Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?

Abstract Background About 40–50% of patients with familial microscopic hematuria (FMH) caused by thin basement membrane nephropathy (TBMN) inherit heterozygous mutations in collagen IV genes (COL4A3, COL4A4). On long follow-up, the full phenotypic spectrum of these patients varies a lot, ranging from isolated MH or MH plus low-grade proteinuria to chronic renal failure of variable degree, including end-stage renal disease (ESRD). Methods Here, we performed Whole Exome Sequencing (WES) in patients of six families, presenting with autosomal dominant FMH, with or without progression to proteinuria and loss of renal function, all previously found negative for severe collagen IV mutations. Hierarchical filtering of the WES data was performed, followed by mutation prediction analysis, Sanger sequencing and genetic segregation analysis. Results In one family with four patients, we found evidence for the contribution of two co-inherited variants in two crucial genes expressed in the glomerular basement membrane (GBM); LAMA5-p.Pro1243Leu and COL4A5-p.Asp654Tyr. Mutations in COL4A5 cause classical X-linked Alport Syndrome, while rare mutations in the LAMA5 have been reported in patients with focal segmental glomerulosclerosis. The phenotypic spectrum of the patients includes hematuria, proteinuria, focal segmental glomerulosclerosis, loss of kidney function and renal cortical cysts. Conclusions A modifier role of LAMA5 on the background of a hypomorphic Alport syndrome causing mutation is a possible explanation of our findings. Digenic inheritance is another scenario, following the concept that mutations at both loci more accurately explain the spectrum of symptoms, but further investigation is needed under this concept. This is the third report linking a LAMA5 variant with human renal disease and expanding the spectrum of genes involved in glomerular pathologies accompanied by familial hematurias. The cystic phenotype overlaps with that of a mouse model, which carried a Lama5 hypomorphic mutation that caused severely reduced Lama5 protein levels and produced kidney cysts

Additional file 1: of COL4A5 and LAMA5 variants co-inherited in familial hematuria: digenic inheritance or genetic modifier effect?

WES statistics. Number of genetic variants called after the WES analysis. (DOCX 15 kb

Frequency of COL4A3/COL4A4 mutations amongst families segregating glomerular microscopic hematuria and evidence for activation of the unfolded protein response. Focal and segmental glomerulosclerosis is a frequent development during ageing.

Familial glomerular hematuria(s) comprise a genetically heterogeneous group of conditions which include Alport Syndrome (AS) and thin basement membrane nephropathy (TBMN). Here we investigated 57 Greek-Cypriot families presenting glomerular microscopic hematuria (GMH), with or without proteinuria or chronic kidney function decline, but excluded classical AS. We specifically searched the COL4A3/A4 genes and identified 8 heterozygous mutations in 16 families (28,1%). Eight non-related families featured the founder mutation COL4A3-p.(G1334E). Renal biopsies from 8 patients showed TBMN and focal segmental glomerulosclerosis (FSGS). Ten patients (11.5%) reached end-stage kidney disease (ESKD) at ages ranging from 37-69-yo (mean 50,1-yo). Next generation sequencing of the patients who progressed to ESKD failed to reveal a second mutation in any of the COL4A3/A4/A5 genes, supporting that true heterozygosity for COL4A3/A4 mutations predisposes to CRF/ESKD. Although this could be viewed as a milder and late-onset form of autosomal dominant AS, we had no evidence of ultrastructural features or extrarenal manifestations that would justify this diagnosis. Functional studies in cultured podocytes transfected with wild type or mutant COL4A3 chains showed retention of mutant collagens and differential activation of the unfolded protein response (UPR) cascade. This signifies the potential role of the UPR cascade in modulating the final phenotype in patients with collagen IV nephropathies

Clinical, pathologic and mutational analysis results for the families that mutations were found in the present patient cohort.

<p>Clinical, pathologic and mutational analysis results for the families that mutations were found in the present patient cohort.</p

Details of mutagenic primers used in this work for introducing mutations in cDNA constructs that were transiently transfected into cultured podocytes AB8/13.

<p>Details of mutagenic primers used in this work for introducing mutations in cDNA constructs that were transiently transfected into cultured podocytes AB8/13.</p

Chaperone BiP protein and PERK, a transmembrane protein kinase of the PEK family resident in the endoplasmic reticulum membrane, are deregulated in AB8/13 podocytes transfected with various <i>COL4A3</i> mutant chains.

<p><b><u>a, c</u>:</b> AB8/13 cells were transiently transfected with expression vectors containing either wild-type <i>COL4A3</i> chain or one of several mutant chains. Transfection with lipofectamine only (lipo) served as a negative control. Protein expression of the UPR markers was measured 48 hours after transfection via Western blotting. β-tubulin expression in the same samples was used as equal loading control. Shown are representative blots with differential expression levels of BiP and p-PERK for the various mutant proteins. <b><u>b, d</u>:</b> Western blotting as above, was quantified via densitometric analysis. BiP and p-PERK are up-regulated in cells over-expressing the mutant <i>COL4A3</i>-p.(G1334E), <i>COL4A3</i>-p.(G871C) and <i>COL4A3</i>-p.(G484R) while there is a trend for <i>COL4A3</i>-p.(A587G), as compared to cells expressing the wild type chain. Data are means ± SEM (n = 4 for BiP; n = 7 for p-PERK) *p<0.05; **p<0.01.</p

Electropherograms showing causative mutations found in <i>COL4A3</i> (a) and in <i>COL4A4</i> (b) genes during the course of this work.

<p>In (c) is shown a 52 bp deletion in <i>COL4A4</i> which encompasses 50 bp of exon 20 plus the two conserved <b><i>gt</i></b> bp at the donor site of intron 20. In addition to the translation frameshift introduced, it is expected that aberrant splicing will occur.</p

Summary of pathogenic <i>COL4A3/A4</i> mutations found in Greek-Cypriot families studied here.

<p>One additional deletion mutation was detected in a Cypriot of Romanian origin.</p><p>Summary of pathogenic <i>COL4A3/A4</i> mutations found in Greek-Cypriot families studied here.</p