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Supplemental material, sj-docx-1-jao-10.1177_03913988221112684 for Impact of digoxin utilization on clinical outcomes following left ventricular assist device implantation by Muhannad Aboud Abbasi, Douglas A Stoller, Elizabeth Lyden, Brian D Lowes, Ronald Zolty and Scott W Lundgren in The International Journal of Artificial Organs

Supplemental material, sj-docx-1-jao-10.1177_03913988221112684 for Impact of digoxin utilization on clinical outcomes following left ventricular assist device implantation by Muhannad Aboud Abbasi, Douglas A Stoller, Elizabeth Lyden, Brian D Lowes, Ronald Zolty and Scott W Lundgren in The International Journal of Artificial Organs

Additional file 1.

Background: Next generation sequencing technology, coupled with population genetic databases, have made broad genetic evaluation relatively inexpensive and widely available. Our objective was to assess the prevalence of potentially damaging cancer and cardiac gene variants in advanced non-ischemic cardiomyopathy patients. Methods: Explanted human heart tissue procured at LVAD placement was obtained from the University of Nebraska Medical Center Heart Tissue Bank. Genomic DNA was isolated from tissues and amplified by PCR using targeted ampliseq primer pools from an inherited disease panel. Individual libraries were amplified by emulsion PCR on Ion Sphere particles and sequencing was performed on a PGM sequencer (Ion torrent) using the Ion 316 chip. The Ion Torrent browser suite was used to map the reads and call the variants. The identified single nucleotide polymorphisms, insertions, and deletions were then annotated and characterized with ANNOVAR. Non-synonymous mutations with a population frequency of less than or equal to 1% were identified and analyzed utilizing an open source integrative genomics viewer. Amino acid substitution effects on protein function were determined by a bioinformatics algorithm. Myocardial recovery was defined as an improvement in EF to greater than 45% at three months post implant. Results: Our sample population included 12 males and 2 females with an average age of 49 and an average EF at presentation of 17%. Damaging cardiac gene variants were present in 11/14 patients. Only 1 of the 11 patients with damaging cardiac gene variants improved their ejection fraction to greater than 45% post LVAD. Two of the 2 patients without mutations improved their ejection fraction to greater than 45%, p-value=.04. Nine of the 14 patients in this population had damaging oncogene mutations. Conclusions: Damaging variants in cancer and cardiac genes are common in end-stage non-ischemic cardiomyopathy patients undergoing LVAD placement. Genetic variation likely contributes to disease progression and cancer risk.

Background— When β-blockers produce reverse-remodeling in idiopathic dilated cardiomyopathy, they partially reverse changes in fetal–adult/contractile protein, natriuretic peptide, SR-Ca 2+ -ATPase gene program constituents. The objective of the current study was to further test the hypothesis that reverse-remodeling is associated with favorable changes in myocardial gene expression by measuring additional contractile, signaling, and metabolic genes that exhibit a fetal/adult expression predominance, are thyroid hormone-responsive, and are regulated by β 1 -adrenergic receptor signaling. A secondary objective was to identify which of these putative regulatory networks is most closely associated with observed changes. Methods and Results— Forty-seven patients with idiopathic dilated cardiomyopathy (left ventricular ejection fraction, 0.24±0.09) were randomized to the adrenergic-receptor blockers metoprolol (β 1- selective), metoprolol+doxazosin (β 1 /α 1 ), or carvedilol (β 1 /β 2 /α 1 ). Serial radionuclide ventriculography and endomyocardial biopsies were performed at baseline, 3, and 12 months. Expression of 50 mRNA gene products was measured by quantitative polymerase chain reaction. Thirty-one patients achieved left ventricular ejection fraction reverse-remodeling response defined as improvement by ≥0.08 at 12 months or by ≥0.05 at 3 months (Δ left ventricular ejection fraction, 0.21±0.10). Changes in gene expression in responders versus nonresponders were decreases in NPPA and NPPB and increases in MYH6 , ATP2A2 , PLN , RYR2 , ADRA1A , ADRB1 , MYL3 , PDFKM , PDHX , and CPT1B . All except PDHX involved increase in adult or decrease in fetal cardiac genes, but 100% were concordant with changes predicted by inhibition of β 1 -adrenergic signaling. Conclusions— In addition to known gene expression changes, additional calcium-handling, sarcomeric, adrenergic signaling, and metabolic genes were associated with reverse-remodeling. The pattern suggests a fetal–adult paradigm but may be because of reversal of gene expression controlled by a β 1 -adrenergic receptor gene network. Clinical Trial Registration— URL: www.clinicaltrials.gov . Unique Identifier: NCT01798992.

ObjectivesThe aim of this study was to determine echocardiographic predictors of outcome in patients with advanced heart failure (HF) due to severe left ventricular (LV) systolic dysfunction in the Beta-blocker Evaluation of Survival Trial (BEST).BackgroundPrevious studies indicate that echocardiographic measurements of LV size and function, mitral deceleration time, and mitral regurgitation (MR) predict adverse outcomes in HF. However, complete quantitative echocardiograms evaluating all of these parameters have not been reported in a prospective randomized clinical trial in the era of modern HF therapy.MethodsComplete echocardiograms were performed in 336 patients at 26 sites and analyzed by a core laboratory. A Cox proportional-hazards regression model was used to determine which echocardiographic variables predicted the primary end point of death or the secondary end point of death, HF hospitalization, or transplant. Significant variables were then entered into a multivariable model adjusted for clinical and demographic covariates.ResultsOn multivariable analysis adjusted for clinical covariates, only LV end-diastolic volume index predicted death (events = 75), with a cut point of 120 ml/m2. Three echocardiographic variables predicted the combined end point of death (events = 75), HF hospitalization (events = 97), and transplant (events = 9): LV end-diastolic volume index, mitral deceleration time, and the vena contracta width of MR. Optimal cut points for these variables were 120 ml/m2, 150 ms, and 0.4 cm, respectively.ConclusionsEchocardiographic predictors of outcome in advanced HF include LV end-diastolic volume index, mitral deceleration time, and vena contracta width. These variables indicate that LV remodeling, increased LV stiffness, and MR are independent predictors of outcome in patients with advanced HF.