Research Spotlight

Kristek, J., Johannesson, L., Novotny, R., Kachlik, D. and Fronek, J. (2020). “Human uterine vasculature with respect to uterus transplantation: A comprehensive review.” J Obstet Gynaecol Res Aug 24. [Epub ahead of print.].

Full text of this article.

Due to the novelty of uterus transplantation, data on preferable inflow and outflow of the graft are limited. This paper reviews the technique, type of vessels and the outcome. A systematic search of the PubMed database was conducted. We extracted and analyzed data on the arteries and veins utilized, types of anastomosis, types of donors, complications and the outcome. Thirty eight sources reported 51 human uterine transplantations, 10 graft thromboses and 25 live births. Inflow was established with two uterine arteries (UA) with/without the anterior division of the internal iliac artery in 62% (n = 31) of cases, two UA arteries with a segment/patch of the internal iliac artery in 34% (n = 17) of cases or two UA with a conduit in 4% of cases (n = 2). Both cases with a conduit developed thrombosis (n = 2). Arterial thrombosis/ischemia developed in 8 of the 51 cases. In 50% of cases with arterial thrombosis, atherosclerosis was identified as a possible cause. Outflow was established by two internal iliac veins with patches/segments in 27.5% of cases (n = 14) followed by two utero-ovarian veins in 25.5% (n = 13). Venous thrombosis occurred in 3 of the 51 cases. Uterine arteries with/without anterior division of the internal iliac artery were the most frequent arteries used for inflow and produced the highest patency rate. The presence of atherosclerosis and complex arterial reconstruction was associated with a high rate of arterial thrombosis. None of the veins utilized in the procedures appeared to be superior. There are insufficient data to draw a definite conclusion.

Kelling, J.A., Erickson, C.R., Pin, J.A. and Pin, P.G. (2020). “Additional Comments on the Anatomical Dissection of the Dorsal Nerve of the Clitoris.” Aesthet Surg J Aug 6;sjaa186. [Epub ahead of print.].

Full text of this article.

We appreciate the compliments and constructive criticism from Drs Turin and Placik, who are such experts in the field of genital surgery. We recognize the inherent limitations of our cadaver study, and their relevance to real patients. We agree that multiple cross-sections of the clitoris would be useful, and we encourage further study in this area. [No abstract; excerpt from article.].

Ferreira, J.P., Mogensen, U.M., Jhund, P.S., Desai, A.S., Rouleau, J.L., Zile, M.R., Rossignol, P., Zannad, F., Packer, M., Solomon, S.D. and McMurray, J.J.V. (2020). “Serum Potassium in the PARADIGM-HF trial.” Eur J Heart Fail Aug 18. [Epub ahead of print.].

Full text of this article.

BACKGROUND: We studied the association between potassium and outcomes, the effect of sacubitril/valsartan on potassium, and whether potassium level modified the effect of sacubitril/valsartan in patients with heart failure and a reduced ejection fraction in PARADIGM-HF. AIMS: We examined several outcomes including cardiovascular death, sudden-death, pump-failure death, non-cardiovascular death and heart failure hospitalization. METHODS: 8399 patients were randomized to either enalapril or sacubitril/valsartan. Potassium at randomization and follow-up was examined as a continuous and categorical variable (≤3.5, 3.6-4.0, 4.1-4.9, 5.0-5.4, and ≥5.5mmol/L) in various statistical models. Hyperkalemia was defined as K(+) ≥5.5mmol/L and hypokalemia as K(+) ≤3.5mmol/L. RESULTS: Compared to potassium 4.1-4.9mmol/L, both hypokalemia (HR 2.40, 95%CI 1.84-3.14) and hyperkalemia (HR 1.42, 1.10-1.83) were associated with a higher risk of cardiovascular death. However, potassium abnormalities were similarly associated with sudden death and pump failure death, as well as non-cardiovascular death and heart failure hospitalization. Sacubitril/valsartan had no effect on potassium overall. The benefit of sacubitril/valsartan over enalapril was consistent across the range of baseline potassium. CONCLUSIONS: Although both higher and lower potassium were independent predictors of cardiovascular death, potassium abnormalities may mainly be markers rather than mediators of risk of death.

Packer, M. (2020). “Uric Acid Is a Biomarker of Oxidative Stress in the Failing Heart: Lessons Learned from Trials With Allopurinol and SGLT2 Inhibitors.” J Card Fail Sep 2;S1071-9164(20)30948-9 [Epub ahead of print.].

Full text of this article.

Hyperuricemia increases the risk of heart failure, and higher levels of serum uric acid are seen in patients who have worse ventricular function, functional capacity and prognosis. Heart failure is also accompanied by upregulation of xanthine oxidase, the enzyme that catalyzes the formation of uric acid and a purported source of reactive oxygen species. However, the available evidence does not support the premise that either uric acid or the activation of xanthine oxidase has direct injurious effects on the heart in the clinical setting. Xanthine oxidase inhibitors (allopurinol and oxypurinol) have had little benefit and may exert detrimental effects in patients with chronic heart failure in randomized controlled trials, and the more selective and potent inhibitor febuxostat increases the risk of cardiovascular death more than allopurinol. Instead, the available evidence indicates that changes in xanthine oxidase and uric acid are biomarkers of oxidative stress (particularly in heart failure) and that xanthine oxidase may provide an important source of nitric oxide that quenches the injurious effects of reactive oxygen species. A primary determinant of the cellular redox state is nicotinamide adenine dinucleotide (NAD+), whose levels drive an inverse relationship between xanthine oxidase and sirtuin-1 (SIRT1), a nutrient deprivation sensor that exerts important antioxidant and cardioprotective effects. Interestingly, sodium-glucose cotransporter 2 (SGLT2) inhibitors induce a state of nutrient deprivation that includes activation of sirtuin-1, suppression of xanthine oxidase and lowering of serum uric acid. The intermediary role of sirtuin-1 in both uric acid-lowering and cardioprotection may explain why, in mediation analyses of large-scale cardiovascular trials, the effect of SGLT2 inhibitors to decrease serum uric acid is a major predictor of the ability of these drugs to reduce serious heart failure events.

Mc Causland, F.R., Lefkowitz, M.P., Claggett, B., Anavekar, N.S., Senni, M., Gori, M., Jhund, P.S., McGrath, M.M., Packer, M., Shi, V., van Veldhuisen, D.J., Zannad, F., Comin-Colet, J., Pfeffer, M.A., McMurray, J.J.V. and Solomon, S.D. (2020). “Angiotensin-Neprilysin Inhibition and Renal Outcomes in Heart Failure with Preserved Ejection Fraction.” Circulation Aug 17. [Epub ahead of print.].

Full text of this article.

Background: In patients with heart failure, chronic kidney disease (CKD) is common and associated with a higher risk of renal events than in patients without CKD. We assessed the renal effects of angiotensin/neprilysin inhibition in patients with heart failure and preserved ejection fraction (HFpEF) enrolled in PARAGON-HF. Methods: In this randomized, double-blind, event-driven trial, we assigned 4,822 patients with HFpEF to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein we present the results of the pre-specified renal composite outcome (time to first occurrence of either: ≥50% reduction in eGFR, end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope. Results: At randomization, eGFR was 63±19 ml/min/1.73m(2). At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio [HR], 0.50; 95%CI, 0.33 to 0.77; P=0.001). The treatment effect on the composite renal endpoint did not differ according to the baseline eGFR (<60 vs ≥ 60 ml/min/1.73 m(2) (P-interaction=0.92). The decline in eGFR was less for sacubitril/valsartan compared with valsartan (-1.8 [95%CI, -2.0 to -1.6] vs. -2.4 [95%CI, -2.6 to - 2.2] ml/min/1.73m(2)/year). Conclusions: In patients with HFpEF, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, compared with valsartan.