Association between QRS voltages and amyloid burden in patients with cardiac amyloidosis.

PRKAG2 Gene Mutation Indicating Myocardial Hypertrophy and Wolff-Parkinson-White Syndrome in a 28-Year-Old Woman.

Association between left atrial myopathy and sarcomere mutation in patients with hypertrophic cardiomyopathy: insights into left atrial strain by MRI feature tracking.

OBJECTIVES:Left atrial (LA) myopathy, characterized by LA enlargement and mechanical dysfunction, is associated with worse prognosis in hypertrophic cardiomyopathy (HCM) while the impact of sarcomere mutation on LA myopathy remains unclear. We aimed to assess the association between LA myopathy and sarcomere mutation and to explore the incremental utility of LA strain in mutation prediction.METHODS:A total of 105 consecutive HCM patients (mean age 47.8 ± 11.9 years, 71% male) who underwent HCM-related gene screening and cardiac MRI were retrospectively enrolled. LA volume, ejection fraction and strain indices in reservoir, conduit, and booster-pump phases were investigated respectively.RESULTS:Fifty mutation-positive patients showed higher LA maximal volume index (59.4 ± 28.2 vs 43.8 ± 18.1 mL/m2, p = 0.001), lower reservoir (21.3 ± 7.9 vs 26.2 ± 6.6%, p < 0.001), and booster-pump strain (12.1 ± 5.4 vs 17.1 ± 5.0%, p < 0.001) but similar conduit strain (9.2 ± 4.5 vs 9.1 ± 4.5%, p = 0.909) compared with mutation-negative patients. In multivariate logistic regression, LA booster-pump strain was associated with sarcomere mutation (odds ratio = 0.86, 95% confidence interval: 0.77-0.96, p = 0.010) independent of maximal wall thickness, late gadolinium enhancement, and LA volume. Furthermore, LA booster-pump strain showed incremental value for mutation prediction added to Mayo II score (AUC 0.798 vs 0.709, p = 0.024).CONCLUSIONS:In HCM, mutation-positive patients suffered worse LA enlargement and worse reservoir and booster-pump functions. LA booster-pump strain was a strong factor for sarcomere mutation prediction added to Mayo II score.CLINICAL RELEVANCE STATEMENT:The independent association between sarcomere mutation and left atrial mechanical dysfunction provide new insights into the pathogenesis of atrial myopathy and is helpful to understand the adverse prognosis regarding atrial fibrillation and stroke in mutation-positive patients.KEY POINTS:• In patients with hypertrophic cardiomyopathy, left atrial (LA) reservoir and booster-pump function, but not conduit function, were significantly impaired in mutation-positive patients compared with mutation-negative patients. • LA booster-pump strain measured by MRI-derived feature tracking is feasible to predict sarcomere mutation with high incremental value added to Mayo II score.

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study.

BACKGROUND:The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear.METHODS:Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined.RESULTS:In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A, TET2, RUNX1, and ASXL1. During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively (P<0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257-3.816]; P=0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1β and interleukin-6 and lower interleukin-4 and IgG galactosylation levels.CONCLUSIONS:This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.

Danon Disease Manifesting as Dilated Cardiomyopathy in a 37-Year-Old Woman.

Subendocardial Involvement as an Underrecognized LGE Subtype Related to Adverse Outcomes in Hypertrophic Cardiomyopathy.

BACKGROUND:Late gadolinium enhancement (LGE) has been established as an independent predictor for adverse outcomes in hypertrophic cardiomyopathy (HCM). However, the prevalence and clinical significance of some LGE subtypes have not been well demonstrated.OBJECTIVES:In this study, the authors sought to investigate the prognostic value of subendocardium-involved LGE pattern and location of right ventricle insertion points (RVIPs) with LGE in HCM patients.METHODS:In this single-center retrospective study, 497 consecutive HCM patients with LGE confirmed by cardiac magnetic resonance (CMR) were included. Subendocardium-involved LGE was defined as LGE involving subendocardium not corresponding to a coronary vascular distribution. Subjects with ischemic heart disease that would contribute to subendocardial LGE were excluded. Endpoints included a composite of heart failure-related events, arrhythmic events, and stroke.RESULTS:Of the 497 patients, subendocardium-involved LGE and RVIP LGE were observed in 184 (37.0%) and 414 (83.3%), respectively. Extensive LGE (≥15% of left ventricular mass) was detected in 135 patients. During a median follow-up of 57.9 months, 66 patients (13.3%) experienced composite endpoints. Patients with extensive LGE had a significantly higher annual incidence of adverse events (5.1% vs 1.9% per year; P < 0.001). However, spline analysis showed that the association between LGE extent and HRs for adverse outcomes tended to be nonlinear. The risk of composite endpoint increased with percentage increase in LGE extent in patients with extensive LGE, whereas a similar trend was not observed in patients with nonextensive LGE (<15%). In patients with extensive LGE, LGE extent significantly correlated with composite endpoints (HR: 1.05; P = 0.03) after adjusting for left ventricular ejection fraction <50%, atrial fibrillation, and nonsustained ventricular tachycardia, whereas in patients with nonextensive LGE, subendocardium-involved LGE rather than LGE extent was independently associated with adverse outcomes (HR: 2.12; P = 0.03). RVIP LGE was not significantly associated with poor outcomes.CONCLUSIONS:In HCM patients with nonextensive LGE, the presence of subendocardium-involved LGE rather than LGE extent is associated with unfavorable outcomes. Given that the prognostic value of extensive LGE has been broadly recognized, subendocardial involvement as an underrecognized LGE pattern shows the potential to improve risk stratification in HCM patients with nonextensive LGE.

A novel AGK splicing mutation in a patient with Sengers syndrome and left ventricular non-compaction cardiomyopathy.

BACKGROUND:Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described.METHODS:Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review.RESULTS:The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome.CONCLUSIONS:The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment.IMPACT:First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.

Isolated left atrial amyloidosis: masquerading as a left atrial mass.

Molecular immuno-imaging improves tumor detection in head and neck cancer.

Detection and accurate delineation of tumor is important for the management of head and neck squamous cell carcinoma (HNSCC) but is challenging with current imaging techniques. In this study, we evaluated whether molecular immuno-imaging targeting myeloperoxidase (MPO) activity, an oxidative enzyme secreted by many myeloid innate immune cells, would be superior in detecting tumor extent compared to conventional contrast agent (DTPA-Gd) in a carcinogen-induced immunocompetent HNSCC murine model and corroborated in human surgical specimens. In C57BL/6 mice given 4-nitroquinoline-N-oxide (4-NQO), there was increased MPO activity in the head and neck region as detected by luminol bioluminescence compared to that of the control group. On magnetic resonance imaging, the mean enhancing volume detected by the MPO-targeting agent (MPO-Gd) was higher than that by the conventional agent DTPA-Gd. The tumor volume detected by MPO-Gd strongly correlated with tumor size on histology, and higher MPO-Gd signal corresponded to larger tumor size found by imaging and histology. On the contrary, the tumor volume detected by DTPA-Gd did not correlate as well with tumor size on histology. Importantly, MPO-Gd imaging detected areas not visualized with DTPA-Gd imaging that were confirmed histopathologically to represent early tumor. In human specimens, MPO was similarly associated with tumors, especially at the tumor margins. Thus, molecular immuno-imaging targeting MPO not only detects oxidative immune response in HNSCC, but can better detect and delineate tumor extent than nonselective imaging agents. Thus, our findings revealed that MPO imaging could improve tumor resection as well as be a useful imaging biomarker for tumor progression, and potentially improve clinical management of HNSCC once translated.

Late gadolinium enhancement characteristics in giant cell myocarditis.

AIMS:This study aims to demonstrate the characteristics of late gadolinium enhancement (LGE) assessed by cardiovascular magnetic resonance (CMR) imaging in patients with giant cell myocarditis (GCM).METHODS AND RESULTS:Six patients histologically diagnosed with GCM were retrospectively recruited in this study. All of them underwent CMR during hospitalization. The distribution and extent of LGE were assessed on both ventricles, and the AHA-17 segment model was used for left ventricular (LV) analysis. Nine case reports with CMR in GCM were reviewed and summarized to investigate the features of LGE further. LGE was detected on both ventricular walls in all subjects. For a detailed analysis of LGE in the LV, the extent ranged from 21.6% to 56%. Among 70 segments (68.6%) involved by LGE, the subendocardial LGE was the most common pattern (46/102, including 24 segments located in the right-sided septum), followed by the subepicardial pattern (23/102). The right-sided septum, the subepicardial anterior wall, and the subendocardial right ventricular (RV) wall were observed in all subjects. To summarize the results of the present study with these case reports, the three most common patterns of LGE are the right-sided septum (73%), the subepicardial anterior wall (60%), and the subendocardial RV wall (53%).CONCLUSIONS:Extensive LGE seems to be common in GCM, affecting both LV and RV walls. Apart from subepicardial LGE, subendocardial LGE, which was used to be implicated in ischaemic disease, was frequently presented in GCM. The right-sided subendocardial septum, the subepicardial anterior wall, and the subendocardial RV wall might be the vulnerable areas of LGE in GCM.

Association between QRS voltages and amyloid burden in patients with cardiac amyloidosis.

PRKAG2 Gene Mutation Indicating Myocardial Hypertrophy and Wolff-Parkinson-White Syndrome in a 28-Year-Old Woman.

Association between left atrial myopathy and sarcomere mutation in patients with hypertrophic cardiomyopathy: insights into left atrial strain by MRI feature tracking.

OBJECTIVES:Left atrial (LA) myopathy, characterized by LA enlargement and mechanical dysfunction, is associated with worse prognosis in hypertrophic cardiomyopathy (HCM) while the impact of sarcomere mutation on LA myopathy remains unclear. We aimed to assess the association between LA myopathy and sarcomere mutation and to explore the incremental utility of LA strain in mutation prediction.METHODS:A total of 105 consecutive HCM patients (mean age 47.8 ± 11.9 years, 71% male) who underwent HCM-related gene screening and cardiac MRI were retrospectively enrolled. LA volume, ejection fraction and strain indices in reservoir, conduit, and booster-pump phases were investigated respectively.RESULTS:Fifty mutation-positive patients showed higher LA maximal volume index (59.4 ± 28.2 vs 43.8 ± 18.1 mL/m2, p = 0.001), lower reservoir (21.3 ± 7.9 vs 26.2 ± 6.6%, p < 0.001), and booster-pump strain (12.1 ± 5.4 vs 17.1 ± 5.0%, p < 0.001) but similar conduit strain (9.2 ± 4.5 vs 9.1 ± 4.5%, p = 0.909) compared with mutation-negative patients. In multivariate logistic regression, LA booster-pump strain was associated with sarcomere mutation (odds ratio = 0.86, 95% confidence interval: 0.77-0.96, p = 0.010) independent of maximal wall thickness, late gadolinium enhancement, and LA volume. Furthermore, LA booster-pump strain showed incremental value for mutation prediction added to Mayo II score (AUC 0.798 vs 0.709, p = 0.024).CONCLUSIONS:In HCM, mutation-positive patients suffered worse LA enlargement and worse reservoir and booster-pump functions. LA booster-pump strain was a strong factor for sarcomere mutation prediction added to Mayo II score.CLINICAL RELEVANCE STATEMENT:The independent association between sarcomere mutation and left atrial mechanical dysfunction provide new insights into the pathogenesis of atrial myopathy and is helpful to understand the adverse prognosis regarding atrial fibrillation and stroke in mutation-positive patients.KEY POINTS:• In patients with hypertrophic cardiomyopathy, left atrial (LA) reservoir and booster-pump function, but not conduit function, were significantly impaired in mutation-positive patients compared with mutation-negative patients. • LA booster-pump strain measured by MRI-derived feature tracking is feasible to predict sarcomere mutation with high incremental value added to Mayo II score.

Clonal Hematopoiesis of Indeterminate Potential in Chronic Thromboembolic Pulmonary Hypertension: A Multicenter Study.

BACKGROUND:The pathogenesis of chronic thromboembolic pulmonary hypertension (CTEPH) is multifactorial and growing evidence has indicated that hematological disorders are involved. Clonal hematopoiesis of indeterminate potential (CHIP) has recently been associated with an increased risk of both hematological malignancies and cardiovascular diseases. However, the prevalence and clinical relevance of CHIP in patients with CTEPH remains unclear.METHODS:Using stepwise calling on next-generation sequencing data from 499 patients with CTEPH referred to 3 centers between October 2006 and December 2021, CHIP mutations were identified. We associated CHIP with all-cause mortality in patients with CTEPH. To provide insights into potential mechanisms, the associations between CHIP and inflammatory markers were also determined.RESULTS:In total, 47 (9.4%) patients with CTEPH carried at least 1 CHIP mutation at a variant allele frequency of ≥2%. The most common mutations were in DNMT3A, TET2, RUNX1, and ASXL1. During follow-up (mean, 55 months), deaths occurred in 22 (46.8%) and 104 (23.0%) patients in the CHIP and non-CHIP groups, respectively (P<0.001, log-rank test). The association of CHIP with mortality remained robust in the fully adjusted model (hazard ratio, 2.190 [95% CI, 1.257-3.816]; P=0.006). Moreover, patients with CHIP mutations showed higher circulating interleukin-1β and interleukin-6 and lower interleukin-4 and IgG galactosylation levels.CONCLUSIONS:This is the first study to show that CHIP mutations occurred in 9.4% of patients with CTEPH are associated with a severe inflammatory state and confer a poorer prognosis in long-term follow-up.

Danon Disease Manifesting as Dilated Cardiomyopathy in a 37-Year-Old Woman.

Subendocardial Involvement as an Underrecognized LGE Subtype Related to Adverse Outcomes in Hypertrophic Cardiomyopathy.

BACKGROUND:Late gadolinium enhancement (LGE) has been established as an independent predictor for adverse outcomes in hypertrophic cardiomyopathy (HCM). However, the prevalence and clinical significance of some LGE subtypes have not been well demonstrated.OBJECTIVES:In this study, the authors sought to investigate the prognostic value of subendocardium-involved LGE pattern and location of right ventricle insertion points (RVIPs) with LGE in HCM patients.METHODS:In this single-center retrospective study, 497 consecutive HCM patients with LGE confirmed by cardiac magnetic resonance (CMR) were included. Subendocardium-involved LGE was defined as LGE involving subendocardium not corresponding to a coronary vascular distribution. Subjects with ischemic heart disease that would contribute to subendocardial LGE were excluded. Endpoints included a composite of heart failure-related events, arrhythmic events, and stroke.RESULTS:Of the 497 patients, subendocardium-involved LGE and RVIP LGE were observed in 184 (37.0%) and 414 (83.3%), respectively. Extensive LGE (≥15% of left ventricular mass) was detected in 135 patients. During a median follow-up of 57.9 months, 66 patients (13.3%) experienced composite endpoints. Patients with extensive LGE had a significantly higher annual incidence of adverse events (5.1% vs 1.9% per year; P < 0.001). However, spline analysis showed that the association between LGE extent and HRs for adverse outcomes tended to be nonlinear. The risk of composite endpoint increased with percentage increase in LGE extent in patients with extensive LGE, whereas a similar trend was not observed in patients with nonextensive LGE (<15%). In patients with extensive LGE, LGE extent significantly correlated with composite endpoints (HR: 1.05; P = 0.03) after adjusting for left ventricular ejection fraction <50%, atrial fibrillation, and nonsustained ventricular tachycardia, whereas in patients with nonextensive LGE, subendocardium-involved LGE rather than LGE extent was independently associated with adverse outcomes (HR: 2.12; P = 0.03). RVIP LGE was not significantly associated with poor outcomes.CONCLUSIONS:In HCM patients with nonextensive LGE, the presence of subendocardium-involved LGE rather than LGE extent is associated with unfavorable outcomes. Given that the prognostic value of extensive LGE has been broadly recognized, subendocardial involvement as an underrecognized LGE pattern shows the potential to improve risk stratification in HCM patients with nonextensive LGE.

A novel AGK splicing mutation in a patient with Sengers syndrome and left ventricular non-compaction cardiomyopathy.

BACKGROUND:Sengers syndrome characterized by hypertrophic cardiomyopathy is an extremely rare genetic disorder. Sengers syndrome associated with left ventricular non-compaction (LVNC) has not been described.METHODS:Genetic testing was used to identify candidate AGK variants in the proband. The predicted molecular structures were constructed by protein modeling. Exon skipping caused by the identified splicing mutations was verified by in silico analyses and in vitro assays. The genotypic and phenotypic features of patients with AGK splicing mutations were extracted by a systematic review.RESULTS:The proband was characterized by Sengers syndrome and LVNC and caused by a novel compound heterozygous AGK splicing mutation. This compound mutation simultaneously perturbed the protein sequences and spatial conformation of the acylglycerol kinase protein. In silico and in vitro analyses demonstrated skipping of exons 7 and 8 and premature truncation as a result of exon 8 skipping. The systematic review indicated that patients with an AGK splicing mutation may have milder phenotypes of Sengers syndrome.CONCLUSIONS:The genotypic and phenotypic spectrums of Sengers syndrome have been expanded, which will provide essential information for genetic counseling. The molecular mechanism in AGK mutations can offer insights into the potential targets for treatment.IMPACT:First description of a child with Sengers syndrome and left ventricular non-compaction cardiomyopathy. A novel pathogenic compound heterozygous splicing mutation in AGK for Sengers syndrome was identified. The identified mutations led to exons skipping by in silico analyses and in vitro assays.

Isolated left atrial amyloidosis: masquerading as a left atrial mass.

Molecular immuno-imaging improves tumor detection in head and neck cancer.

Detection and accurate delineation of tumor is important for the management of head and neck squamous cell carcinoma (HNSCC) but is challenging with current imaging techniques. In this study, we evaluated whether molecular immuno-imaging targeting myeloperoxidase (MPO) activity, an oxidative enzyme secreted by many myeloid innate immune cells, would be superior in detecting tumor extent compared to conventional contrast agent (DTPA-Gd) in a carcinogen-induced immunocompetent HNSCC murine model and corroborated in human surgical specimens. In C57BL/6 mice given 4-nitroquinoline-N-oxide (4-NQO), there was increased MPO activity in the head and neck region as detected by luminol bioluminescence compared to that of the control group. On magnetic resonance imaging, the mean enhancing volume detected by the MPO-targeting agent (MPO-Gd) was higher than that by the conventional agent DTPA-Gd. The tumor volume detected by MPO-Gd strongly correlated with tumor size on histology, and higher MPO-Gd signal corresponded to larger tumor size found by imaging and histology. On the contrary, the tumor volume detected by DTPA-Gd did not correlate as well with tumor size on histology. Importantly, MPO-Gd imaging detected areas not visualized with DTPA-Gd imaging that were confirmed histopathologically to represent early tumor. In human specimens, MPO was similarly associated with tumors, especially at the tumor margins. Thus, molecular immuno-imaging targeting MPO not only detects oxidative immune response in HNSCC, but can better detect and delineate tumor extent than nonselective imaging agents. Thus, our findings revealed that MPO imaging could improve tumor resection as well as be a useful imaging biomarker for tumor progression, and potentially improve clinical management of HNSCC once translated.

Late gadolinium enhancement characteristics in giant cell myocarditis.

AIMS:This study aims to demonstrate the characteristics of late gadolinium enhancement (LGE) assessed by cardiovascular magnetic resonance (CMR) imaging in patients with giant cell myocarditis (GCM).METHODS AND RESULTS:Six patients histologically diagnosed with GCM were retrospectively recruited in this study. All of them underwent CMR during hospitalization. The distribution and extent of LGE were assessed on both ventricles, and the AHA-17 segment model was used for left ventricular (LV) analysis. Nine case reports with CMR in GCM were reviewed and summarized to investigate the features of LGE further. LGE was detected on both ventricular walls in all subjects. For a detailed analysis of LGE in the LV, the extent ranged from 21.6% to 56%. Among 70 segments (68.6%) involved by LGE, the subendocardial LGE was the most common pattern (46/102, including 24 segments located in the right-sided septum), followed by the subepicardial pattern (23/102). The right-sided septum, the subepicardial anterior wall, and the subendocardial right ventricular (RV) wall were observed in all subjects. To summarize the results of the present study with these case reports, the three most common patterns of LGE are the right-sided septum (73%), the subepicardial anterior wall (60%), and the subendocardial RV wall (53%).CONCLUSIONS:Extensive LGE seems to be common in GCM, affecting both LV and RV walls. Apart from subepicardial LGE, subendocardial LGE, which was used to be implicated in ischaemic disease, was frequently presented in GCM. The right-sided subendocardial septum, the subepicardial anterior wall, and the subendocardial RV wall might be the vulnerable areas of LGE in GCM.