When small vessels become big problems! Microvascular dysfunction in NSTEMI.

In a carefully selected cohort of 83 NSTEMI patients, there was a wide variation in the index of microcirculatory resistance (IMR) Elevated IMR, which correlates with microvascular obstruction by MRI, was an independent predictor of adverse cardiovascular outcomes in patients with NSTEMI Further investigation is warranted to understand the influence of the microvascular on prognosis following myocardial infarction.

Genome-wide association and pathway analysis of left ventricular function after anthracycline exposure in adults.

BACKGROUND: Anthracyclines are important chemotherapeutic agents, but their use is limited by cardiotoxicity. Candidate gene and genome-wide studies have identified putative risk loci for overt cardiotoxicity and heart failure, but there has been no comprehensive assessment of genomic variation influencing the intermediate phenotype of anthracycline-related changes in left ventricular (LV) function. The purpose of this study was to identify genetic factors influencing changes in LV function after anthracycline chemotherapy. METHODS: We conducted a genome-wide association study (GWAS) of change in LV function after anthracycline exposure in 385 patients identified from BioVU, a resource linking DNA samples to de-identified electronic medical record data. Variants with P values less than 1×10 were independently tested for replication in a cohort of 181 anthracycline-exposed patients from a prospective clinical trial. Pathway analysis was performed to assess combined effects of multiple genetic variants. RESULTS: Both cohorts were middle-aged adults of predominantly European descent. Among 11 candidate loci identified in discovery GWAS, one single nucleotide polymorphism near PR domain containing 2, with ZNF domain (PRDM2), rs7542939, had a combined P value of 6.5×10 in meta-analysis. Eighteen Kyoto Encyclopedia of Gene and Genomes pathways showed strong enrichment for variants associated with the primary outcome. Identified pathways related to DNA repair, cellular metabolism, and cardiac remodeling. CONCLUSION: Using genome-wide association we identified a novel candidate susceptibility locus near PRDM2. Variation in genes belonging to pathways related to DNA repair, metabolism, and cardiac remodeling may influence changes in LV function after anthracycline exposure.

Elevated serum gamma-glutamyltransferase activity and immunohistochemistry in two dogs with renal carcinoma.

During a 3-year time period, a 15-year-old male castrated Terrier mix (dog 1) and a 6-year-old female spayed Labrador Retriever (dog 2) presented to the North Carolina State Veterinary Hospital with similar blood work abnormalities and no significant physical examination findings. A CBC, chemistry panel, and urinalysis performed on both dogs were relatively unremarkable, other than a marked increase in serum gamma-glutamyltransferase (GGT) activity. Through imaging, both patients were diagnosed with a renal mass, and histopathology of both masses revealed a carcinoma. Immunohistochemical staining of the renal mass in both dog 1 and dog 2 were intensely positive for GGT. Dog 1 had the affected kidney removed, which normalized the GGT value. Dog 2 was euthanized, and metastasis to the lung was noted upon postmortem examination. There have been limited case studies documenting an elevation in serum GGT in dogs diagnosed with renal carcinoma. While renal carcinoma is uncommon in dogs, it is an important differential to keep in mind when there is a marked increase in serum GGT without accompanying increases in other measured liver enzymes. In addition, serum GGT can serve as a helpful biomarker for disease resolution and recurrence, as surgical removal of the renal mass (dog 1) led to the resolution of the elevated serum GGT. To our knowledge, this is the first report demonstrating IHC staining for GGT in a canine renal carcinoma.

Toward an integrated model of capsule regulation in Cryptococcus neoformans.

Cryptococcus neoformans is an opportunistic fungal pathogen that causes serious human disease in immunocompromised populations. Its polysaccharide capsule is a key virulence factor which is regulated in response to growth conditions, becoming enlarged in the context of infection. We used microarray analysis of cells stimulated to form capsule over a range of growth conditions to identify a transcriptional signature associated with capsule enlargement. The signature contains 880 genes, is enriched for genes encoding known capsule regulators, and includes many uncharacterized sequences. One uncharacterized sequence encodes a novel regulator of capsule and of fungal virulence. This factor is a homolog of the yeast protein Ada2, a member of the Spt-Ada-Gcn5 Acetyltransferase (SAGA) complex that regulates transcription of stress response genes via histone acetylation. Consistent with this homology, the C. neoformans null mutant exhibits reduced histone H3 lysine 9 acetylation. It is also defective in response to a variety of stress conditions, demonstrating phenotypes that overlap with, but are not identical to, those of other fungi with altered SAGA complexes. The mutant also exhibits significant defects in sexual development and virulence. To establish the role of Ada2 in the broader network of capsule regulation we performed RNA-Seq on strains lacking either Ada2 or one of two other capsule regulators: Cir1 and Nrg1. Analysis of the results suggested that Ada2 functions downstream of both Cir1 and Nrg1 via components of the high osmolarity glycerol (HOG) pathway. To identify direct targets of Ada2, we performed ChIP-Seq analysis of histone acetylation in the Ada2 null mutant. These studies supported the role of Ada2 in the direct regulation of capsule and mating responses and suggested that it may also play a direct role in regulating capsule-independent antiphagocytic virulence factors. These results validate our experimental approach to dissecting capsule regulation and provide multiple targets for future investigation.

Recurrent Out-of-Hospital Sudden Cardiac Arrest: Prevalence and Clinical Factors.

BACKGROUND: Despite improvements in management following survival from sudden cardiac arrest (SCA) and wide availability of implantable cardioverter defibrillators for secondary prevention, a subgroup of individuals will suffer multiple distinct episodes of SCA. The objective of this study was to characterize and evaluate the burden of recurrent out-of-hospital SCA among survivors of SCA in a single large US community. METHODS: SCA cases were prospectively ascertained in the Oregon Sudden Unexpected Death Study. Individuals that experienced recurrent SCA were identified both prospectively and retrospectively. RESULTS: We ascertained 6649 individuals with SCA (2002-2020) and 924 (14%) survived to hospital discharge. Of these, 88 survivors (10%) experienced recurrent SCA. Of the nonsurvivors (n=5725), 35 had suffered a recurrent SCA. Of the total 123 SCA cases with recurrent SCA, >60% occurred at least 1 year after the initial SCA (median 23 months, range: 6 days to 31 years). SCA occurred despite a secondary prevention implantable cardioverter defibrillator in 22% (n=26). Prevalence of coronary disease (36% versus 25%), hypertension (69% versus 43%), diabetes (44% versus 21%), and chronic kidney disease (35% versus 14%) was significantly higher in recurrent SCA versus single SCA survivors (n=80, P=0.01). Among individuals with no secondary prevention implantable cardioverter defibrillators before recurrent SCA, the majority had apparently reversible etiologies identified at initial SCA, with one-quarter undergoing coronary revascularization and over half diagnosed with noncoronary cardiac etiologies. CONCLUSIONS: At least 10% of SCA survivors had recurrent SCA, and a large subgroup suffered their repeat SCA despite treatment for an apparently reversible etiology. A renewed focus on careful assessment of cardiac substrate as well as management of coronary disease, hypertension, diabetes, and chronic kidney disease in SCA survivors could reduce recurrent SCA.

Remodeling of the 12-lead electrocardiogram in immediate survivors of sudden cardiac arrest.

BACKGROUND: The ECG is a critical diagnostic tool for the management of immediate sudden cardiac arrest (SCA) survivors, but can be altered as a consequence of the SCA event. A limited number of studies report that electrical remodeling post SCA is due to prolonged myocardial repolarization, but a better understanding of this phenomenon is needed. AIM: To identify specific ECG abnormalities that follow SCA in immediate survivors. METHODS: SCA survivors with a pre-arrest ECG and an ECG obtained within 48 h post-SCA were prospectively collected in the Oregon Sudden Unexpected Death Study (Portland metro region) from 2002-2015. Ventricular depolarization and repolarization measurements were compared between pre-arrest and post-arrest ECGs using paired t-tests and assessed for association with survival using unpaired t-tests and Pearson's chi-square tests. RESULTS: A pre-arrest ECG and post-arrest ECG were available for 297 SCA cases (67.8 ±â€¯13.4 years; 65.3% male). From the pre- to post-arrest setting, there was a significant mean increase in QRS (21 ms, p < 0.001) and QTc (35 ms, p < 0.001) in each SCA case, while there was no significant change in the JTc (4 ms, p = 0.361). Post-arrest QRS duration was significantly shorter in cases who survived to hospital discharge compared with those who did not survive (mean QRSD 115 ±â€¯29 ms vs 127 ±â€¯34 ms; p = 0.006). CONCLUSIONS: Contrary to expectations, electrical remodeling of the ECG due to SCA occurs due to prolongation of ventricular depolarization (QRSD), and not repolarization (JTc). Prolonged QRSD may also assist with prognostication and warrants further evaluation.

Neurosarcoidosis Presenting as Aseptic Meningitis in an Immunosuppressed Renal Transplant Recipient.

BACKGROUND: Sarcoidosis is a presumptive autoimmune disorder characterized by the presence of noncaseating granulomas and is usually treated successfully with immunosuppression. METHODS AND RESULTS: Here, we describe the case of a 63-year-old male renal transplant recipient with a remote history of pulmonary sarcoidosis on chronic immunosuppression who developed recurrent aseptic meningitis and underwent brain biopsy revealing a diagnosis of neurosarcoidosis. CONCLUSIONS: This case highlights the possibility of recurrence of sarcoidosis in the setting of maintenance immunosuppression, the need for heightened awareness of alternative sites of recurrence of autoimmune disease, and future studies to determine the underlying mechanism of recurrence in organ transplant recipients.