[Cluster Analysis and Ablation Success Rate in Atrial Fibrillation Patients Undergoing Catheter Ablation]. / æˆ¿é¢¤å°„é¢‘æ¶ˆèžæ‚£è€ çš„èšç±»åˆ†æžåŠæ¶ˆèžæˆåŠŸçŽ‡è¯„ä»·.

Objective: Atrial fibrillation (AF) is a disease of high heterogeneity, and the association between AF phenotypes and the outcome of different catheter ablation strategies remains unclear. Conventional classification of AF (e.g. according to duration, atrial size, and thromboembolism risk) fails to provide reference for the optimal stratification of the prognostic risks or to guide individualized treatment plan. In recent years, research on machine learning has found that cluster analysis, an unsupervised data-driven approach, can uncover the intrinsic structure of data and identify clusters of patients with pathophysiological similarity. It has been demonstrated that cluster analysis helps improve the characterization of AF phenotypes and provide valuable prognostic information. In our cohort of AF inpatients undergoing radiofrequency catheter ablation, we used unsupervised cluster analysis to identify patient subgroups, to compare them with previous studies, and to evaluate their association with different suitable ablation patterns and outcomes. Methods: The participants were AF patients undergoing radiofrequency catheter ablation at West China Hospital between October 2015 and December 2017. All participants were aged 18 years or older. They underwent radiofrequency catheter ablation during their hospitalization. They completed the follow-up process under explicit informed consent. Patients with AF of a reversible cause, severe mitral stenosis or prosthetic heart valve, congenital heart disease, new-onset acute coronary syndrome within three months prior to the surgery, or a life expectancy less than 12 months were excluded according to the exclusion criteria. The cohort consisted of 1102 participants with paroxysmal or persistent/long-standing persistent AF. Data on 59 variables representing demographics, AF type, comorbidities, therapeutic history, vital signs, electrocardiographic and echocardiographic findings, and laboratory findings were collected. Overall, data for the variables were rarely missing (<5%), and multiple imputation was used for correction of missing data. Follow-up surveys were conducted through outpatient clinic visits or by telephone. Patients were scheduled for follow-up with 12-lead resting electrocardiography and 24-hours Holter monitoring at 3 months and 6 months after the ablation procedure. Early ablation success was defined as the absence of documented AF, atrial flutter, or atrial tachycardia >30 seconds at 6-month follow-up. Hierarchical clustering was performed on the 59 baseline variables. All characteristic variables were standardized to have a mean of zero and a standard deviation of one. Initially, each patient was regarded as a separate cluster, and the distance between these clusters was calculated. Then, the Ward minimum variance method of clustering was used to merge the pair of clusters with the minimum total variance. This process continued until all patients formed one whole cluster. The "NbClust" package in R software, capable of calculating various statistical indices, including pseudo t2 index, cubic clustering criterion, silhouette index etc, was applied to determine the optimal number of clusters. The most frequently chosen number of clusters by these indices was selected. A heatmap was generated to illustrate the clinical features of clusters, while a tree diagram was used to depict the clustering process and the heterogeneity among clusters. Ablation strategies were compared within each cluster regarding ablation efficacy. Results: Five statistically driven clusters were identified: 1) the younger age cluster (n=404), characterized by the lowest prevalence of cardiovascular and cerebrovascular comorbidities but the highest prevalence of obstructive sleep apnea syndrome (14.4%); 2) a cluster of elderly adults with chronic diseases (n=438), the largest cluster, showing relatively higher rates of hypertension, diabetes, stroke, and chronic obstructive pulmonary disease; 3) a cluster with high prevalence of sinus node dysfunction (n=160), with patients showing the highest prevalence of sick sinus syndrome and pacemaker implantation; 4) the heart failure cluster (n=80), with the highest prevalence of heart failure (58.8%) and persistent/long-standing persistent AF (73.7%); 5) prior coronary artery revascularization cluster (n=20), with patients of the most advanced age (median: 69.0 years old) and predominantly male patients, all of whom had prior myocardial infarction and coronary artery revascularization. Patients in cluster 2 achieved higher early ablation success with pulmonary veins isolation alone compared to extensive ablation strategies (79.6% vs. 66.5%; odds ratio [OR]=1.97, 95% confidence interval [CI]: 1.28-3.03). Although extensive ablation strategies had a slightly higher success rate in the heart failure group, the difference was not statistically significant. Conclusions: This study provided a unique classification of AF patients undergoing catheter ablation by cluster analysis. Age, chronic disease, sinus node dysfunction, heart failure and history of coronary artery revascularization contributed to the formation of the five clinically relevant subtypes. These subtypes showed differences in ablation success rates, highlighting the potential of cluster analysis in guiding individualized risk stratification and treatment decisions for AF patients.

Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis.

Tissue stiffening is a predominant feature of fibrotic disorders, but the response of macrophages to changes in tissue stiffness and cellular context in fibrotic diseases remains unclear. Here, we found that the mechanosensitive ion channel Piezo1 was up-regulated in hepatic fibrosis. Macrophages lacking Piezo1 showed sustained inflammation and impaired spontaneous resolution of early liver fibrosis. Further analysis revealed an impairment of clearance of apoptotic cells by macrophages in the fibrotic liver. Macrophages showed enhanced efferocytosis when cultured on rigid substrates but not soft ones, suggesting stiffness-dependent efferocytosis of macrophages required Piezo1 activation. Besides, Piezo1 was involved in the efficient acidification of the engulfed cargo in the phagolysosomes and affected the subsequent expression of anti-inflammation genes after efferocytosis. Pharmacological activation of Piezo1 increased the efferocytosis capacity of macrophages and accelerated the resolution of inflammation and fibrosis. Our study supports the antifibrotic role of Piezo1-mediated mechanical sensation in liver fibrosis, suggesting that targeting PIEZO1 to enhance macrophage efferocytosis could induce fibrosis regression.

Neutrophil-macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome.

Cytokine storm syndrome (CSS) is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies, infections, and autoimmune conditions. However, the potential interplay between innate immune cells is not fully understood. Here, using poly I:C and lipopolysaccharide (LPS)-induced cytokine storm models, a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model. Intravital imaging revealed neutrophil-derived extracellular vesicles (NDEVs) in the liver and spleen, which were captured by macrophages. NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models. Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite, itaconate, which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase (Acod1, encoded by Irg1). Irg1 in macrophages, but not in neutrophils, was critical for the NDEV-mediated anti-inflammatory effects. Mechanistically, NDEVs delivered miR-27a-3p, which suppressed the expression of Suclg1, the gene encoding the enzyme that metabolizes itaconate, thereby resulting in the accumulation of itaconate in macrophages. These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.

PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury.

Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease.

Assessment of mitral valve geometry in nonvalvular atrial fibrillation patients with or without ventricular dysfunction: insights from high volume rate three-dimensional transesophageal echocardiography.

Meticulous understanding of the mechanisms underpinning mitral regurgitation in atrial fibrillation (AF) patients is crucial to optimize therapeutic strategies. The morphologic characteristics of mitral valves in atrial functional mitral regurgitation (FMR) patients with and without left ventricular (LV) dysfunction were evaluated by high volume rate (HVR) three-dimensional transesophageal echocardiography (3D-TEE). In our study, 68 of 265 AF patients who underwent 3D-TEE were selected, including 36 patients with AF, FMR, and preserved LV function (AFMR group) and 32 patients with AF, FMR, and LV dysfunction (VFMR group). In addition, 36 fever patients without heart disease were included in the control group. Group comparisons were performed by one-way analysis of variance for continuous variables. The left atrium (LA) was enlarged in the AFMR and VFMR groups compared with the control group. The mitral annulus (MA) in the AFMR group was enlarged and flattened compared with the control group and was smaller than in the VFMR group. The annulus area fraction was significantly diminished in the AFMR and VFMR groups, indicative of reduced MA contractility. The posterior mitral leaflet (PML) angle was smallest in the AFMR group and largest in the control group, whereas the distal anterior mitral leaflet angle did not significantly differ among the three groups. LA remodeling causes expansion of the MA and reduced MA contractility, disruption of the annular saddle shape, and atriogenic PML tethering. Comparison of atrial FMR patients with and without LV dysfunction indicates that atriogenic PML tethering is an important factor that aggravates FMR. HVR 3D-TEE improves the 3D temporal resolution greatly.

Vinblastine resets tumor-associated macrophages toward M1 phenotype and promotes antitumor immune response.

BACKGROUND: Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be converted to an M1-like antitumor phenotype due to their high degree of plasticity. The macrophage polarization state is associated with changes in cell shape, macrophage morphology is associated with activation status. M1 macrophages appeared large and rounded, while M2 macrophages were stretched and elongated cells. Manipulating cell morphology has been shown to affect the polarization state of macrophages. The shape of the cell is largely dependent on cytoskeletal proteins, especially, microtubules. As a microtubule-targetting drug, vinblastine (VBL) has been used in chemotherapy. However, no study to date has explored the effect of VBL on TAM shape changes and its role in tumor immune response. METHOD: We used fluorescent staining of the cytoskeleton and quantitative analysis to reveal the morphological differences between M0, M1, M2, TAM and VBL-treated TAM. Flow cytometry was used to confirm the polarization states of these macrophages using a cell surface marker-based classification. In vivo antibody depletion experiments in tumor mouse models were performed to test whether macrophages and CD8+ T cell populations were required for the antitumor effect of VBL. VBL and anti-PD-1 combination therapy was then investigated in comparison with monotherapy. RNA-seq of TAM of treated and untreated with VBL was performed to explore the changes in pathway activities. siRNA mediated knockdown experiments were performed to verify the target pathway that was affected by VBL treatment. RESULTS: Here, we showed that VBL, an antineoplastic agent that destabilizes microtubule, drove macrophage polarization into the M1-like phenotype both in vitro and in tumor models. The antitumor effect of VBL was attenuated in the absence of macrophages or CD8+ T cells. Mechanistically, VBL induces the activation of NF-κB and Cyba-dependent reactive oxygen species generation, thus polarizing TAMs to the M1 phenotype. In parallel, VBL promotes the nuclear translocation of transcription factor EB, inducing lysosome biogenesis and a dramatic increase in phagocytic activity in macrophages. CONCLUSIONS: This study explored whether manipulating cellular morphology affects macrophage polarization and consequently induces an antitumor response. Our data reveal a previously unrecognized antitumor mechanism of VBL and suggest a drug repurposing strategy combining VBL with immune checkpoint inhibitors to improve malignant tumor immunotherapy.

A novel reporter mouse line for studying alveolar macrophages.

Alveolar macrophages (AMs) are self-maintained immune cells that play vital roles in lung homeostasis and immunity. Although reporter mice and culture systems have been established for studying macrophages, an accurate and specific reporter line for alveolar macrophage study is still not available. Here we reported a novel Rspo1-tdTomato gene reporter mouse line that could specifically label mouse AMs in a cell-intrinsic manner. Using this reporter system, we visualized the dynamics of alveolar macrophages intravitally under steady state and characterized the alveolar macrophage differentiation under in vitro condition. By performing ATAC-seq, we found that insertion of the tdTomato cassette in the Rspo1 locus increased the accessibility of a PPARE motif within the Rspo1 locus and revealed a potential regulation by key transcription factor PPAR-γ for alveolar macrophage differentiation in vitro and in vivo. Consistently, perturbation of PPAR-γ by its agonist rosiglitazone or inhibitor GW9662 resulted in corresponding alteration of tdTomato expression in alveolar macrophages together with the transcription of PPAR-γ downstream target genes. Furthermore, global transcriptomic analyses of AMs from the wild type mice and the Rspo1-tdTomato mice showed comparable gene expression profiles, especially those AM-specific genes, confirming that the insertion of the tdTomato cassette in the Rspo1 locus does not impact the cell identity and biological function of AMs under normal condition. Taken together, our study provides an alternative tool for in vivo and in vitro labeling of alveolar macrophages with high specificity which could also be utilized as an indicator of PPAR-γ activity for future development of PPAR-γ specific targeting drugs.

Oxidized mitochondrial DNA induces gasdermin D oligomerization in systemic lupus erythematosus.

Although extracellular DNA is known to form immune complexes (ICs) with autoantibodies in systemic lupus erythematosus (SLE), the mechanisms leading to the release of DNA from cells remain poorly characterized. Here, we show that the pore-forming protein, gasdermin D (GSDMD), is required for nuclear DNA and mitochondrial DNA (mtDNA) release from neutrophils and lytic cell death following ex vivo stimulation with serum from patients with SLE and IFN-γ. Mechanistically, the activation of FcγR downregulated Serpinb1 following ex vivo stimulation with serum from patients with SLE, leading to spontaneous activation of both caspase-1/caspase-11 and cleavage of GSDMD into GSDMD-N. Furthermore, mtDNA oxidization promoted GSDMD-N oligomerization and cell death. In addition, GSDMD, but not peptidyl arginine deiminase 4 is necessary for extracellular mtDNA release from low-density granulocytes from SLE patients or healthy human neutrophils following incubation with ICs. Using the pristane-induced lupus model, we show that disease severity is significantly reduced in mice with neutrophil-specific Gsdmd deficiency or following treatment with the GSDMD inhibitor, disulfiram. Altogether, our study highlights an important role for oxidized mtDNA in inducing GSDMD oligomerization and pore formation. These findings also suggest that GSDMD might represent a possible therapeutic target in SLE.

Activating NO-sGC crosstalk in the mouse vascular niche promotes vascular integrity and mitigates acute lung injury.

Disruption of endothelial cell (ECs) and pericytes interactions results in vascular leakage in acute lung injury (ALI). However, molecular signals mediating EC-pericyte crosstalk have not been systemically investigated, and whether targeting such crosstalk could be adopted to combat ALI remains elusive. Using comparative genome-wide EC-pericyte crosstalk analysis of healthy and LPS-challenged lungs, we discovered that crosstalk between endothelial nitric oxide and pericyte soluble guanylate cyclase (NO-sGC) is impaired in ALI. Indeed, stimulating the NO-sGC pathway promotes vascular integrity and reduces lung edema and inflammation-induced lung injury, while pericyte-specific sGC knockout abolishes this protective effect. Mechanistically, sGC activation suppresses cytoskeleton rearrangement in pericytes through inhibiting VASP-dependent F-actin formation and MRTFA/SRF-dependent de novo synthesis of genes associated with cytoskeleton rearrangement, thereby leading to the stabilization of EC-pericyte interactions. Collectively, our data demonstrate that impaired NO-sGC crosstalk in the vascular niche results in elevated vascular permeability, and pharmacological activation of this crosstalk represents a promising translational therapy for ALI.

Short-term associations of PM2.5 and PM2.5 constituents with immune biomarkers: A panel study in people living with HIV/AIDS.

Studies on associations of fine particulate matter (PM2.5) with immunity in people living with HIV/AIDS (PLWHA) were absent. We aimed to explore whether changes of immune biomarkers were associated with short-term exposure to PM2.5 in PLWHA. Based on a panel study in Wuhan, we selected 163 PLWHA as participants with up to 4 repeated visits from March 2020 to January 2021. Immune biomarkers, including CD4+T cell count, CD8+T cell count, HIV viral load (VL) and CD4+T/CD8+T ratio were tested for all participants at each visit. Residential exposures of PM2.5 and PM2.5 constituents for each participant were assessed using spatial-temporal models. Linear mixed-effect models and general linear mixed models were applied to evaluate the associations between PM2.5 and immune biomarkers. To estimate the combined effect of PM2.5 constituents, weighted quantile sum regression and Bayesian kernel machine regression were employed. Each 10 µg/m3 increase of 7-day average PM2.5 concentrations was associated with an 8.75 cells/mm3 (95%CI: -15.55, -1.98) decrease in CD4+T cell count and a 92% (OR: 1.92, 95%CI: 1.43, 2.58) increased odds ratio of detectable HIV VL. However, the odds ratio of inverted CD4+T/CD8+T was only positively associated with PM2.5 concentrations at lag2 day (OR:1.27, 95%CI:1.02, 1.57). CD4+T may be a potential mediator between PM2.5 and detectable HIV VL with 3.83% mediated proportion. Besides, the combined effect of PM2.5 chemical constituents indicated that NO3- and SO42- were the main constituents in reducing CD4+T cell count and increasing odds ratio of detectable HIV VL. Our finding revealed that short-term exposure to PM2.5 was negatively associated with CD4+T cell count but positively related to the odds ratio of detectable HIV VL in PLWHA. This research may provide new evidence in associations between PM2.5 and immune biomarkers as well as improving prognosis of PLWHA.

Adsorption and Removal of Antibiotic Pollutants using CuO-Co3 O4 Co-modified Porous Boron Nitride Fibers in Aqueous Solution.

The presence of antibiotic contaminants in aqueous environment already poses significant risks to ecological sustainability, biodiversity and human public health and safety. Therefore, it is urgent to develop practical water pollution control technologies and new materials. Here, we prepared CuO-Co3 O4 co-modified porous boron nitride fibers (P-BNFs) for the adsorption and removal of tetracycline antibiotics (TCs) in aqueous environment. The prepared adsorbents were characterized by XRD, FTIR, XPS, SEM, TEM and BET, and the adsorption behavior was explored by batch experiments. The results show that the removal percentage for doxycycline (DC) reaches 98.68 %, which was much higher than that of P-BNFs, and the modification results of P-BNFs with CuO or Co3 O4 alone. After five regeneration cycles, the removal rate of DC by CuO-Co3 O4 /P-BNFs was still as high as 89.33 %. This is promising and indicates that the prepared CuO-Co3 O4 /P-BNFs adsorbent has good renewable recycling performance and practical application prospects.

Papillary muscle avulsion following balloon mitral valvotomy evaluated with three-dimensional echocardiography.

BACKGROUND: Percutaneous balloon mitral valvotomy is a common therapeutic approach for rheumatic mitral stenosis. Avulsion of the papillary muscle is a rare but serious complication of balloon mitral valvotomy. The papillary muscles are derived from the trabecular layer of the developing ventricular walls. When subjected to a force, avulsion of papillary muscle from the trabecular layer may occur. CASE PRESENTATION: In this case report, we describe a patient with rheumatic mitral stenosis, who experienced avulsion of the mitral papillary muscle from the left ventricular wall after undergoing balloon mitral valvotomy. Papillary muscle alvusion resulted in severe mitral regurgitation, which was finally treated by mitral valve replacement. CONCLUSION: We successfully diagnosed avulsion of the papillary muscle following balloon mitral valvotomy. Three-dimensional transthoracic echocardiography provides more information on mitral apparatus structure than two-dimensional transthoracic echocardiography.

Correlation of electroencephalogram background evolution with the degree of brain injury in neonates with hypoxic-ischemic encephalopathy. / æ–°ç”Ÿå„¿ç¼ºæ°§ç¼ºè¡€æ€§è„‘ç— è„‘ç”µèƒŒæ™¯æ¼”å˜ä¸Žè„‘æŸä¼¤ç¨‹åº¦çš„ç›¸å ³æ€§ç ”ç©¶.

OBJECTIVES: To study the correlation of electroencephalogram (EEG) background evolution with the degree of brain injury in neonates with hypoxic-ischemic encephalopathy (HIE). METHODS: A retrospective analysis was performed for 56 neonates with HIE who underwent continuous video electroencephalogram (cVEEG) and brain magnetic resonance imaging (MRI) examinations. According to clinical symptoms, they were divided into a mild group with 3 neonates, a moderate group with 36 neonates, and a severe group with 17 neonates. EEG background grading and MRI score were determined for each group to analyze the correlation of EEG background evolution with the degree of brain injury. RESULTS: Compared with the moderate group, the severe group had significantly lower gestational age and Apgar score at 5 minutes after birth, a significantly higher resuscitation score, significantly lower base excess in umbilical cord blood or blood gas within 1 hour, a significantly higher proportion of neonates on mechanical ventilation, and a significantly higher incidence rate of short-term adverse outcomes (P<0.05). For the neonates in the mild and moderate groups, MRI mainly showed no brain injury (67%, 2/3) and watershed injury (67%, 16/24) respectively, and EEG showed mild abnormality in 62% (13/21) of the neonates on the 3rd day after birth. For the neonates in the severe group, MRI mainly showed basal ganglia/thalamus + brainstem injury (24%, 4/17) and whole brain injury (71%, 12/17), and EEG showed moderate or severe abnormalities on the 3rd day after birth. EEG background grading was correlated with clinical grading, MRI score, and short-term outcome on days 1, 2, 3 and 7-14 after birth (P<0.01). The highest correlation coefficient between EEG grading and MRI score was observed on the 3rd day after birth (rs=0.751, P<0.001), and the highest correlation coefficients between EEG grading and clinical grading (rs=0.592, P=0.002) and between EEG grading and short-term outcome (rs=0.737, P<0.001) were observed 7-14 days after birth. Among the neonates with severe abnormal EEG, the neonates without brain electrical activity had the highest MRI score, followed by those with status epileptics and persistent low voltage (P<0.05). CONCLUSIONS: There is a good correlation between EEG background grading and degree of brain injury in neonates with HIE, which can help to evaluate the degree and prognosis of brain injury in the early stage.

Left ventricular diastolic pressure gradient and outcome in advanced chronic kidney disease patients with preserved ejection fraction.

Assessment of left ventricular (LV) diastolic dysfunction is important in patients with chronic kidney disease (CKD). The early diastolic peak intraventricular pressure gradient (IVPG) has a vital role in diastolic function. Relative pressure imaging (RPI) is a new echocardiographic method to quantify IVPG. The purpose of this study was to analyze RPI-derived IVPG in advanced CKD patients with preserved LV ejection fraction. The study population consisted of 51 advanced CKD patients and 39 healthy controls. Patients were stratified by the evidence of heart failure with preserved ejection fraction (HFpEF) into HFpEF group (32 patients) and non-HFpEF group (19 patients). RPI analysis was used to determine the early diastolic LV relative pressure and pressure distribution. The total IVPG and segmental IVPGs corresponding to basal, mid, and apical part of the LV were calculated. Total IVPG, along with apical and mid IVPGs were all significantly reduced in HFpEF Group compared with non-HFpEF Group and controls (all P < 0.05). But no significant difference of total or segmental IVPGs was found between non-HFpEF Group and the controls. Additionally, apical IVPG < 0.02 mmHg/cm (Hazard ratio 9.82, 95 % confidence interval 2.01-48.01, P = 0.005) was the independent risk factor for the composite outcome (mortality and cardiovascular hospitalization) during a median follow-up of 24 months. Advanced CKD patients with HFpEF exhibited decreased apical and mid IVPG of the LV, and the severity of apical IVPG reduction correlated with poor outcome.

A dissecting aneurysm of the sinus of Valsalva involving the inter-ventricsular septum in a patient with syphilis and a quadricuspid aortic valve.

Aneurysms of the sinus of Valsalva are rare, with dissecting aneurysms of the sinus of Valsalva that extend into the inter-ventricular septum being even more rare. This report describes a young patient with syphilis and a quadricuspid aortic valve who experienced a spontaneously dissecting aneurysm of the sinus of Valsalva and the basal inter-ventricular septum.