Research Spotlight

Palazzuoli, A., Tecson, K.M., Ronco, C. and McCullough, P.A. (2021). “Nomenclature for Kidney Function from KDIGO: Shortcomings of Terminology Oversimplification.” Cardiorenal Med Jun 4;1-4. [Epub ahead of print].

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The recent Kidney Disease: Improving Global Outcomes (KDIGO) consensus conference proposed a universal nomenclature calling for “Kidney Disease” (KD) to be applied to every form of kidney dysfunction, regardless of etiology. We recognize that the estimated glomerular filtration rate and urine albumin:creatinine ratio are limited in their application to the broad spectrum of KD. However, there are additional in vitro and advanced diagnostic options that can help identify the underlying cause of KD and inform about prognosis and management. While the overarching benefit of generalizing KD as a medical problem lies with screening and detection, the downsides attributable to a nonexact diagnosis (i.e., unclear prognosis and management strategy) are considerable. Finally, the terms “acute kidney injury” and “worsening renal function” are currently used interchangeably by nephrologists and cardiologists alike, and a universal adoption of one term will likely be a sizeable challenge. To be of greater benefit, we propose KD be used as a starting point and that the etiology and other epigenetic determinants of illness continue to be evaluated and characterized.

Magombedze, G., Pasipanodya, J.G. and Gumbo, T. (2021). “Bacterial load slopes represent biomarkers of tuberculosis therapy success, failure, and relapse.” Commun Biol 4(1): 664.

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There is an urgent need to discover biomarkers that are predictive of long-term TB treatment outcomes, since treatment is expense and prolonged to document relapse. We used mathematical modeling and machine learning to characterize a predictive biomarker for TB treatment outcomes. We computed bacterial kill rates, γ(f) for fast- and γ(s) for slow/non-replicating bacteria, using patient sputum data to determine treatment duration by computing time-to-extinction of all bacterial subpopulations. We then derived a γ(s-)slope-based rule using first 8 weeks sputum data, that demonstrated a sensitivity of 92% and a specificity of 89% at predicting relapse-free cure for 2, 3, 4, and 6 months TB regimens. In comparison, current methods (two-month sputum culture conversion and the Extended-EBA) methods performed poorly, with sensitivities less than 34%. These biomarkers will accelerate evaluation of novel TB regimens, aid better clinical trial designs and will allow personalization of therapy duration in routine treatment programs.

Takahashi, K., Serruys, P.W., Gao, C., Ono, M., Wang, R., Thuijs, D., Mack, M.J., Curzen, N., Mohr, F.W., Davierwala, P., Milojevic, M., Wykrzykowska, J.J., de Winter, R.J., Sharif, F., Onuma, Y., Head, S.J., Kappetein, A.P., Morice, M.C. and Holmes, D.R., Jr. (2021). “Ten-Year All-Cause Death According to Completeness of Revascularization in Patients with Three-Vessel Disease or Left Main Coronary Artery Disease: Insights from the SYNTAX Extended Survival Study.” Circulation May 20. [Epub ahead of print].

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Background: Ten-year all-cause death according to incomplete (IR) versus complete revascularization (CR) has not been fully investigated in patients with three-vessel disease (3VD) and/or left main coronary artery disease (LMCAD) undergoing percutaneous coronary intervention (PCI) versus coronary artery bypass grafting (CABG). Methods: The SYNTAX Extended Survival Study evaluated vital status up to 10 years in patients who were originally enrolled in the SYNTAX trial. In the present sub-study, outcomes of the CABG CR group were compared with the CABG IR, PCI CR, and PCI IR groups. In addition, in the PCI cohort, the residual SYNTAX score (rSS) was used to quantify the extent of IR and to assess its association with fatal late outcome. The rSS of 0 suggests CR, whereas a rSS>0 identifies degree of IR. Results: IR was more frequently observed in patients with PCI vs. CABG (56.6% vs. 36.8%) and more common in those with 3VD than LMCAD in both PCI (58.5% vs. 53.8%) and CABG arm (42.8% vs. 27.5%). Patients undergoing PCI with CR had no significant difference in 10-year all-cause death compared with those undergoing CABG (22.2% for PCI with CR vs. 24.3% for CABG with IR vs. 23.8% for CABG with CR). In contrast, those with PCI and IR had a significantly higher risk of all-cause death at 10 years compared with CABG and CR (33.5% vs. 23.7%; adjusted hazard ratio [aHR]:1.48; 95% confidence interval [CI]:1.15-1.91). When patients with PCI were stratified according to the rSS, those with a rSS≤8 had no significant difference in all-cause death at 10 years as the other terciles (22.2% for rSS=0 vs. 23.9% for rSS>0-4 vs. 28.9% for rSS>4-8), whereas a rSS> 8 had a significantly higher risk of 10-year all-cause death as compared with those undergoing PCI with CR (50.1% vs. 22.2%; aHR:3.40; 95% CI:2.13-5.43). Conclusions: IR is common after PCI, and the degree of incompleteness was associated with 10-year mortality. If it is unlikely that complete (or nearly complete; rSS<8) revascularization can be achieved with PCI in patients with 3VD, CABG should be considered. Clinical Trial Registration: SYNTAX: https://www.clinicaltrials.gov Unique Identifier: NCT00114972. SYNTAX Extended Survival: https://www.clinicaltrials.gov Unique Identifier: NCT03417050.

Ono, M., Kawashima, H., Hara, H., O’Leary, N., Gao, C., Wang, R., Takahashi, K., Wykrzykowska, J.J., Piek, J.J., Mack, M.J., Holmes, D.R., Morice, M.C., Head, S.J., Kappetein, A.P., Thuijs, D., Noack, T., Friedrich, M.W., Davierwala, P.M., McEvoy, J.W., Onuma, Y. and Serruys, P.W. (2021). “Impact of Body Composition Indices on Ten-year Mortality After Revascularization of Complex Coronary Artery Disease (From the Syntax Extended Survival Trial).” Am J Cardiol May 25;S0002-9149(21)00361-1. [Epub ahead of print].

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Numerous studies have demonstrated a paradoxical association between higher baseline body mass index (BMI) and lower long-term mortality risk after coronary revascularization, known as the “obesity paradox”, possibly relying on the single use of BMI. The current study is a post-hoc analysis of the SYNTAX Extended Survival (SYNTAXES) trial, which is the extended follow-up of the SYNTAX trial comparing percutaneous coronary intervention (PCI) versus coronary artery bypass graft (CABG) in patients with left-main coronary artery disease (LMCAD) or three-vessel disease (3VD). Patients were stratified according to baseline BMI and/or waist circumference (WC). Out of 1,800 patients, 1,799 (99.9%) and 1,587 (88.2%) had available baseline BMI and WC data, respectively. Of those, 1,327 (73.8%) patients had High BMI (≥25 kg/m(2)), whereas 705 (44.4%) patients had High WC (>102 cm for men or >88 cm for women). When stratified by both BMI and WC, 10-year mortality risk was significantly higher in patients with Low BMI/Low WC (adjusted hazard ratio [HR]: 1.65; 95% confidence interval [CI]: 1.09 to 2.51), Low BMI/ High WC (adjusted HR: 2.74; 95% CI: 1.12 to 6.69), or High BMI/High WC (adjusted HR: 1.59; 95% CI: 1.11 to 2.27) compared to those with High BMI/Low WC. In conclusion, the “obesity paradox” following coronary revascularization would be driven by low long-term mortality risk of the High BMI/Low WC group. Body composition should be assessed by the combination of BMI and WC in the appropriate evaluation of the long-term risk of obesity in patients with LMCAD or 3VD.

Mack, M.J., Fullerton, D.A. and Fann, J.I. (2021). “The Answers You Get Depend on the Questions You Ask: Insights From the Recent EXCEL Trial Controversy.” Ann Thorac Surg 111(6): 1743-1745.

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Scientific evidence to inform clinical practice can be generally categorized as coming from 2 sources—observational registry or database studies and randomized clinical trials (RCTs). Observational studies have the advantage of being more readily available, and the outcomes are for the most part reflective of the way patients are actually treated. They are, however, not ideal to assess comparative effectiveness of treatments, since they are subject to selection bias for the treatment received, which can only be partially corrected by various methods of post hoc statistical matching. RCTs are considered to be the highest level of evidence and provide the strongest evidentiary support for society clinical practice guidelines. With RCTs, a treatment is assigned randomly, therefore obviating any concerns regarding selection bias of enrolled patients. [No abstract; excerpt from Editorial].