An asymptomatic 61-year-old man presented with a grade 3 crescendo murmur best heard at the apex, which started in the mid-systole without a click, and lasted up to the second sound. A diagnosis of moderate to severe mitral regurgitation due to MVP of P2 scallop was confirmed by echocardiography. At his regular follow-up visit, changes in cardiac auscultation were recognized although the patient was still asymptomatic. A grade 2, high-pitched crescendo murmur, which was softer than the previous findings, started immediately after the first sound and ended approximately 100 ms before the second sound on phonocardiography. On echocardiography, the severity of mitral regurgitation was abated in comparison with the previous findings, and mitral regurgitation abruptly ended in mid-systole but continued to the end of systole during increased preload due to an elevation of the legs. The present case highlights the importance of careful auscultation to estimate hemodynamic conditions in patients with MVP.

Jugular Venous Pressure Response to Inspiration for Risk Assessment of Heart Failure.

Simplifying jugular venous pressure (JVP), visibility of the right internal jugular vein above the right clavicle in the sitting position, has been proposed in the management of heart failure (HF) because of its convenience. However, this method may be undervalued for the detection of mildly to moderately increased JVP. Increased JVP on inspiration, known as Kussmaul sign, may be a useful physical finding in this condition. This study consisted of 138 patients who were admitted for the management of HF. Using this simple method, JVP was assessed at rest in the sitting position before discharge; its response to inspiration was also examined if no high JVP was noted at rest. The primary outcome was a composite of cardiac death and hospitalization for worsening HF. Among all the patients, 16 patients (12%) had high JVP at rest and another 16 patients (12%) had high JVP not at rest but on inspiration. During a follow-up period of 249 ± 182 days, a primary outcome event occurred in 63 patients (46%). The incidence of adverse cardiac events was higher in patients with a high JVP at rest (69%; hazard ratio 3.31, 95% confidence interval 1.64 to 6.67, p = 0.0009) and in patients with a high JVP on inspiration (56%; hazard ratio 2.18, 95% confidence interval 1.02 to 4.63, p = 0.043) than in patients without a high JVP in both conditions (41%). In conclusion, a high JVP not only at rest but also on inspiration was associated with a poor prognosis. The response of JVP to inspiration using this simple technique of physical examination may be a new approach in the management of HF.

Constrictive pericarditis after SARS-CoV-2 vaccination: A case report.

Coronavirus disease 2019 (COVID-19) and vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with cardiovascular complications. Here, we report a case of right-sided heart failure caused by constrictive pericarditis that developed after the administration of messenger ribonucleic acid (mRNA) vaccine against SARS-CoV-2. A 70-year-old woman presented with body weight gain, peripheral edema, and dyspnea on effort, which developed over a period of 1 week after the second dose of vaccine. The jugular venous pressure was high with a prominent y descent (Friedreich's sign) and paradoxical increase on inspiration (Kussmaul's sign). The results of IgM and IgG testing specific to SARS-CoV-2 spike and nucleocapsid proteins indicated the presence of mRNA vaccine-induced antibody and were not suggestive of COVID-19 infection. Echocardiography showed pericardial thickening and septal bounce of the interventricular septum. Computed tomography (CT) also showed pericardial thickening compared with the results of the previous CT scan performed 4 months earlier. A diagnosis of right-sided heart failure due to constrictive pericarditis was confirmed on the basis of pressure analysis during cardiac catheterization.

Impaired Left Ventricular Contractile Reserve in Patients With Hypertrophic Cardiomyopathy and Abnormal Blood Pressure Response: A Stress Echocardiographic Study.

BACKGROUND: Abnormal blood pressure response (ABPR) has been reported to be a risk factor for sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM). We aimed to elucidate the relationship between ABPR during exercise stress echocardiography (ESE) and impaired left ventricular (LV) contractile reserve based on two-dimensional strain in patients with HCM. METHODS: Patients with HCM underwent ESE with treadmill exercise. Patients whose blood pressure elevation at maximum workload was lower than 20 mmHg from baseline were classified as having ABPR. Echocardiographic parameters were compared between patients with and without ABPR.  Results: Of 26 patients with HCM, nine patients were diagnosed with ABPR. Significant LV outflow tract obstruction (>50 mmHg) was provoked only in one patient with ABPR (baseline to the conclusion of the exercise, 15.2 mmHg to 63.0 mmHg). Change in cardiac output (CO) and the ratio of early diastolic velocity to early annular velocity (E/e') from baseline to just after the conclusion of exercise did not differ between patients with and without ABPR (CO, 102±40% vs. 122±45%, P = 0.19; E/e', 4±22% vs. 2±20%, P = 0.86). Change in systemic vascular resistance change was not significant (patients with vs. without ABPR, -52±10% vs. -46±13%, P = 0.24). Percent change in LV global longitudinal strain was lower in patients with ABPR than patients without ABPR (12±17% vs. 27±15%, P = 0.02). CONCLUSION: In conclusion, impaired LV contractile reserve during exercise might contribute to ABPR in patients with HCM.

Cellular senescence promotes endothelial activation through epigenetic alteration, and consequently accelerates atherosclerosis.

Senescent vascular cells are detected in atherosclerotic lesion, and its involvement in the development of atherosclerosis has been revealed; however, whether and the mechanism by which endothelial cell (EC) senescence is causally implicated in atherosclerosis remains unclear. We here investigate a role of EC senescence in atherosclerosis by utilizing EC-specific progeroid mice that overexpress the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 or vascular endothelial cadherin promoter. EC-specific progeria accelerated atherosclerosis in mice with target deletion of ApoE. Mechanistically, senescent ECs were markedly sensitive for inflammation-mediated VCAM-1 induction, leading to enhanced monocyte adhesion. Inhibition of NF-κB signaling abolished the enhanced inflammatory responses in senescent ECs, while NF-κB nuclear translocation in response to TNF-α were similar between young and senescent ECs. We found a higher association of VCAM-1 gene with active histone H3 trimethylated on lysine 4, leading to increased NF-κB accessibility in senescent ECs. Our data revealed that EC cellular senescence causes endothelial hyper-inflammability through epigenetic alteration, which consequently accelerates atherosclerosis. Therefore, EC senescence is a promising therapeutic target for the prevention and/or treatment of atherosclerotic disease in elderly population.

TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension.

Yamanaka R, Hoshino A, Fukai K, Urata R, Minami Y, Honda S, Fushimura Y, Hato D, Iwai-Kanai E, Matoba S. TIGAR reduces smooth muscle cell autophagy to prevent pulmonary hypertension. Am J Physiol Heart Circ Physiol 319: H1087-H1096, 2020. First published September 18, 2020; doi:10.1152/ajpheart.00314.2020.-Pulmonary arterial hypertension (PAH) is a refractory disease. Its prognosis remains poor; hence, establishment of novel therapeutic targets is urgent. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53 and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). Recently, p53 was shown to suppress PAH progression. Because inhibition of autophagy and ROS is known to improve PAH, we examined the effect of TIGAR on PAH progression. We compared pulmonary hypertension (PH) development between TIGAR-deficient knockout (KO) and wild-type (WT) mice using a hypoxia-induced PH model. Human pulmonary artery smooth muscle cells (PASMCs) were used for in vitro experiments with small interfering RNA (siRNA) to investigate the possible molecular mechanisms. From the analysis of right ventricular pressure, right ventricular weight, and mortality rate, we concluded that the hypoxia-induced PH development was remarkably higher in TIGAR KO than in WT mice. Pathological investigation revealed that medial thickening of the pulmonary arterioles and cell proliferation were increased in TIGAR KO mice. Autophagy and ROS activity were also increased in TIGAR KO mice. TIGAR knockdown by siRNA increased cell proliferation and migration, exacerbated autophagy, and increased ROS generation during hypoxia. Autophagy inhibition by chloroquine and ROS inhibition by N-acetylcysteine attenuated the proliferation and migration of PASMCs caused by TIGAR knockdown and hypoxia exposure. TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS and, therefore, improved hypoxia-induced PH. Thus, TIGAR might be a promising therapeutic target for PAH.NEW & NOTEWORTHY Pulmonary arterial hypertension is a refractory disease. TP53-induced glycolysis and apoptosis regulator (TIGAR) is a downstream target of p53 and exhibits functions inhibiting autophagy and reactive oxygen species (ROS). By using TIGAR-deficient knockout mice and human pulmonary artery smooth muscle cells, we found that TIGAR suppressed the proliferation and migration of PASMCs via inhibiting autophagy and ROS and, therefore, improved hypoxia-induced PH. TIGAR will be a promising therapeutic target for PAH.

Publisher Correction: Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Endothelial progeria induces adipose tissue senescence and impairs insulin sensitivity through senescence associated secretory phenotype.

Vascular senescence is thought to play a crucial role in an ageing-associated decline of organ functions; however, whether vascular senescence is causally implicated in age-related disease remains unclear. Here we show that endothelial cell (EC) senescence induces metabolic disorders through the senescence-associated secretory phenotype. Senescence-messaging secretomes from senescent ECs induced a senescence-like state and reduced insulin receptor substrate-1 in adipocytes, which thereby impaired insulin signaling. We generated EC-specific progeroid mice that overexpressed the dominant negative form of telomeric repeat-binding factor 2 under the control of the Tie2 promoter. EC-specific progeria impaired systemic metabolic health in mice in association with adipose tissue dysfunction even while consuming normal chow. Notably, shared circulation with EC-specific progeroid mice by parabiosis sufficiently transmitted the metabolic disorders into wild-type recipient mice. Our data provides direct evidence that EC senescence impairs systemic metabolic health, and thus establishes EC senescence as a bona fide risk for age-related metabolic disease.

A Case of Isolated Septal Myocardial Infarction: Myocardial Perfusion-metabolism Mismatch as a Tool for Diagnosis.

Isolated septal myocardial infarction is an uncommon condition with diagnostic difficulty due to small infarction size and anatomical variations. We report a case of isolated septal myocardial infarction, in which the diagnosis was confirmed not by electrocardiographic, echocardiographic, or angiographic findings, but by nuclear imaging. A 46-year-old man with chest discomfort exhibited ST-segment elevations in leads V1 and V2, and borderline abnormalities of the septal wall motion on echocardiography. Emergency coronary angiography demonstrated delayed flow in the second septal branch of the left anterior descending coronary artery. Intravascular ultrasound showed plaque in the proximal portion of the septal branch without evidence of plaque rupture. No balloon angioplasty or stent implantation was required because the flow delay in the septal branch disappeared after the intravascular ultrasound procedure. Myocardial perfusion-metabolism mismatch, as assessed by resting thallium-201 and iodine-123-beta-methyl-p-iodophenyl-pentadecanoic acid, was seen in the mid-septal region.

Third and Fourth Heart Sounds and Myocardial Fibrosis in Hypertrophic Cardiomyopathy.

BACKGROUND: The 4th heart sound (S4) is commonly heard in patients with hypertrophic cardiomyopathy (HCM). The 3rd heart sound (S3) is also audible in HCM patients regardless of the presence or absence of heart failure. These extra heart sounds may be associated with myocardial fibrosis because myocardial fibrosis has been suggested to affect left ventricular compliance.Methods and Results:The present retrospective study evaluated 53 consecutive HCM patients with sinus rhythm who had no symptoms of heart failure and underwent an initial assessment including phonocardiography, echocardiography, and late gadolinium enhancement (LGE) magnetic resonance imaging (MRI). S3 was detected on phonocardiography in 13% of all patients, and S4 was recorded in 75% of patients. Patients with S3 had a higher incidence of LGE and larger LGE volumes (86% and 11.5±2.4 g/cm, respectively) than patients without S3 (33% and 2.5±0.8 g/cm, respectively; P=0.02 and P=0.002). The presence of S4 was not associated with MRI findings, including the incidence of LGE and LGE volume. The diagnostic value of S3 for the detection of LGE was highly specific (97%), with a low sensitivity (29%). CONCLUSIONS: Myocardial fibrosis, as assessed by LGE, was associated with S3 but not with S4 in patients with HCM. These results may contribute to the risk stratification of patients with HCM.

Cardiac-Specific Bdh1 Overexpression Ameliorates Oxidative Stress and Cardiac Remodeling in Pressure Overload-Induced Heart Failure.

BACKGROUND: Energy starvation and the shift of energy substrate from fatty acids to glucose is the hallmark of metabolic remodeling during heart failure progression. However, ketone body metabolism in the failing heart has not been fully investigated. METHODS AND RESULTS: Microarray data analysis and mitochondrial isobaric tags for relative and absolute quantification proteomics revealed that the expression of D-ß-hydroxybutyrate dehydrogenase I (Bdh1), an enzyme that catalyzes the NAD+/NADH coupled interconversion of acetoacetate and ß-hydroxybutyrate, was increased 2.5- and 2.8-fold, respectively, in the heart after transverse aortic constriction. In addition, ketone body oxidation was upregulated 2.2-fold in transverse aortic constriction hearts, as determined by the amount of 14CO2 released from the metabolism of [1-14C] ß-hydroxybutyrate in isolated perfused hearts. To investigate the significance of this augmented ketone body oxidation, we generated heart-specific Bdh1-overexpressing transgenic mice to recapitulate the observed increase in basal ketone body oxidation. Bdh1 transgenic mice showed a 1.7-fold increase in ketone body oxidation but did not exhibit any differences in other baseline characteristics. When subjected to transverse aortic constriction, Bdh1 transgenic mice were resistant to fibrosis, contractile dysfunction, and oxidative damage, as determined by the immunochemical detection of carbonylated proteins and histone acetylation. Upregulation of Bdh1 enhanced antioxidant enzyme expression. In our in vitro study, flow cytometry revealed that rotenone-induced reactive oxygen species production was decreased by adenovirus-mediated Bdh1 overexpression. Furthermore, hydrogen peroxide-induced apoptosis was attenuated by Bdh1 overexpression. CONCLUSIONS: We demonstrated that ketone body oxidation increased in failing hearts, and increased ketone body utilization decreased oxidative stress and protected against heart failure.

Rhabdomyolysis after High Intensity Resistance Training.

Rhabdomyolysis, which is a characteristic occurrence in associated with muscle cell necrosis, develops due to various causes. We herein report a rare case of a patient with rhabdomyolysis after high intensity resistance training, in which markedly elevated levels of serum creatine kinase (CK) and urine myoglobin were observed. A previously healthy 37-year-old man presented with severe myalgia and dark urine after performing high-intensity exercise. The patient's serum CK level was 95,100 U/L and his urine myoglobin level was 160,000 ng/mL. His symptoms and laboratory findings gradually improved with the intravenous administration of saline and no complications (including electrolyte imbalance and acute renal failure) developed.