Prognostic Implications of Coronary Artery Sclerosis in Troponin-Positive Patients with Non-Obstructive Coronary Arteries.

INTRODUCTION: Coronary sclerosis is a risk factor for the progression to obstructive coronary artery disease (CAD). However, understanding its impact on the outcomes of patients with myocardial infarction and non-obstructive coronary arteries is limited. This study aimed to explore the prognostic influence of coronary sclerosis on in- and out-of-hospital events in troponin-positive patients with non-obstructive coronary arteries. METHODS: This study was a retrospective cohort analysis based on prospectively collected data. A total of 24,775 patients who underwent coronary angiography from 2010 to 2021 in a German university hospital were screened, resulting in a final study cohort of 373 troponin-positive patients with non-obstructive coronary arteries and a follow-up period of 6.2 ± 3.1 years. Coronary sclerosis was defined as coronary plaques without angiographically detectable stenotic lesions of 50% or more in the large epicardial coronary arteries. The primary study endpoint was the occurrence of in-hospital events. Secondary endpoints included events during follow-up. RESULTS: Patients with coronary sclerosis were significantly older (70 ± 12 vs. 58 ± 16 years, p < 0.001), had ST-segment elevation less frequently on electrocardiogram (9.4% vs. 18.7%, p = 0.013), and suffered more often from diabetes mellitus (23.3% vs. 13.1%, p = 0.009), arterial hypertension (79.6% vs. 59.8%, p < 0.001), chronic obstructive pulmonary disease (17.1% vs. 9.4%, p = 0.028), chronic kidney disease (22.2% vs. 8.4%, p < 0.001), atrial fibrillation (19.8% vs. 12.2%, p = 0.045), and valvular diseases than patients without CAD. Patients with coronary sclerosis were more likely to receive medication for primary/secondary prevention on admission and at discharge. The incidence of in- and out-of-hospital events was significantly higher in patients with coronary sclerosis (in-hospital: 42.8% vs. 29.9%, p = 0.010; out-of-hospital: 46.0% vs. 26.1%, p < 0.001). Mortality rates tended to be higher in the coronary sclerosis group (29.4% vs. 20.0%, p = 0.066). CONCLUSION: Patients diagnosed with coronary sclerosis presented a higher incidence of comorbidities and increased medication use, and experienced higher rates of both in-hospital and out-of-hospital events, primarily due to the clustering of cardiovascular risk factors.

Whole genome sequencing identifies a homozygous splicing variant in TDRKH segregating with non-obstructive azoospermia in an Iranian family.

Non-obstructive azoospermia (NOA) resulting from primary spermatogenic failure represents one of the most severe forms of male infertility, largely because therapeutic options are very limited. Beyond their diagnostic value, genetic tests for NOA also hold prognostic potential. Specifically, genetic diagnosis enables the establishment of genotype-testicular phenotype correlations, which, in some cases, provide a negative predictive value for testicular sperm extraction (TESE), thereby preventing unnecessary surgical procedures. In this study, we employed whole-genome sequencing (WGS) to investigate two generations of an Iranian family with NOA and identified a homozygous splicing variant in TDRKH (NM_001083965.2: c.562-2A>T). TDRKH encodes a conserved mitochondrial membrane-anchored factor essential for piRNA biogenesis in germ cells. In Tdrkh knockout mice, de-repression of retrotransposons in germ cells leads to spermatogenic arrest and male infertility. Previously, our team reported TDRKH involvement in human NOA cases through the investigation of a North African cohort. This current study marks the second report of TDRKH's role in NOA and human male infertility, underscoring the significance of the piRNA pathway in spermatogenesis. Furthermore, across both studies, we demonstrated that men carrying TDRKH variants, similar to knockout mice, exhibit complete spermatogenic arrest, correlating with failed testicular sperm retrieval.

Construction of m6A-Related Gene Prediction Model and Subtype Analysis in Non-Obstructive Azoospermia Based on Bioinformatics.

PURPOSE: Non-obstructive azoospermia (NOA) is a severe and common cause of male infertility. Currently, the most reliable predictor of sperm retrieval success in NOA is histopathology, but preoperative testicular biopsy often increases the difficulty of sperm retrieval surgery. This study aims to explore the characteristics of N6-methyladenosine (m6A) modification in NOA patients and investigate the potential biomarkers and molecular mechanisms for pathological diagnosis and treatment of NOA using m6A-related genes. METHODS: NOA-related datasets were downloaded from the GEO database. Based on the results of LASSO regression analysis, a prediction model was established from differentially expressed m6A-related genes, and the predictive performance of the model was evaluated using ROC curves. Cluster analysis was performed based on differentially expressed m6A-related genes to evaluate the differences in different m6A modification patterns in terms of differentially expressed genes (DEGs), biological features, and immune features. RESULTS: There were significant differences in eight m6A-related genes between NOA samples and healthy controls. The ROC curves showed excellent predictive performance for the diagnostic models constructed with ALKBH5 and FTO. DEGs of two m6A modification subtypes indicated the influence of m6A-related genes in the biological processes of mitosis and meiosis in NOA patients, and there were significant immune differences between the two subtypes. CONCLUSION: The NOA pathological diagnostic models constructed with FTO and ALKBH5 have good predictive ability. We have identified two different m6A modification subtypes, which may help predict sperm retrieval success rate and treatment selection in NOA patients.

Severe Hypertrophic Cardiomyopathy Associated With Hydroxychloroquine in a Young Woman With Systemic Lupus Erythematosus: A Case Report and Review of the Literature.

The use of the antimalarial drug hydroxychloroquine is a standard treatment in patients with systemic lupus erythematosus. It helps reduce disease-associated damage, prevents disease flare, and improves overall survival. The mechanism of action of hydroxychloroquine includes interference with lysosomal degradation of cells leading to the accumulation of vacuoles. Retinopathy is a well-described adverse effect of hydroxychloroquine, thus requiring screening with an ophthalmologist after prolonged use. Although rarely reported, cardiac adverse effects of hydroxychloroquine can also occur. In this report, we present a case of a 23-year-old woman with systemic lupus erythematosus on hydroxychloroquine who presented with stroke possibly due to Libman-Sacks endocarditis and was found to have severe hypertrophic cardiomyopathy on transthoracic echocardiogram.

Intraoperative evaluation for endoleaks using the SCORPION procedure during endovascular aortic repair.

OBJECTIVES: Endoleaks are important complications of endovascular aortic repair. Usually, endoleaks are judged indirectly by aortography or postoperative computed tomography. However, findings from these modalities are difficult to distinguish because of the divergency of endoleaks. Few studies have reported direct visualization of endoleaks. Herein, we introduce a direct procedure for intraoperatively evaluating endoleaks using angioscopy. METHODS: From April 2023, consecutive patients with an abdominal aortic aneurysm, except emergency cases and those of narrow access, seen at Sunagawa City Medical Center were enrolled in our study. Endoleaks were detected by intraoperative angioscopy using a novel endovascular procedure. RESULTS: Seven patients underwent endovascular aortic repair of an abdominal aortic aneurysm with intraoperative angioscopy. None of the enrolled patients experienced complications. The procedure revealed types 2, 3a, and 4 endoleaks. CONCLUSIONS: This is the first study to demonstrate intraoperative visualization of endoleaks using angioscopy. Direct findings observed by this novel procedure might provide information on the velocity and volume of the endoleak, providing comprehensive insights into the intra-sac hemodynamics after the endovascular aortic repair.

Coronary artery thromboembolism as a cause of myocardial infarction with non-obstructive coronary arteries (MINOCA).

Acute myocardial infarction (AMI) usually represents the clinical manifestation of atherothrombotic coronary artery disease (CAD) resulting from atherosclerotic plaque rupture. However, there are cases in which coronary angiography or coronary computed tomography angiography reveals patients with acute coronary syndrome with non-obstructive CAD. This clinical entity is defined as myocardial infarction with non-obstructive coronary arteries (MINOCA) and often considered as a clinical dynamic working diagnosis that needs further investigations for the establishment of a final etiologic diagnosis. The main causes of a MINOCA working diagnosis include atherosclerotic, non-atherosclerotic (vessel-related and non-vessel-related), and thromboembolic causes This literature review aimed to investigate the major thromboembolic causes in patients presenting with MINOCA regarding their etiology and pathophysiologic mechanisms, as well as diagnostic and treatment methods.

FANCM Gene Variants in a Male Diagnosed with Sertoli Cell-Only Syndrome and Diffuse Astrocytoma.

Azoospermia is a form of male infertility characterized by a complete lack of spermatozoa in the ejaculate. Sertoli cell-only syndrome (SCOS) is the most severe form of azoospermia, where no germ cells are found in the tubules. Recently, FANCM gene variants were reported as novel genetic causes of spermatogenic failure. At the same time, FANCM variants are known to be associated with cancer predisposition. We performed whole-exome sequencing on a male patient diagnosed with SCOS and a healthy father. Two compound heterozygous missense mutations in the FANCM gene were found in the patient, both being inherited from his parents. After the infertility assessment, the patient was diagnosed with diffuse astrocytoma. Immunohistochemical analyses in the testicular and tumor tissues of the patient and adequate controls showed, for the first time, not only the existence of a cytoplasmic and not nuclear pattern of FANCM in astrocytoma but also in non-mitotic neurons. In the testicular tissue of the SCOS patient, cytoplasmic anti-FANCM staining intensity appeared lower than in the control. Our case report raises a novel possibility that the infertile carriers of FANCM gene missense variants could also be prone to cancer development.

Research progress on the fanconi anemia signaling pathway in non-obstructive azoospermia.

Non-obstructive azoospermia (NOA) is a disease characterized by spermatogenesis failure and comprises phenotypes such as hypospermatogenesis, mature arrest, and Sertoli cell-only syndrome. Studies have shown that FA cross-linked anemia (FA) pathway is closely related to the occurrence of NOA. There are FA gene mutations in male NOA patients, which cause significant damage to male germ cells. The FA pathway is activated in the presence of DNA interstrand cross-links; the key step in activating this pathway is the mono-ubiquitination of the FANCD2-FANCI complex, and the activation of the FA pathway can repair DNA damage such as DNA double-strand breaks. Therefore, we believe that the FA pathway affects germ cells during DNA damage repair, resulting in minimal or even disappearance of mature sperm in males. This review summarizes the regulatory mechanisms of FA-related genes in male azoospermia, with the aim of providing a theoretical reference for clinical research and exploration of related genes.

Whole transcriptome analysis to identify non-coding RNA regulators and hub genes in sperm of non-obstructive azoospermia by microarray, single-cell RNA sequencing, weighted gene co-expression network analysis, and mRNA-miRNA-lncRNA interaction analysis.

BACKGROUND: The issue of male fertility is becoming increasingly common due to genetic differences inherited over generations. Gene expression and evaluation of non-coding RNA (ncRNA), crucial for sperm development, are significant factors. This gene expression can affect sperm motility and, consequently, fertility. Understanding the intricate protein interactions that play essential roles in sperm differentiation and development is vital. This knowledge could lead to more effective treatments and interventions for male infertility. MATERIALS AND METHODS: Our research aim to identify new and key genes and ncRNA involved in non-obstructive azoospermia (NOA), improving genetic diagnosis and offering more accurate estimates for successful sperm extraction based on an individual's genotype. RESULTS: We analyzed the transcript of three NOA patients who tested negative for genetic sperm issues, employing comprehensive genome-wide analysis of approximately 50,000 transcript sequences using microarray technology. This compared gene expression profiles between NOA sperm and normal sperm. We found significant gene expression differences: 150 genes were up-regulated, and 78 genes were down-regulated, along with 24 ncRNAs up-regulated and 13 ncRNAs down-regulated compared to normal conditions. By cross-referencing our results with a single-cell genomics database, we identified overexpressed biological process terms in differentially expressed genes, such as "protein localization to endosomes" and "xenobiotic transport." Overrepresented molecular function terms in up-regulated genes included "voltage-gated calcium channel activity," "growth hormone-releasing hormone receptor activity," and "sialic acid transmembrane transporter activity." Analysis revealed nine hub genes associated with NOA sperm: RPL34, CYB5B, GOL6A6, LSM1, ARL4A, DHX57, STARD9, HSP90B1, and VPS36. CONCLUSIONS: These genes and their interacting proteins may play a role in the pathophysiology of germ cell abnormalities and infertility.

Parameters affecting the success rate of microscopic testicular sperm extraction in male patients with a solitary testis and non-obstructive azoospermia.

PURPOSE: We aimed to compare the success rate of spermatozoa retrieval through microscopic testicular sperm extraction (mTESE) in non-obstructive azoospermic (NOA) men with a solitary testis with that of mTESE in NOA men with bilateral testes and the parameters affecting these rates. METHODS: A retrospective cross-sectional study of factors contributing to infertility in NOA patients with a solitary testis and men with bilateral testes was carried out. In this multicenter study, 74 patients with NOA with a solitary testis were matched with 74 patients with bilateral testes in terms of age, duration of infertility, and volume of the solitary testis from 2770 patients with NOA with bilateral testes. Hormonal parameters, presence of varicocele, history of varicocelectomy, history of undescended testis and karyotype analysis results were compared. RESULTS: Spermatozoa were obtained from 40 (54.1%) patients with a solitary testis and 42 (56.76%) patients with bilateral testes. No differences were found regarding age, duration of infertility, or mean testicular volume between patients with a solitary testis and patients with bilateral testes. When serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were compared regardless of sperm retrieval status, it was observed that both levels were greater in the group of patients with a solitary testis (p < 0.01). Patients with solitary and bilateral testes from whom spermatozoa were obtained had larger testes than those from whom spermatozoa could not be obtained (p < 0.05). Similarly, the serum levels of FSH and LH were significantly greater in patients with a solitary testis than in those with bilateral testes (p < 0.05). CONCLUSIONS: To the best of our knowledge, this is the first study in the literature to evaluate the parameters that influence mTESE outcome in NOA patients with a solitary testis and NOA patients with bilateral testes. Greater testicular volume was found to positively affect spermatozoa retrieval for patients with a solitary testis. The higher levels of FSH and LH in patients with a solitary testis than in patients with bilateral testes of similar testicular volume may be due to a compensatory mechanism developed by the hypothalamic-pituitary-gonadal axis. The fact that these hormones are higher in patients with a solitary testis does not mean that the number of spermatozoa obtained through mTESE will be decreased.

Sacral neuromodulation therapy for urinary and defecatory disorders: experience in a Latin American public hospital.

Objective: To show the experience of a Latin American public hospital, with SNM in the management of either OAB, NOUR or FI, reporting feasibility, short to medium-term success rates, and complications. Methods: A retrospective cohort was conducted using data collected prospectively from patients with urogynecological conditions and referred from colorectal surgery and urology services between 2015 and 2022. Results: Advanced or basic trial phases were performed on 35 patients, 33 (94%) of which were successful and opted to move on Implantable Pulse Generator (GG) implantation. The average follow-up time after definitive implantation was 82 months (SD 59). Of the 33 patients undergoing, 27 (81%)reported an improvement of 50% or more in their symptoms at last follow-up. Moreover, 30 patients (90%) with a definitive implant reported subjective improvement, with an average PGI-I "much better" and 9 of them reporting to be "excellent" on PGI-I. Conclusion: SNM is a feasible and effective treatment for pelvic floor dysfunction. Its implementation requires highly trained groups and innovative leadership. At a nation-wide level, greater diffusion of this therapy among professionals is needed to achieve timely referral of patients who require it.

Comparing planned versus ad hoc coronary microvascular assessment: Early findings from the Coronary Microvascular Disease Registry.

BACKGROUND: Coronary microvascular dysfunction (CMD) is an etiology for angina with non-obstructive coronary disease. However, the initial adoption of CMD assessment, whether planned or conducted ad hoc, is limited. We characterize planned and ad hoc CMD assessments and highlight evolving trends of a CMD referral center. METHODS: We analyzed outpatient data from the Coronary Microvascular Disease Registry from 2021 to 2023. Patients were categorized into planned or ad hoc CMD assessment groups, and baseline characteristics, hospital stay, medications, and physiological measurements were compared. Secondary analysis evaluated a CMD referral center's evolution. RESULTS: Of 101 included outpatients, 67.3 % underwent ad hoc procedures and 32.7 % planned procedures. Average age was 63.1 ± 10.1 years. The planned procedure group was 87.9 % female, and the ad hoc procedure group was 51.5 % female. There were no significant differences in index of microvascular resistance or coronary flow reserve between groups. Hospital stay duration was <1 day for both groups, and neither reported complications. Ad hoc patients were more frequently prescribed aspirin before (64.7 % vs. 36.4 %, p = 0.007) and after the procedure (66.2 % vs. 39.4 %, p = 0.01). CMD rates were higher for planned procedures (30.3 % vs. 10.3 %, p = 0.01). We observed that CMD referral centers have more planned procedures and a higher rate of positive results over time. CONCLUSION: CMD referral centers' planned procedures, and subsequent positive cases, increased over time. This emphasizes the importance of planned procedures, appropriate patient selection, and increased awareness of CMD among healthcare providers. CLINICAL TRIAL REGISTRATION: Coronary Microvascular Disease (CMD) Registry, NCT05960474, https://clinicaltrials.gov/study/NCT05960474.

Immune-inflammatory biomarkers for the occurrence of MACE in patients with myocardial infarction with non-obstructive coronary arteries.

Background: Neutrophil-to-high-density lipoprotein cholesterol ratio (NHR), monocyte-to-high-density lipoprotein cholesterol ratio (MHR), lymphocyte-to-high-density lipoprotein cholesterol ratio (LHR), platelet-to-high-density lipoprotein cholesterol ratio (PHR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and aggregate index of systemic inflammation (AISI) have been identified as immune-inflammatory biomarkers associated with the prognosis of cardiovascular diseases. However, the relationship of these biomarkers with the prognosis of myocardial infarction with non-obstructive coronary arteries (MINOCA) remains unclear. Method: Patients with MINOCA who underwent coronary angiography at the 920th Hospital of Joint Logistics Support Force were included in our study. Clinical baseline characteristics and laboratory testing data were collected from the hospital record system. The patients were divided into two groups on the basis of major adverse cardiovascular events (MACE) occurrence. Multiple logistic regression analysis was conducted to assess the relationship between NHR, MHR, LHR, PHR, SII, SIRI, AISI, and MACE. Receiver operating characteristic (ROC) curves were generated to evaluate the predictive value of NHR, MHR, LHR, PHR, SII, SIRI, and AISI for MACE in patients with MINOCA. The accuracy of the prediction was indicated by the area under the curve (AUC) value. Results: The study included 335 patients with MINOCA. (81 in the MACE group and 254 in the No-MACE group). The MACE group had higher levels of NHR, MHR, LHR, PHR, SII, SIRI, and AISI than the No-MACE group. Multiple logistic regression analysis adjusted for confounding factors indicated that the higher levels of NHR, MHR, PHR, SII, SIRI, and AISI were associated with the occurrence of MACE in patients with MINOCA (P < 0.001). The AUC values for NHR, MHR, PHR, SII, SIRI, and AISI were 0.695, 0.747, 0.674, 0.673, 0.688, and 0.676, respectively. The combination of NHR, MHR, PHR, SII, SIRI, and AISI improved the accuracy of predicting MACE in patients with MINOCA (AUC = 0.804). Conclusion: Higher levels of NHR, MHR, PHR, SII, SIRI, and AISI were associated with the occurrence of MACE, and the combination of NHR, MHR, PHR, SII, SIRI, and AISI improved the accuracy for predicting the incidence of MACE events in patients with MINOCA.

Eligibility for the medical therapy among men with non-obstructive azoospermia-Findings from a multi-centric cross-sectional study.

BACKGROUND: Existing literature does not provide accurate epidemiological data regarding the true prevalence of men with non-obstructive azoospermia (NOA) who would be eligible for hormonal optimization therapy, according to specific pre-treatment criteria. OBJECTIVES: To investigate the characteristics of those men with NOA who would qualify for the medical therapy prior to any SR procedure in a large multi-centric cross-sectional study. MATERIALS AND METHODS: Complete data from 1644 NOA patients seeking medical help for primary infertility at three tertiary referral centers from USA, Brazil, and Italy were analyzed. Baseline serum hormone levels were collected for all patients. NOA was confirmed after two consecutive semen analyses. Genetic tests, including karyotype analysis and Y microdeletions, were performed on all patients. Patients with secondary hypogonadism (total testosterone (T) levels less than 300 ng/dL and luteinizing hormone (LH) levels less than 8 mIU/mL) were earmarked as potential candidates for receiving clomiphene citrate (CC) and/or human chorionic gonadotropin (hCG). Patients with a T to 17ß-estradiol (E2) ratio < 10 were classified as eligible for aromatase inhibitors (AIs) therapy (e.g., anastrazole). A third sub-cohort was created by combining the criteria of the first two sub-cohorts. Descriptive statistics was used to detail overall characteristics and differences between the different sub-cohorts. RESULTS: Among the 1,644 men, 28% (n = 460) had T < 300 ng/dL and LH < 8 mIU/mL, thereby being potentially suitable for CC and/or hCG, while 37% (n = 607) had a T to E2 ratio < 10 thus potentially suitable for AIs. Lastly, 17.7% (n = 280) met the criteria for potential eligibility for both CC and/or hCG and AIs. CONCLUSIONS: Findings from this multicentric cross-sectional study reveal that about 30% of men with NOA were eligible for hormonal treatment with CC and/or hCG while 37% were found to be potential candidates for AIs, and 17% for both therapies. Therefore, these findings show that a only a small subset of NOA patients can benefit from medical therapy prior to considering any SR procedures.

Non-invasive biomarkers for sperm retrieval in non-obstructive patients: a comprehensive review.

Recent advancements in reproductive medicine have guided novel strategies for addressing male infertility, particularly in cases of non-obstructive azoospermia (NOA). Two prominent invasive interventions, namely testicular sperm extraction (TESE) and microdissection TESE (micro-TESE), have emerged as key techniques to retrieve gametes for assisted reproduction technologies (ART). Both heterogeneity and complexity of NOA pose a multifaceted challenge to clinicians, as the invasiveness of these procedures and their unpredictable success underscore the need for more precise guidance. Seminal plasma can be aptly regarded as a liquid biopsy of the male reproductive tract, encompassing secretions from the testes, epididymides, seminal vesicles, bulbourethral glands, and prostate. This fluid harbors a variety of cell-free nucleic acids, microvesicles, proteins, and metabolites intricately linked to gonadal activity. However, despite numerous investigations exploring potential biomarkers from seminal fluid, their widespread inclusion into the clinical practice remains limited. This could be partially due to the complex interplay of diverse clinical and genetic factors inherent to NOA that likely contributes to the absence of definitive biomarkers for residual spermatogenesis. It is conceivable that the integration of clinical data with biomarkers could increase the potential in predicting surgical procedure outcomes and their choice in NOA cases. This comprehensive review addresses the challenge of sperm retrieval in NOA through non-invasive biomarkers. Moreover, we delve into promising perspectives, elucidating innovative approaches grounded in multi-omics methodologies, including genomics, transcriptomics and proteomics. These cutting-edge techniques, combined with the clinical and genetics features of patients, could improve the use of biomarkers in personalized medical approaches, patient counseling, and the decision-making continuum. Finally, Artificial intelligence (AI) holds significant potential in the realm of combining biomarkers and clinical data, also in the context of identifying non-invasive biomarkers for sperm retrieval.

Chemokine Fractalkine and Non-Obstructive Coronary Artery Disease-Is There a Link?

Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major coronary artery with a fractional flow reserve (FFR) of ≤0.80 observed in coronary angiography. The pathogenesis and progression of NO-CAD are still not fully understood, however, inflammatory processes, particularly atherosclerosis and microvascular dysfunction are known to play a major role in it. Chemokine fractalkine (FKN/CX3CL1) is inherently linked to these processes. FKN/CX3CL1 functions predominantly as a chemoattractant for immune cells, facilitating their transmigration through the vessel wall and inhibiting their apoptosis. Its concentrations correlate positively with major cardiovascular risk factors. Moreover, promising preliminary results have shown that FKN/CX3CL1 receptor inhibitor (KAND567) administered in the population of patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), inhibits the adverse reaction of the immune system that causes hyperinflammation. Whereas the link between FKN/CX3CL1 and NO-CAD appears evident, further studies are necessary to unveil this complex relationship. In this review, we critically overview the current data on FKN/CX3CL1 in the context of NO-CAD and present the novel clinical implications of the unique structure and function of FKN/CX3CL1 as a compound which distinctively contributes to the pathomechanism of this condition.

Coronary Microvascular Disease Registry (CMDR): Study design and rationale.

BACKGROUND: Coronary microvascular dysfunction (CMD) is a prevalent condition among patients with cardiovascular risk factors, leading to a reduced quality of life and an increased risk of major adverse cardiovascular events. Novel invasive techniques have emerged to more accurately diagnose CMD. However, CMD's natural history remains poorly understood due to limited data. To address this knowledge gap, the Coronary Microvascular Disease Registry (CMDR) was established with the primary aim of standardizing comprehensive coronary functional testing and understanding of CMD. DESIGN: CMDR is a prospective, multicenter registry enrolling an unlimited number of consecutive subjects who undergo comprehensive invasive hemodynamic assessment of the entire coronary arterial vasculature. Patients undergoing acetylcholine provocation test for coronary vasospasm will also be included. Follow-up assessments will be conducted at 30 days and annually for up to 5 years. The primary endpoint is Canadian Cardiovascular Society angina grade over time. Secondary endpoints, including all-cause mortality, cardiovascular death, acute myocardial infarction, stroke, hospitalizations, medication changes, and subsequent coronary interventions, will be analyzed to establish long-term safety and clinical outcomes in patients undergoing invasive CMD assessment. SUMMARY: CMDR aims to characterize the clinical and physiologic profile of patients undergoing comprehensive invasive coronary functional testing, simultaneously providing crucial longitudinal information on the natural history and outcomes of these patients. This will shed light on CMD's course and clinical implications, which, in turn, holds the potential to significantly improve diagnostic and treatment strategies for CMD patients, ultimately leading to the enhancement of their overall prognosis and quality of life. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov, NCT05960474.

Comparison of Baseline and Post-Nitrate Exercise Testing in Patients with Angina but Non-Obstructed Coronary Arteries with Different Acetylcholine Test Results.

Background: Intracoronary acetylcholine testing may induce epicardial coronary artery spasm (CAS) or coronary microvascular spasm (CMVS) in patients with angina syndromes but non-obstructive coronary artery disease, but their causal role in individual patients is not always clear. In this prospective, observational single-center study, we aimed to assess whether (1) the induction of myocardial ischemia/angina by electrocardiogram (ECG) exercise stress test (EST) differs between patients showing different results in response to acetylcholine testing (i.e., CAS, CMVS, or no spasm); (2) the preventive administration of short-acting nitrates has any different effects on the EST of those patients who showed a positive basal EST. We expected that if exercise-induced angina and/or ischemic ECG changes are related to CAS, they should improve after nitrates administration, whereas they should not significantly improve if they are caused by CMVS. Methods: We enrolled 81 patients with angina syndromes and non-obstructive coronary artery disease, who were divided into three groups according to acetylcholine testing: 40 patients with CAS (CAS-group), 14 with CMVS (CMVS-groups), and 27 with a negative test (NEG-group). All patients underwent a basal EST (B-EST). Patients with a positive B-EST repeated the test 24-48 h later, 5 min after the administration of short-acting nitrates (N-EST). Results: There were no significant differences among the groups in terms of the B-EST results. B-EST was positive in eight (20%) patients in the CAS-group, seven (50%) in the CMVS-group, and six (22%) in the NEG-group (p = 0.076). N-EST, performed in eight, six, and five of these patients, also showed similar results in the three groups. Furthermore, the N-EST results also did not significantly differ compared to B-EST in any group, remaining positive in seven (87.5%), four (66.7%), and four (80%) patients in the CAS-group, CMVS-group, and NEG-group, respectively (p = 0.78). Conclusions: Our data show that patients with angina and non-obstructive coronary artery disease show largely comparable results of the ECG exercise stress test and similar poor effects of short-acting nitrates on abnormal ECG exercise stress test results. On the whole, our findings suggest caution in attributing to the results of Ach testing a definite causal role for the clinical syndrome in individual patients.

Recurrent angina and cardiac ischaemia as a presentation of pheochromocytoma: a case report.

Background: We present a case of a pregnant patient with recurrent angina, in which her symptoms were initially attributed to coronary artery spasm. However, during follow-up, she was diagnosed as having pheochromocytoma, a rare neuroendocrine tumour. Case summary: The 35-year-old patient was admitted to the hospital because of chest pain and elevated cardiac troponins after the use of MDMA. Physical examination, electrocardiogram, echocardiography, coronary angiogram, and cardiac MRI were normal. Symptoms were attributed to coronary spasm, and a calcium antagonist was started. Ten months later, when 36 weeks pregnant, her symptoms returned. One week later, the patient was readmitted to the hospital with signs of acute left ventricular (LV) failure, highly elevated troponins, and severe global LV dysfunction. Urgent section caesarean was performed due to maternal morbidity and foetal tachycardia. During section, flushes and marked variability in blood pressure were noted. Laboratory metanephrines testing was performed. LV function recovered within 3 days without any therapeutic intervention. However, chest pain reoccurred, now accompanied with headaches, malignant hypertension, and accelerated idiopathic ventricular rhythms. (Nor)metanephrines tests were positive. A solid lesion in the right adrenal on CT scan confirmed the diagnosis of pheochromocytoma. Fluid repletion and alpha-blocker therapy were started. Due to persistent symptoms, urgent laparoscopic adrenalectomy was performed. Hereafter, the patient remained without symptoms. Discussion: A pheochromocytoma may present with recurrent angina and can result in a catecholamine-induced cardiomyopathy. It is important to timely recognize this diagnosis in order to minimize morbidity and mortality.

Psychosocial distress and health status as risk factors for ten-year major adverse cardiac events and mortality in patients with non-obstructive coronary artery disease.

BACKGROUND: We examined the risk of psychosocial distress, including Type D personality, depressive symptoms, anxiety, positive mood, hostility, and health status fatigue and disease specific and generic quality of life for MACE in patients with non-obstructive coronary artery disease (NOCAD). METHODS: In the Tweesteden mild stenosis (TWIST) study, 546 patients with NOCAD were followed for 10 years to examine the occurrence of cardiac mortality, a major cardiac event, or non-cardiac mortality in the absence of a cardiac event. Cox proportional hazard models were used to examine the impact of psychosocial distress and health status on the occurrence of MACE while adjusting for age, sex, disease severity, and lifestyle covariates. RESULTS: In total 19% of the patients (mean age baseline = 61, SD 9 years; 52% women) experienced MACE, with a lower risk for women compared to men. Positive mood (HR 0.97, 95%CI 0.95-1.00), fatigue (HR 1.03, 95%CI 1.00-1.06), and physical limitation (HR 0.99, 95%CI 0.98-1.00) were associated with MACE in adjusted models. No significant interactions between sex and psychosocial factors were present. Depressive symptoms were predictive of MACE, but no longer after adjustment. CONCLUSIONS: In patients with NOCAD fatigue, low positive mood, and a lower physical limitation score were associated with MACE, without marked sex differences. Type D personality, psychosocial factors, and health status were not predictive of adverse outcomes. Reducing psychosocial distress is a valid intervention goal by itself, though it is less likely to affect MACE in patients with NOCAD.