Publications by authors named "Paul C Tang"

62 Publications

Mitral regurgitation severity at left ventricular assist device implantation is associated with distinct myocardial transcriptomic signatures.

J Thorac Cardiovasc Surg 2021 Sep 14. Epub 2021 Sep 14.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Mich. Electronic address:

Objectives: We examined for differences in pre-left ventricular assist device (LVAD) implantation myocardial transcriptome signatures among patients with different degrees of mitral regurgitation (MR).

Methods: Between January 2018 and October 2019, we collected left ventricular (LV) cores during durable LVAD implantation (n = 72). A retrospective chart review was performed. Total RNA was isolated from LV cores and used to construct cDNA sequence libraries. The libraries were sequenced with the NovaSeq system, and data were quantified using Kallisto. Gene Set Enrichment Analysis (GSEA) and Gene Ontology analyses were performed, with a false discovery rate <0.05 considered significant.

Results: Comparing patients with preoperative mild or less MR (n = 30) and those with moderate-severe MR (n = 42), the moderate-severe MR group weighted less (P = .004) and had more tricuspid valve repairs (P = .043), without differences in demographics or comorbidities. We then compared both groups with a group of human donor hearts without heart failure (n = 8). Compared with the donor hearts, there were 3985 differentially expressed genes (DEGs) for mild or less MR and 4587 DEGs for moderate-severe MR. Specifically altered genes included 448 DEGs for specific for mild or less MR and 1050 DEGs for moderate-severe MR. On GSEA, common regulated genes showed increased immune gene expression and reduced expression of contraction and energetic genes. Of the 1050 genes specific for moderate-severe MR, there were additional up-regulated genes related to inflammation and reduced expression of genes related to cellular proliferation.

Conclusions: Patients undergoing durable LVAD implantation with moderate-severe MR had increased activation of genes related to inflammation and reduction of cellular proliferation genes. This may have important implications for myocardial recovery.
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http://dx.doi.org/10.1016/j.jtcvs.2021.08.061DOI Listing
September 2021

Commentary: The next chapter in donor heart preservation: Modulation of preservation biology by targeted molecular therapies.

JTCVS Tech 2021 Oct 1;9:95-96. Epub 2021 Jul 1.

Department of Cardiac Surgery, University of Michigan, Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.xjtc.2021.06.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501207PMC
October 2021

Left Ventricular Assist Device Implantation in Patients with Preoperative Severe Mitral Regurgitation.

ASAIO J 2021 10;67(10):1139-1147

From the Department of Cardiac Surgery.

We examined cardiac features associated with residual mitral regurgitation (MR) following continuous-flow left ventricular assist device (cfLVAD) implant. From 2003 to 2017, 134 patients with severe MR underwent cfVLAD implant without mitral valve (MV) intervention. Echocardiographic (echo) assessment occurred pre-cfLVAD, early post-cfLVAD, and at last available echo. Ventricular and atrial volumes were calculated from established formulas and normalized to be predicted. Cluster analysis based on preoperative normalized left ventricular and atrial volumes, and MV height identified grades 1, 2, and 3 with progressively larger cardiac chamber sizes. Median early echo follow-up was 0.92 (0.55, 1.45) months and the last follow-up was 15.12 (5.28, 38.28) months. Mitral regurgitation improved early after cfLVAD by 2.10 ± 1.16 grades (p < 0.01). Mitral regurgitation severity at the last echocardiogram positively correlated with the preoperative left ventricular volume (p = 0.014, R = 0.212), left atrial volume (p = 0.007, R = 0.233), MV anteroposterior height (p = 0.032, R = 0.185), and MV mediolateral diameter (p = 0.043, R = 0.175). Morphologically, smaller grade 1 hearts were correlated with MR resolution at the late follow-up (p = 0.023). Late right ventricular failure (RVF) at the last clinical follow-up was less in grade 1 (4/48 [8.3%]) compared with grades 2 and 3 (26/86 [30.2%]), p = 0.004). Grade 1 cardiac dimensions correlates with improvement in severe MR and had less late RVF.
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http://dx.doi.org/10.1097/MAT.0000000000001379DOI Listing
October 2021

Untargeted metabolomics identifies succinate as a biomarker and therapeutic target in aortic aneurysm and dissection.

Eur Heart J 2021 11;42(42):4373-4385

The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Sciences of Ministry of Education, Health Sciences Center, Peking University, Xueyuan Road NO.38, Haidian District, Beijing 100871, China.

Aims: Aortic aneurysm and dissection (AAD) are high-risk cardiovascular diseases with no effective cure. Macrophages play an important role in the development of AAD. As succinate triggers inflammatory changes in macrophages, we investigated the significance of succinate in the pathogenesis of AAD and its clinical relevance.

Methods And Results: We used untargeted metabolomics and mass spectrometry to determine plasma succinate concentrations in 40 and 1665 individuals of the discovery and validation cohorts, respectively. Three different murine AAD models were used to determine the role of succinate in AAD development. We further examined the role of oxoglutarate dehydrogenase (OGDH) and its transcription factor cyclic adenosine monophosphate-responsive element-binding protein 1 (CREB) in the context of macrophage-mediated inflammation and established p38αMKOApoe-/- mice. Succinate was the most upregulated metabolite in the discovery cohort; this was confirmed in the validation cohort. Plasma succinate concentrations were higher in patients with AAD compared with those in healthy controls, patients with acute myocardial infarction (AMI), and patients with pulmonary embolism (PE). Moreover, succinate administration aggravated angiotensin II-induced AAD and vascular inflammation in mice. In contrast, knockdown of OGDH reduced the expression of inflammatory factors in macrophages. The conditional deletion of p38α decreased CREB phosphorylation, OGDH expression, and succinate concentrations. Conditional deletion of p38α in macrophages reduced angiotensin II-induced AAD.

Conclusion: Plasma succinate concentrations allow to distinguish patients with AAD from both healthy controls and patients with AMI or PE. Succinate concentrations are regulated by the p38α-CREB-OGDH axis in macrophages.
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http://dx.doi.org/10.1093/eurheartj/ehab605DOI Listing
November 2021

Differential inflammatory responses of the native left and right ventricle associated with donor heart preservation.

Physiol Rep 2021 09;9(17):e15004

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Michigan, USA.

Background: Dysfunction and inflammation of hearts subjected to cold ischemic preservation may differ between left and right ventricles, suggesting distinct strategies for amelioration.

Methods And Results: Explanted murine hearts subjected to cold ischemia for 0, 4, or 8 h in preservation solution were assessed for function during 60 min of warm perfusion and then analyzed for cell death and inflammation by immunohistochemistry and western blotting and total RNA sequencing. Increased cold ischemic times led to greater left ventricle (LV) dysfunction compared to right ventricle (RV). The LV experienced greater cell death assessed by TUNEL cells and cleaved caspase-3 expression (n = 4). While IL-6 protein levels were upregulated in both LV and RV, IL-1β, TNFα, IL-10, and MyD88 were disproportionately increased in the LV. Inflammasome components (NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3), adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1) and products (cleaved IL-1β and gasdermin D) were also more upregulated in the LV. Pathway analysis of RNA sequencing showed increased signaling related to tumor necrosis factor, interferon, and innate immunity with ex-vivo ischemia, but no significant differences were found between the LV and RV. Human donor hearts showed comparable inflammatory responses to cold ischemia with greater LV increases of TNFα, IL-10, and inflammasomes (n = 3).

Conclusions: Mouse hearts subjected to cold ischemia showed time-dependent contractile dysfunction and increased cell death, inflammatory cytokine expression and inflammasome expression that are greater in the LV than RV. However, IL-6 protein elevations and altered transcriptional profiles were similar in both ventricles. Similar changes are observed in human hearts.
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http://dx.doi.org/10.14814/phy2.15004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387788PMC
September 2021

Commentary: Surgical necessity is the mother of innovation when determining left ventricular assist device inflow access.

JTCVS Tech 2021 Aug 27;8:93-94. Epub 2021 Apr 27.

Department of Cardiac Surgery, University of Michigan, Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.xjtc.2021.04.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350810PMC
August 2021

Commentary: Belt and suspenders! Maximizing safety in central to peripheral extracorporeal membrane oxygenation conversions.

JTCVS Tech 2020 Dec 15;4:193-194. Epub 2020 Oct 15.

Department of Cardiac Surgery, University of Michigan, Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.xjtc.2020.10.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307309PMC
December 2020

Commentary: Permanent dialysis access following total artificial heart implantation: A question of maturity.

JTCVS Tech 2020 Sep 21;3:225-226. Epub 2020 Jul 21.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.xjtc.2020.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305694PMC
September 2020

Response to letter by Miyauchi et al.

J Card Surg 2021 10 7;36(10):3987-3988. Epub 2021 Jul 7.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Michigan, USA.

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http://dx.doi.org/10.1111/jocs.15790DOI Listing
October 2021

Commentary: How to predict a harmonious relationship between patients and their left ventricular assist device?

J Thorac Cardiovasc Surg 2021 May 19. Epub 2021 May 19.

University of Michigan, Ann Arbor, Mich. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2021.05.024DOI Listing
May 2021

Risk factors for heart transplant survival with greater than 5 h of donor heart ischemic time.

J Card Surg 2021 Aug 20;36(8):2677-2684. Epub 2021 May 20.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Michigan, USA.

Objective: Implantation of donor hearts with prolonged ischemic times is associated with worse survival. We sought to identify risk factors that modulate the effects of prolonged preservation.

Methods: Retrospective review of the United Network for Organ Sharing database (2000-2018) to identify transplants with >5 (n = 1526) or ≤5 h (n = 35,733) of donor heart preservation. In transplanted hearts preserved for >5 h, Cox-proportional hazards identify modifiers for survival.

Results: Compared to ≤5 h, transplanted patients with >5 h of preservation spent less time in status 1B (76 ± 160 vs. 85 ± 173 days, p = .027), more commonly had ischemic cardiomyopathy (42.3% vs. 38.3%, p = .002), and less commonly received a blood type O heart (45.4% vs. 50.8%, p < .001). Longer heart preservation time was associated with a higher incidence of postoperative stroke (4.5% vs. 2.5%, p < .001), and dialysis (16.4% vs. 10.6%, p < .001). Prolonged preservation was associated with a greater likelihood of death from primary graft dysfunction (2.8% vs. 1.5%, p < .001) but there was no difference in death from acute (2.0% vs. 1.7%, p = .402) or chronic rejection (2.0% vs. 1.9%, p = .618). In transplanted patients with >5 h of heart preservation, multivariable analysis identified greater mortality with ischemic cardiomyopathy etiology (hazard ratio [HR] = 1.36, p < 0.01), pre-transplant dialysis (HR = 1.84, p < .01), pre-transplant extracorporeal membrane oxygenation (ECMO, HR = 2.36, p = .09), and O blood type donor hearts (HR = 1.35, p < .01).

Conclusion: Preservation time >5 h is associated with worse survival. This mortality risk is further amplified by preoperative dialysis and ECMO, ischemic cardiomyopathy etiology, and use of O blood type donor hearts.
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http://dx.doi.org/10.1111/jocs.15621DOI Listing
August 2021

STratification risk analysis in OPerative management (STOP score) for drug-induced endocarditis.

J Card Surg 2021 Jul 24;36(7):2442-2451. Epub 2021 Apr 24.

Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

Background: The opioid epidemic has seen a drastic increase in the incidence of drug-associated infective endocarditis (IE). No clinical tool exists to predict operative morbidity and mortality in patients undergoing surgery.

Methods: A multi-institutional database was reviewed between 2011 and 2018. Multivariate logistic regression was fitted in an automated stepwise fashion. The STratification risk analysis in OPerative management of drug-associated IE (STOP) score was constructed. Morbidity was defined as reintubation, prolonged ventilation, pneumonia, renal failure, dialysis, stroke, reoperation for bleeding, and a permanent pacemaker. Cross-validation provided an unbiased estimate of out-of-sample performance.

Results: A total of 1181 patients underwent surgery for drug-associated IE (median age, 39; interquartile range [IQR], 30-54, 386 women [32.7%], 341 reoperations for prosthetic valve endocarditis [28.9%], 316 patients with multivalve disease [26.8%]). Operative morbidity and mortality were 41.1% and 5.9%, respectively. Predictors of morbidity were dialysis (95% confidence interval [CI], 1.16-2.82), emergent intervention (1.83-4.73), multivalve procedure (1.01-1.98), causative organisms other than Streptococcus (1.09-2.02), and type of valve procedure performed [aortic valve procedure (1.07-2.15), mitral valve replacement (1.03-2.05), tricuspid valve replacement (1.21-2.60)]. Predictors of mortality were dialysis (1.29-5.74), active endocarditis (1.32-83), lung disease (1.25-5.43), emergent intervention (1.69-6.60), prosthetic valve endocarditis (1.24-3.69), aortic valve procedure (1.49-5.92) and multivalve disease (1.00-2.95). Variables maximizing explanatory power were translated into a scoring system. Each point increased odds of morbidity and mortality by 22.0% and 22.4% with an accuracy of 94.0% and 94.1%, respectively.

Conclusion: Drug-related IE is associated with significant morbidity and mortality. An easily-applied risk stratification score may aid in clinical decision-making.
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http://dx.doi.org/10.1111/jocs.15570DOI Listing
July 2021

Commentary: Significant Mitral Regurgitation at the Time of LVAD Implantation: Looking Together in the Same Direction But We Need to Look Closer.

Semin Thorac Cardiovasc Surg 2021 Winter;33(4):996-997. Epub 2021 Feb 18.

University of Michigan, Ann Arbor, Michigan. Electronic address:

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http://dx.doi.org/10.1053/j.semtcvs.2021.01.046DOI Listing
February 2021

Fate of preoperative moderate mitral regurgitation following left ventricular assist device implantation.

J Card Surg 2021 Jun 18;36(6):1843-1849. Epub 2021 Feb 18.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Michigan, USA.

Objective: We examined for improvements in preoperative moderate mitral regurgitation following continuous-flow left ventricular assist device (cfLVAD) implantation.

Methods: From 2006 to 2020, 190 patients with moderate MR underwent cfVLAD implant without concomitant mitral valve (MV) surgery. Cardiac dimensions and contractility, as well as valve function, were assessed with an echocardiogram (echo) pre-cfLVAD, and at approximately 1 month post-cfLVAD. Outcomes were determined by retrospective chart review.

Results: Median echo follow-up was 0.94 (0.53, 1.38) months. Residual significant moderate or greater MR was present in 30/190 (15.8%) on follow-up. Patients with significant residual MR had larger preoperative left ventricular internal diameters in diastole (74.4 ± 8.7 vs. 71.1.0 ± 9.1 mm, p = .034). Significant residual MR was associated with higher preoperative mean pulmonary artery pressures (OR = 1.055, p = .035) and pulmonary capillary wedge pressures (OR = 1.060, p = .034). Significant residual MR on echo was not associated with any survival difference (p = .325). The 1, 5, and 10 year survival were 89.9%, 55.2%, and 34.2%, respectively.

Conclusions: For patients with moderate MR undergoing LVAD implantation, the likelihood of significant residual MR is low and mitral intervention in this population is not recommended. However, select patients with larger preoperative left heart dimensions and pulmonary vascular pressures may be at risk for persistent residual MR.
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http://dx.doi.org/10.1111/jocs.15428DOI Listing
June 2021

Impact of donor blood type on outcomes after prolonged allograft ischemic times.

J Thorac Cardiovasc Surg 2021 Jan 12. Epub 2021 Jan 12.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Mich.

Objective: The study objective was to determine the influence of allograft ischemic time on heart transplant outcomes among ABO donor organ types given limited prior reports of its survival impact.

Methods: We identified 32,454 heart transplants (2000-2016) from the United Network for Organ Sharing database. Continuous and categoric variables were analyzed by parametric and nonparametric testing. Survival was determined using log-rank or Cox regression tests. Propensity matching adjusted for preoperative variables.

Results: By comparing allograft ischemic time less than 4 hours (n = 6579) with 4 hours or more (n = 25,875), the hazard ratios for death at 15 years after prolonged ischemic time (≥4 hours) for blood types O, A, B, and AB were 1.106 (P < .001), 1.062 (P < .001), 1.059 (P = .062), and 1.114 (P = .221), respectively. Unadjusted data demonstrated higher mortality for transplantation of O versus non-O donor hearts for ischemic time 4 hours or more (hazard ratio, 1.164; P < .001). After propensity matching, O donor hearts continued to have worse survival if preserved for 4 hours or more (hazard ratio, 1.137, P = .008), but not if ischemic time was less than 4 hours (hazard ratio, 1.042, P = .113). In a matched group with 4 hours or more of ischemic time, patients receiving O donor organs were more likely to experience death from primary graft dysfunction (2.5% vs 1.7%, P = .052) and chronic allograft rejection (1.9% vs 1.1%, P = .021). No difference in death from primary graft dysfunction or chronic allograft rejection was seen with less than 4 hours of ischemic time (P > .150).

Conclusions: Compared with non-O donor hearts, transplantation with O donor hearts with ischemic time 4 hours or more leads to worse survival, with higher rates of primary graft dysfunction and chronic rejection. Caution should be practiced when considering donor hearts with the O blood type when anticipating extended cold ischemic times.
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http://dx.doi.org/10.1016/j.jtcvs.2020.12.123DOI Listing
January 2021

Personalized treatment options for chronic diseases using precision cohort analytics.

Sci Rep 2021 01 13;11(1):1139. Epub 2021 Jan 13.

Stanford Clinical Excellence Research Center, Stanford, CA, USA.

To support point-of-care decision making by presenting outcomes of past treatment choices for cohorts of similar patients based on observational data from electronic health records (EHRs), a machine-learning precision cohort treatment option (PCTO) workflow consisting of (1) data extraction, (2) similarity model training, (3) precision cohort identification, and (4) treatment options analysis was developed. The similarity model is used to dynamically create a cohort of similar patients, to inform clinical decisions about an individual patient. The workflow was implemented using EHR data from a large health care provider for three different highly prevalent chronic diseases: hypertension (HTN), type 2 diabetes mellitus (T2DM), and hyperlipidemia (HL). A retrospective analysis demonstrated that treatment options with better outcomes were available for a majority of cases (75%, 74%, 85% for HTN, T2DM, HL, respectively). The models for HTN and T2DM were deployed in a pilot study with primary care physicians using it during clinic visits. A novel data-analytic workflow was developed to create patient-similarity models that dynamically generate personalized treatment insights at the point-of-care. By leveraging both knowledge-driven treatment guidelines and data-driven EHR data, physicians can incorporate real-world evidence in their medical decision-making process when considering treatment options for individual patients.
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http://dx.doi.org/10.1038/s41598-021-80967-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806725PMC
January 2021

Precision population analytics: population management at the point-of-care.

J Am Med Inform Assoc 2021 03;28(3):588-595

Center for Computational Health, IBM Research, Cambridge, Massachusetts, USA.

Objective: To present clinicians at the point-of-care with real-world data on the effectiveness of various treatment options in a precision cohort of patients closely matched to the index patient.

Materials And Methods: We developed disease-specific, machine-learning, patient-similarity models for hypertension (HTN), type II diabetes mellitus (T2DM), and hyperlipidemia (HL) using data on approximately 2.5 million patients in a large medical group practice. For each identified decision point, an encounter during which the patient's condition was not controlled, we compared the actual outcome of the treatment decision administered to that of the best-achieved outcome for similar patients in similar clinical situations.

Results: For the majority of decision points (66.8%, 59.0%, and 83.5% for HTN, T2DM, and HL, respectively), there were alternative treatment options administered to patients in the precision cohort that resulted in a significantly increased proportion of patients under control than the treatment option chosen for the index patient. The expected percentage of patients whose condition would have been controlled if the best-practice treatment option had been chosen would have been better than the actual percentage by: 36% (65.1% vs 48.0%, HTN), 68% (37.7% vs 22.5%, T2DM), and 138% (75.3% vs 31.7%, HL).

Conclusion: Clinical guidelines are primarily based on the results of randomized controlled trials, which apply to a homogeneous subject population. Providing the effectiveness of various treatment options used in a precision cohort of patients similar to the index patient can provide complementary information to tailor guideline recommendations for individual patients and potentially improve outcomes.
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http://dx.doi.org/10.1093/jamia/ocaa247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7936526PMC
March 2021

A Discussion on Interpreting Primary Graft Dysfunction Outcomes: Reply.

Authors:
Paul C Tang

Ann Thorac Surg 2021 02 20;111(2):735-736. Epub 2020 Oct 20.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, 5158 Cardiovascular Center, SPC 5864, 1500 E Medical Center Dr, Ann Arbor, MI 48109-5864. Electronic address:

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http://dx.doi.org/10.1016/j.athoracsur.2020.07.081DOI Listing
February 2021

Commentary: "Preparedness in the time of COVID": Implications for engagement of the health care team with acute respiratory failure.

JTCVS Tech 2020 Sep 15;3:385-386. Epub 2020 Jun 15.

Department of Cardiac Surgery, University of Michigan, Ann Arbor, Mich.

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http://dx.doi.org/10.1016/j.xjtc.2020.05.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294293PMC
September 2020

Commentary: A Novel Technique of Percutaneous Left Ventricular Assist Device Deactivation: Just Plug and Stop the Pump or Remove it? That is the Question.

Semin Thorac Cardiovasc Surg 2020 3;32(3):473-474. Epub 2020 May 3.

Department of Cardiac Surgery, University of Michigan, Ann Arbor Michigan. Electronic address:

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http://dx.doi.org/10.1053/j.semtcvs.2020.03.013DOI Listing
October 2020

"The Secret Life of Human Donor Hearts": An Examination of Transcriptomic Events During Cold Storage.

Circ Heart Fail 2020 04 8;13(4):e006409. Epub 2020 Apr 8.

Department of Cardiac Surgery (I.L., Z.W., Y.E.C., W.H., E.K., F.D.P., P.C.T.).

Background: Ischemic tolerance of donor hearts has a major impact on the efficiency in utilization and clinical outcomes. Molecular events during storage may influence the severity of ischemic injury.

Methods: RNA sequencing was used to study the transcriptional profile of the human left ventricle (LV, n=4) and right ventricle (RV, n=4) after 0, 4, and 8 hours of cold storage in histidine-tryptophan-ketoglutarate preservation solution. Gene set enrichment analysis and gene ontology analysis was used to examine transcriptomic changes with cold storage. Terminal deoxynucleotidyl transferase 2´-Deoxyuridine, 5´-Triphosphate nick end labeling and p65 staining was used to examine for cell death and NFκB activation, respectively.

Results: The LV showed activation of genes related to inflammation and allograft rejection but downregulation of oxidative phosphorylation and fatty acid metabolism pathway genes. In contrast, inflammation-related genes were down-regulated in the RV and while oxidative phosphorylation genes were activated. These transcriptomic changes were most significant at the 8 hours with much lower differences observed between 0 and 4 hours. RNA velocity estimates corroborated the finding that immune-related genes were activated in the LV but not in the RV during storage. With increasing preservation duration, the LV showed an increase in nuclear translocation of NFκB (p65), whereas the RV showed increased cell death close to the endocardium especially at 8 hours.

Conclusions: Our results demonstrated that the LV and RV of human donor hearts have distinct responses to cold ischemic storage. Transcriptomic changes related to inflammation, oxidative phosphorylation, and fatty acid metabolism pathways as well as cell death and NFκB activation were most pronounced after 8 hours of storage.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.119.006409DOI Listing
April 2020

Aortic Valve Repair Versus Replacement Associated With Durable Left Ventricular Assist Devices.

Ann Thorac Surg 2020 10 24;110(4):1259-1264. Epub 2020 Feb 24.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Michigan.

Background: Aortic valve (AV) repair (AVr) using a central coaptation stitch or bioprosthetic AV replacement (AVR) are most commonly performed at the time of durable left ventricular assist device implant to address AV insufficiency (AI).

Methods: Prospective data collection on 46 patients undergoing left ventricular assist device implant from 2007 through 2018 who received concomitant AVr (n = 40) or AVR (n = 6) was retrospectively analyzed to assess freedom from recurrent aortic insufficiency. Paired Wilcoxon rank-sum test was used to compare echocardiographic findings. Mantel-Cox statistics were used to analyze survival.

Results: For AVr, central coaptation led to a mean decrease in AI severity by 2.1 ± 1.0 grades (P < .001). Three patients (7.5%) had recurrence of at least moderate AI by 3 years. In comparison, all patients in the AVR group had mild or less AI on subsequent follow-up. Success of AVr in downgrading AI severity was associated with a smaller aortic root diameter (P = .011) and sinotubular junction diameter (P = .003). An aortic root diameter greater than 3.5 cm was predictive of less improvement in AI severity compared with 3.5 cm or less (1.83 ± 1.03 versus 2.47 ± 0.80 grades of improvement; P = .038). Duration of cardiopulmonary bypass was 32 minutes longer and duration of aortic cross-clamp was 38 minutes longer for AVR versus AVr cohorts. No difference in 30-day (P = .418) or overall survival (P = .572) between the AVr and AVR groups was seen.

Conclusions: Aortic valve repair for addressing AI has a recurrence rate of 7.5% at 3 years. Success in downgrading AI is more likely with a smaller aortic root. No difference in survival was observed between AVr and AVR.
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http://dx.doi.org/10.1016/j.athoracsur.2020.01.015DOI Listing
October 2020

Histidine-Tryptophan-Ketoglutarate Solution for Donor Heart Preservation Is Safe for Transplantation.

Ann Thorac Surg 2020 03 27;109(3):763-770. Epub 2019 Aug 27.

Department of Cardiac Surgery. Electronic address:

Background: Various solutions are used for donor heart preservation. We examined the outcomes in our heart transplant population where histidine-tryptophan-ketoglutarate (HTK) solution has been used for heart preservation since 2004.

Methods: This was a retrospective review of the United Network for Organ Sharing (UNOS) database (2004-2016) comparing our heart transplant outcomes with other national centers. Propensity matching in a 1:3 ratio was performed to adjust for preoperative recipient variables.

Results: After propensity matching comparing UNOS outcomes (n = 1080) with our institutional data (n = 360), there was no difference in matched preoperative variables. Donor hearts were similar for donor age, sex, donor-to-recipient size ratio, LVEF, and ischemic time. Our HTK cohort had a larger proportion with donor cardiac arrest (26.3% vs 6.1%, P < .001) and longer cardiac arrest duration (22.1 ± 16.0 vs 17.2 ± 14.0 minutes, P = .052). Our primary graft dysfunction (PGD) rate requiring mechanical support was 4.2% (n = 1). Postoperative mechanical support use for PGD included extracorporeal membrane oxygenation in 9 (60.0%), intraaortic balloon pump in 4 (26.7%), right ventricular assist device in 3 (20%), and biventricular assist device in 3 (20%). Overall survival at our institution was similar to the national average (P = .649). Survival at 1, 5, and 10 years with HTK was 92.2%, 81.3%, and 70.8%, and for the UNOS population was 91.6%, 80.3%, and 62.0%, respectively.

Conclusions: Use of HTK solution for donor hearts was associated with a low rate of severe PGD. Overall survival was not significantly different from other institutions using a variety of preservation solutions in the UNOS database during the same period. HTK solution is efficacious for preservation of donor hearts.
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http://dx.doi.org/10.1016/j.athoracsur.2019.07.012DOI Listing
March 2020

Editorial commentary: Durable mechanical circulatory support, the challenges ahead.

Authors:
Paul C Tang

Trends Cardiovasc Med 2020 05 14;30(4):230-231. Epub 2019 Jun 14.

University of Michigan, Ann Arbor, MI, United States. Electronic address:

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http://dx.doi.org/10.1016/j.tcm.2019.06.002DOI Listing
May 2020

Right ventricular function and residual mitral regurgitation after left ventricular assist device implantation determines the incidence of right heart failure.

J Thorac Cardiovasc Surg 2020 03 5;159(3):897-905.e4. Epub 2019 Apr 5.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Mich.

Background: The effect of significant mitral regurgitation (MR) on outcomes after continuous flow left ventricular assist device (cfLVAD) implantation remains unclear.

Methods: We performed a retrospective review of prospectively collected data from 159 patients with preoperative severe MR who underwent cfLVAD implantation (2003-2017). Two-step cluster analysis using the log-likelihood distance for post-cfLVAD implantation parameters, which included right ventricular (RV) dysfunction, MR severity, and tricuspid regurgitation (TR) severity. Post-cfLVAD implantation echocardiographic parameters were obtained within the first month.

Results: Cluster analysis resulted in 3 groups. Group 1 (n = 67) had mild or less MR with moderate-severe RV dysfunction (RVD). Group 2 (n = 43) had moderate-severe MR with moderate-severe RVD. Group 3 (n = 49) had moderate MR with mild RVD. Group 2 had the largest proportion with Interagency Registry for Mechanically Assisted Circulatory Support score of 1 (30.2%) and 2 (41.9%). They were more likely to undergo temporary mechanical circulatory support (18.6%) and tricuspid valve procedure (62.8%). Group 2 had the highest rate of stroke (30.2%; P = .02), hemolysis (39.5%; P = .01), device thrombosis (30%; P = .01), and worst survival (46.5%; P = .01). Survival at 5 years for groups 1, 2, and 3 were 56.0%, 17.6%, and 55.8%. Regression analysis of the entire population showed that greater MR severity after cfLVAD was associated with RV failure (P < .05; odds ratio, 1.6) and RV assist device use (P = .09; odds ratio, 1.6). After excluding tricuspid valve repairs, MR severity had a positive correlation with TR severity (R = 0.33; P < .01).

Conclusions: After cfLVAD implantation, moderate-severe MR and RVD predicted RV failure. Patients with preoperative moderate-severe MR and TR coupled with moderate-severe RVD might benefit the most from mitral and tricuspid valve intervention.
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http://dx.doi.org/10.1016/j.jtcvs.2019.03.089DOI Listing
March 2020

Right ventricular failure following left ventricular assist device implantation is associated with a preoperative pro-inflammatory response.

J Cardiothorac Surg 2019 Apr 25;14(1):80. Epub 2019 Apr 25.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, 5158 Cardiovascular Center, SPC 5864, 1500 E. Medical Center Drive, Ann Arbor, MI, 48109-5864, USA.

Background: Systemic inflammation during implant of a durable left ventricular assist device (LVAD) may contribute to adverse outcomes. We investigated the association of the preoperative inflammatory markers with subsequent right ventricular failure (RVF).

Materials And Methods: Prospective data was collected on 489 patients from 2003 through 2017 who underwent implantation of a durable LVAD. Uni- and multivariable correlation with leukocytosis was determined using linear and binary logistic regression. The population was also separated into low (< 10.5 K/ul, n = 362) and high (> 10.5 K/ul, n = 127) white blood cell count (WBC) groups. Mantel-Cox statistics was used to analyze survival data.

Results: Postop RVF was associated with a higher preop WBC (11.3 + 5.7 vs 8.7 + 3.1) and C-reactive protein (CRP, 5.6 + 4.4 vs 3.3 + 4.7) levels. Multivariable analysis identified an independent association between increased WBC preoperatively with increased lactate dehydrogenase (LDH, P < 0.001), heart rate (P < 0.001), CRP (P = 0.006), creatinine (P = 0.048), and INR (P = 0.049). The high WBC group was more likely to be on preoperative temporary circulatory support (17.3% vs 6.4%, P < 0.001) with a trend towards greater use of an intra-aortic balloon pump (55.9% vs 47.2%, P = 0.093). The high WBC group had poorer mid-term survival (P = 0.042).

Conclusions: Postop RVF is associated with a preoperative pro-inflammatory environment. This may be secondary to the increased systemic stress of decompensated heart failure. Systemic inflammation in the decompensated heart failure may contribute to RVF after LVAD implant.
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http://dx.doi.org/10.1186/s13019-019-0895-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6482580PMC
April 2019

Cluster analysis of preoperative echocardiographic findings and outcomes following left ventricular device implantation.

J Thorac Cardiovasc Surg 2019 05 11;157(5):1851-1860.e1. Epub 2018 Dec 11.

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, Ann Arbor, Mich.

Objective: To investigate whether preoperative echocardiography findings determine postoperative continuous-flow left ventricular assist device outcomes.

Methods: From January 2003 to June 2017, 490 patients received a durable, continuous-flow left ventricular assist device. Two-step clustering of parameters including heart rate and preoperative echocardiographic findings (ie, left ventricular [LV] ejection fraction, right ventricular [RV] function, aortic insufficiency, mitral regurgitation [MR], tricuspid regurgitation [TR]) was performed and identified 5 distinct clusters associated with LV failure: group 1: moderate right ventricular dysfunction (RVD), severe MR and mild TR (n = 110); group 2: severe RVD, severe MR and TR (n = 64); group 3: moderate RVD and severe aortic insufficiency (n = 16); group 4: mild RVD and mild valvular pathology (n = 163); and group 5: moderate-severe RVD and mild valvular pathology (n = 137). Silhouette measure of cohesion and separation demonstrated satisfactory separation at 0.6.

Results: Group 2 had the greatest Interagency Registry for Mechanically Assisted Circulatory Support Level 1 (25%, P = .010), preoperative right atrial pressure (11 ± 5 mm Hg, P < .001), incidence of postoperative right ventricular failure (RVF; 20%, P = .001), delayed closure of the sternum (61%, P = .002), postoperative permanent dialysis (6%, P = .04), rate of tricuspid valve repair (n = 52; 81%, P < .001), and lowest RV stroke work index (489 ± 228 cc mm Hg/m/beat, P < .001). RVF in groups 1, 3, 4, and 5 was 6%, 0%, 4%, and 9%, respectively. No differences in incidence of heart transplantation (P = .400) or survival (P = .535) were found. Severe TR predicted RVF in those with moderate-severe preoperative RVD (P = .001, odds ratio 3.9).

Conclusions: Clustering demonstrated the importance of preoperative TR in predicting RVF. Combined severe LV and RV failure with severe MR and TR portends the worse prognosis.
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http://dx.doi.org/10.1016/j.jtcvs.2018.11.099DOI Listing
May 2019

Long-Term Survival and Echocardiographic Findings After Surgical Ventricular Restoration.

Ann Thorac Surg 2019 06 23;107(6):1754-1760. Epub 2018 Dec 23.

Department of Cardiac Surgery, University of Michigan, Ann Arbor, Michigan. Electronic address:

Background: This study investigates the long-term survival and durability of mitral procedures on patients undergoing surgical ventricular restoration.

Methods: From 1992 to 2017, 109 patients underwent surgical ventricular restoration. Survival was determined from hospital records and the National Death Index. Preoperative demographics, clinical characteristics and features, operative technique, and follow-up echocardiography findings were analyzed using Cox regression and log-rank to determine variables influencing survival.

Results: The mean age was 61.57 ± 12.81 years. There were 101 (93%) true and 8 (7%) pseudo-aneurysms. Concomitant surgeries included mitral valve (MV) repair (n = 40, 37%), MV replacement (n = 5, 5%), tricuspid valve repair (n = 4, 4%), aortic valve replacement (n = 3, 3%), coronary bypass grafting (n = 76, 70%; 1.6 ± 1.3 grafts), and ventricular septal defect closure (n = 5, 5%). Redo-sternotomies were performed in 12 patients (11%). Median duration of echocardiographic follow up was 2.9 years (interquartile range, 9.0) and was obtained in 59 patients (54%). Left ventricular ejection fraction improved from 28% ± 13% to 33% ± 16% (p = 0.011). Median duration of echocardiographic follow-up of MV repair was 3.6 years (interquartile range, 9.5). MV repair led to sustained improvements in mitral regurgitation (MR; p = 0.001) where only 2 (5%) experienced recurrence of moderate to severe MR. For patients who did not undergo an MV procedure there was no difference in preoperative and follow-up MR severity (p = 0.586). Median patient follow-up was 7.1 years (interquartile range, 8.5). Overall 5-, 10-, and 15-year survival rates were 71.9%, 48.1%, and 26.2%, respectively.

Conclusions: Surgical ventricular restoration was associated with sustained improvement in left ventricular ejection fraction with almost half surviving to 10 years postoperatively. For patients undergoing concomitant MV repair, the improvement in mitral competence is durable.
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http://dx.doi.org/10.1016/j.athoracsur.2018.11.054DOI Listing
June 2019

Continuous-Flow Device Engineering and Pump Technology.

Cardiol Clin 2018 Nov;36(4):451-463

Department of Cardiac Surgery, University of Michigan Frankel Cardiovascular Center, 5158 Cardiovascular Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109-5864, USA.

This article on continuous-flow device technology engages in an in-depth discussion on the engineering aspects of continuous-flow devices. The authors examine the energy transfer mechanics of centrifugal versus axial devices, and the impact of novel noncontact pump bearings. Furthermore, this article reviews the relationship between continuous-flow pump speed, flow, and pressure gradients across the device. Potential future advances in pump design with greater algorithmic responses to changes in patient physiology are also considered.
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http://dx.doi.org/10.1016/j.ccl.2018.06.001DOI Listing
November 2018
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