Evolution of Veterans Affairs Transcatheter Aortic Valve Replacement Program: The First 100 Patients.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is a widely established alternative to surgery in intermediate- and high-risk patients. TAVR program development within the Veterans Affairs (VA) system has been previously described. However, national TAVR registries do not capture VA outcomes data, and few data have been reported regarding TAVR outcomes at lower-volume federal institutions. The study aim was to demonstrate the evolution of a successful VA TAVR program. METHODS: A retrospective analysis was performed of the first 100 TAVR patients at San Francisco VA Medical Center. Mortality and major complications were evaluated. RESULTS: Between 25th November 2013 and 31st August 2016, a total of 100 TAVR procedures was performed at the authors' institution. The mean patient age was 79.7 ± 8.7 years. Patients underwent TAVR via percutaneous-transfemoral (n = 90), surgical cutdown-transfemoral (n = 8), or transapical (n = 2) approaches. The valve systems employed were Edwards SAPIEN (n = 16), SAPIEN XT (n = 31), SAPIEN 3 (n = 23), and Medtronic CoreValve (n = 16) and CoreValve Evolut R (n = 14). The overall device success was 96%. TAVR-in-TAVR was required in the remaining 4% of patients, and was successful. All-cause procedural mortality was 1%. Complications included tamponade (1%), stroke (2%), temporary hemodialysis (1%), vascular injuries requiring intervention (4%), and permanent pacemaker implantation (14%). There were no conversions to surgical aortic valve replacement. Twenty-two (22%) patients had mild, two (2%) had moderate, and none (0%) had severe paravalvular leakage. The post-procedure aortic valve gradient by echocardiography was 8.6 ± 4.5 mmHg. Follow up was 100% complete and survival was 99%, 93%, and 89% at one, six, and 12 months, respectively. CONCLUSIONS: Successful outcomes were demonstrated for a VA TAVR program that compared favorably with benchmarks established by the National Transcatheter Valve Therapies Registry. These results provide a necessary transparency of TAVR outcomes at a federal institution.

Midterm Durability and Structural Valve Degeneration of Transcatheter Aortic Valve Replacement in a Federal Facility.

OBJECTIVE: Transcatheter aortic valve replacement (TAVR), previously reserved for patients of intermediate to prohibitive surgical risk, has now been expanded to patients of any surgical risk with severe aortic stenosis. Bioprostheses are prone to structural valve degeneration (SVD), a progressive and multifactorial process that limits valve durability. As the population undergoing TAVR shifts toward a lower-risk and younger profile, long-term durability is a crucial determinant for patient outcomes. Our objective was to determine the incidence and risk factors of SVD at midterm follow-up in a veteran TAVR population. METHODS: Patients undergoing TAVR at our federal facility were retrospectively evaluated for SVD and other endpoints with standardized consensus criteria. Multivariable Cox proportional hazards analysis was performed to evaluate risk factors for mortality and SVD. RESULTS: From 2013 to 2020, 344 patients (median age, 78 years) underwent TAVR. Survival from all-cause mortality was 91.3% at 1 year, 75.1% at 3 years, and 61.7% at 5 years. Cumulative freedom from SVD was 98.2% at 1 year, 96.5% at 3 years, and 93.7% at 5 years. All 13 patients with SVD met hemodynamic criteria, and 1 required intervention. Median time to hemodynamic SVD was 1.04 years. Independent risk factors for SVD included age (hazard ratio [HR] = 0.92, 95% confidence interval [CI]: 0.86 to 0.99) and valve size (HR = 0.19, 95% CI: 0.04 to 0.89). CONCLUSIONS: SVD was evident at a low but detectable rate at 5-year follow-up. Further understanding of TAVR biomechanics as well as continued longer-term follow-up will be essential for informing patient-specific risk of SVD.

Autologous mesenchymal stem cells produce reverse remodelling in chronic ischaemic cardiomyopathy.

AIMS: The ability of mesenchymal stem cells (MSCs) to heal the chronically injured heart remains controversial. Here we tested the hypothesis that autologous MSCs can be safely injected into a chronic myocardial infarct scar, reduce its size, and improve ventricular function. METHODS AND RESULTS: Female adult Göttingen swine (n = 15) underwent left anterior descending coronary artery balloon occlusion to create reproducible ischaemia-reperfusion infarctions. Bone-marrow-derived MSCs were isolated and expanded from each animal. Twelve weeks post-myocardial infarction (MI), animals were randomized to receive surgical injection of either phosphate buffered saline (placebo, n = 6), 20 million (low dose, n = 3), or 200 million (high dose, n = 6) autologous MSCs in the infarct and border zone. Injections were administered to the beating heart via left anterior thoracotomy. Serial cardiac magnetic resonance imaging was performed to evaluate infarct size, myocardial blood flow (MBF), and left ventricular (LV) function. There was no difference in mortality, post-injection arrhythmias, cardiac enzyme release, or systemic inflammatory markers between groups. Whereas MI size remained constant in placebo and exhibited a trend towards reduction in low dose, high-dose MSC therapy reduced infarct size from 18.2 +/- 0.9 to 14.4 +/- 1.0% (P = 0.02) of LV mass. In addition, both low and high-dose treatments increased regional contractility and MBF in both infarct and border zones. Ectopic tissue formation was not observed with MSCs. CONCLUSION: Together these data demonstrate that autologous MSCs can be safely delivered in an adult heart failure model, producing substantial structural and functional reverse remodelling. These findings demonstrate the safety and efficacy of autologous MSC therapy and support clinical trials of MSC therapy in patients with chronic ischaemic cardiomyopathy.

Veterans Affairs Heart Team Experience With Transcatheter Aortic Valve Replacement and Minimally Invasive Surgical Aortic Valve Replacement.

OBJECTIVES: Aortic valve disease is prevalent in the veteran population. Transcatheter aortic valve replacement (TAVR) and minimally invasive surgical aortic valve replacement (MIAVR) are minimally invasive approaches predominantly performed at higher-volume cardiac centers. The study aim was to evaluate our experience with minimally invasive techniques at a Veterans Affairs Medical Center (VAMC), since outcomes from lower-volume federal facilities are relatively unknown. METHODS: This study examined retrospective data from 228 consecutive patients who underwent treatment for isolated aortic valve disease with MIAVR or TAVR via intent-to-treat at a VAMC between January 2011 and July 2017. Perioperative outcomes were analyzed using Stata version 15. RESULTS: Operative mortality was 1.1% for MIAVR and 0.7% for TAVR (Χ² P=.79). Median length of hospital stay was 10 days (interquartile range [IQR], 7-14 days) for MIAVR and 4 days for TAVR (IQR, 3-6 days; Mann-Whitney P<.001). Postoperative new-onset atrial fibrillation occurred in 52% of MIAVR patients and 5.2% of TAVR patients (Χ² P<.001). Stroke occurred in 2.2% of MIAVR patients and 3.0% of TAVR patients (Χ² P=.71). In patients who underwent MIAVR, 5.4% required placement of a permanent pacemaker postoperatively, compared with 14% of TAVR patients (Χ² P=.04). Mild paravalvular leak (PVL) affected 2.2% of MIAVR and 28% of TAVR patients, with moderate PVL reported in 2.2% of MIAVR and 3% of TAVR patients (Χ² P<.001). CONCLUSIONS: The VAMC heart team offers MIAVR and TAVR to veterans with isolated aortic valve disease, and has achieved excellent outcomes despite relatively lower case volumes. Both offer excellent hemodynamic results, with low mortality in a complex population.

Outcomes of Veterans Undergoing TAVR Within Veterans Affairs Medical Centers: Insights From the Veterans Affairs Clinical Assessment, Reporting, and Tracking Program.

OBJECTIVES: This study sought to describe clinical and procedural characteristics of veterans undergoing transcatheter aortic valve replacement (TAVR) within U.S. Department of Veterans Affairs (VA) centers and to examine their association with short- and long-term mortality, length of stay (LOS), and rehospitalization within 30 days. BACKGROUND: Veterans with severe aortic stenosis frequently undergo TAVR at VA medical centers. METHODS: Consecutive veterans undergoing TAVR between 2012 and 2017 were included. Patient and procedural characteristics were obtained from the VA Clinical Assessment, Reporting, and Tracking system. The primary outcomes were 30-day and 1-year survival, LOS >6 days, and rehospitalization within 30 days. Logistic regression and Cox proportional hazards analyses were performed to evaluate the associations between pre-procedural characteristics and LOS and rehospitalization. RESULTS: Nine hundred fifty-nine veterans underwent TAVR at 8 VA centers during the study period, 860 (90%) by transfemoral access, 50 (5%) transapical, 36 (3.8%) transaxillary, and 3 (0.3%) transaortic. Men predominated (939 of 959 [98%]), with an average age of 78.1 years. There were 28 deaths within 30 days (2.9%) and 134 at 1 year (14.0%). Median LOS was 5 days, and 141 veterans were rehospitalized within 30 days (14.7%). Nonfemoral access (odds ratio: 1.74; 95% confidence interval [CI]: 1.10 to 2.74), heart failure (odds ratio: 2.51; 95% CI: 1.83 to 3.44), and atrial fibrillation (odds ratio: 1.40; 95% CI: 1.01 to 1.95) were associated with increased LOS. Atrial fibrillation was associated with 30-day rehospitalization (hazard ratio: 1.79; 95% CI: 1.22 to 2.63). CONCLUSIONS: Veterans undergoing TAVR at VA centers are predominantly elderly men with significant comorbidities. Clinical outcomes of mortality and rehospitalization at 30 days and 1-year mortality compare favorably with benchmark outcome data outside the VA.

Aging impairs the beneficial effect of granulocyte colony-stimulating factor and stem cell factor on post-myocardial infarction remodeling.

Granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) are potential new therapies to ameliorate post-myocardial infarction (post-MI) remodeling, as they enhance endogenous cardiac repair mechanisms and decrease cardiomyocyte apoptosis. Because both of these pathways undergo alterations with increasing age, we hypothesized that therapeutic efficacy of G-CSF and SCF is impaired in old versus young adult rats. MI was induced in 6- and 20-month-old rats by permanent ligation of the left coronary artery. In young animals, G-CSF/SCF therapy stabilized and reversed a decline in cardiac function, attenuated left ventricular dilation, decreased infarct size, and reduced cardiomyocyte hypertrophy. Remarkably, these effects on cardiac structure and function were absent in aged rodents. This could not be attributed to ineffective mobilization of bone marrow cells or decreased quantity of c-Kit(+) cells within the myocardium with aging. However, whereas the G-CSF/SCF cocktail reduced cardiac myocyte apoptosis in old as well as in young hearts, the degree of reduction was substantially less with age and the rate of cardiomyocyte apoptosis in old animals remained high despite cytokine treatment. These findings demonstrate that G-CSF/SCF lacks therapeutic efficacy in old animals by failing to offset periinfarct apoptosis and therefore raise important concerns regarding the efficacy of novel cytokine therapies in elderly individuals at greatest risk for adverse consequences of MI.

The adult Göttingen minipig as a model for chronic heart failure after myocardial infarction: focus on cardiovascular imaging and regenerative therapies.

Porcine models have become increasingly popular in cardiovascular research. The standard farm pig rapidly increases in body weight and size, potentially confounding serial measurements of cardiac function and morphology. We developed an adult porcine model that does not show physiologic increases in heart mass during the study period and is suitable for long-term study. We compared adult minipigs with the commonly used adolescent Yorkshire swine. Myocardial infarction was induced in adult Göttingen minipigs and adolescent Yorkshire swine by occlusion of the left anterior descending coronary artery followed by reperfusion. At 8 wk after infarction, the left ventricular ejection fraction was 34.1 +/- 2.3% in minipigs and 30.7 +/- 2.0% in Yorkshire swine. The left ventricular end-diastolic mass in Yorkshire pigs assessed by magnetic resonance imaging increased 17 +/- 5 g, from 42.6 +/- 4.3 g at week 1 after infarction to 52.8 +/- 6.6 g at week 8, whereas it remained unchanged in minipigs. Cardiac anatomy and physiology in adult minipigs were evaluated invasively by angiography and noninvasively by Multidetector Computed Tomography and by Magnetic Resonance Imaging at 1.5 T and 3 T prior to myocardial infarction and during folow-up. This porcine heart failure model is reproducible, mimics the pathophysiology in patients who have experienced myocardial infarction, and is suitable for imaging studies. New heart failure therapies and devices can be tested preclinically in this adult animal model of chronic heart failure.

Coronary artery CTA: imaging of atherosclerosis in the coronary arteries and reporting of coronary artery CTA findings.

Invasive coronary angiography remains the standard for assessment of coronary anatomy and pathology, and for determining the extent and severity of coronary lumen obstruction in coronary artery disease. Recent advances in multidetector row computed tomography (MDCT) technology allowing noninvasive imaging of the coronary arteries has led to widespread enthusiasm for the use of noninvasive coronary angiography. A comprehensive and clinically useful MDCT study should incorporate an understanding of the patient history and reason for performance of the test, an overall assessment of study quality, and a complete description of pertinent findings. Because the majority of cardiac computed tomography (CT) studies are now being performed for the evaluation of the coronary arteries and obstructive coronary disease, a clear understanding of what the clinician wants to know from a CTA is critical to its comprehensive interpretation. In this manuscript, we provide an overview of the necessary components of CT coronary angiogram interpretation, from the point of view of the practicing invasive cardiologist.

Risk of contrast-induced nephropathy for patients receiving intravenous vs. intra-arterial iodixanol administration.

PURPOSE: To compare the incidence of contrast-induced nephropathy (CIN) for intravenous vs. intra-arterial administration of iodixanol, compared to non-administration. METHODS: We retrospectively identified 650 patients who had intravenous iodixanol-enhanced CT, 695 with intra-arterial iodixanol cardiac catheterization, 651 with unenhanced CT, and those who also had baseline and follow-up serum creatinine within 5 days of the exam. From the medical records, we recorded the gender, age, baseline and follow-up serum creatinine/eGFR; underlying renal injury risk factors; indication for imaging; contrast material administration volume, concentration, and route of administration; and use of pre-imaging prophylactic measures for CIN. Univariate and multivariate models were used to determine predictors of CIN. RESULTS: Baseline eGFR was lower for patients undergoing unenhanced CT than intravenous or intra-arterial patients (68 vs. 74.6 and 72.2, respectively, p < 0.01) and not different between intravenous and intra-arterial patients (p = 0.735). Simple logistic regression did not show a difference in the rate of CIN in patients who received intravenous vs. intra-arterial iodixanol (28 of 650, 4%, vs. 28 of 695, 4%, respectively, p = 0.798), nor a higher rate of CIN than seen with unenhanced CT (45 of 651, 7%, p = 0.99 and p = 0.98 by one-sided t test). Multivariate regression modeling showed that only elevated baseline creatinine or decreased eGFR and low hematocrit/hemoglobin were associated with CIN incidence (odds ratio 1.28 and 2.5; p < 0.023 and <0.006, respectively). CONCLUSIONS: Elevation in serum creatinine due to intravenous and intra-arterial iodixanol administration is infrequent and is not more common than after unenhanced CT scans.

Persistent renal enhancement after intra-arterial versus intravenous iodixanol administration.

PURPOSE: To examine the clinical significance of persistent renal enhancement after iodixanol administration. METHODS: We retrospectively studied 166 consecutive patients who underwent non-enhanced abdominopelvic CT within 7 days after receiving intra-arterial (n=99) or intravenous (n=67) iodixanol. Renal attenuation was measured for each non-enhanced CT scan. Persistent renal enhancement was defined as CT attenuation>55 Hounsfield units (HU). Contrast-induced nephropathy (CIN) was defined as a rise in serum creatinine>0.5 mg/dL within 5 days after contrast administration. RESULTS: While the intensity and frequency of persistent renal enhancement was higher after intra-arterial (mean CT attenuation of 73.7 HU, seen in 54 of 99 patients, or 55%) than intravenous contrast material administration (51.8 HU, seen in 21 of 67, or 31%, p<0.005), a multivariate regression model showed that the independent predictors of persistent renal enhancement were a shorter time interval until the subsequent non-enhanced CT (p<0.001); higher contrast dose (p<0.001); higher baseline serum creatinine (p<0.01); and older age (p<0.05). The route of contrast administration was not a predictor of persistent renal enhancement in this model. Contrast-induced nephropathy was noted in 9 patients who received intra-arterial (9%) versus 3 who received intravenous iodixanol (4%), and was more common in patients with persistent renal enhancement (p<0.01). CONCLUSION: Persistent renal enhancement at follow-up non-contrast CT suggests a greater risk for contrast-induced nephropathy, but the increased frequency of striking renal enhancement in patients who received intra-arterial rather than intravenous contrast material also reflects the larger doses of contrast and shorter time to subsequent follow-up CT scanning for such patients.

Implantation of mouse embryonic stem cell-derived cardiac progenitor cells preserves function of infarcted murine hearts.

Stem cell transplantation holds great promise for the treatment of myocardial infarction injury. We recently described the embryonic stem cell-derived cardiac progenitor cells (CPCs) capable of differentiating into cardiomyocytes, vascular endothelium, and smooth muscle. In this study, we hypothesized that transplanted CPCs will preserve function of the infarcted heart by participating in both muscle replacement and neovascularization. Differentiated CPCs formed functional electromechanical junctions with cardiomyocytes in vitro and conducted action potentials over cm-scale distances. When transplanted into infarcted mouse hearts, CPCs engrafted long-term in the infarct zone and surrounding myocardium without causing teratomas or arrhythmias. The grafted cells differentiated into cross-striated cardiomyocytes forming gap junctions with the host cells, while also contributing to neovascularization. Serial echocardiography and pressure-volume catheterization demonstrated attenuated ventricular dilatation and preserved left ventricular fractional shortening, systolic and diastolic function. Our results demonstrate that CPCs can engraft, differentiate, and preserve the functional output of the infarcted heart.

Early improvement in cardiac tissue perfusion due to mesenchymal stem cells.

The underlying mechanism(s) of improved left ventricular function (LV) due to mesenchymal stem cell (MSC) administration after myocardial infarction (MI) remains highly controversial. Myocardial regeneration and neovascularization, which leads to increased tissue perfusion, are proposed mechanisms. Here we demonstrate that delivery of MSCs 3 days after MI increased tissue perfusion in a manner that preceded improved LV function in a porcine model. MI was induced in pigs by 60-min occlusion of the left anterior descending coronary artery, followed by reperfusion. Pigs were assigned to receive intramyocardial injection of allogeneic MSCs (200 million, approximately 15 injections) (n = 10), placebo (n = 6), or no intervention (n = 8). Resting myocardial blood flow (MBF) was serially assessed by first-pass perfusion magnetic resonance imaging (MRI) over an 8-wk period. Over the first week, resting MBF in the infarct area of MSC-treated pigs increased compared with placebo-injected and untreated animals [0.17 +/- 0.03, 0.09 +/- 0.01, and 0.08 +/- 0.01, respectively, signal intensity ratio of MI to left ventricular blood pool (LVBP); P < 0.01 vs. placebo, P < 0.01 vs. nontreated]. In contrast, the signal intensity ratios of the three groups were indistinguishable at weeks 4 and 8. However, MSC-treated animals showed larger, more mature vessels and less apoptosis in the infarct zones and improved regional and global LV function at week 8. Together these findings suggest that an early increase in tissue perfusion precedes improvements in LV function and a reduction in apoptosis in MSC-treated hearts. Cardiac MRI-based measures of blood flow may be a useful tool to predict a successful myocardial regenerative process after MSC treatment.

Quantitative automated assessment of myocardial perfusion at cardiac catheterization.

Perfusion assessed in the cardiac catheterization laboratory predicts outcomes after myocardial infarction. The aim of this study was to investigate a novel method of assessing perfusion using digital subtraction angiography to generate a time-density curve (TDC) of myocardial blush, incorporating epicardial and myocardial perfusion. Seven pigs underwent temporary occlusion of the left anterior descending coronary artery for 60 minutes. Angiography was performed in the same projections before, during, and after occlusion. Perfusion parameters were obtained from the TDC and compared with Thrombolysis In Myocardial Infarction (TIMI) frame count and myocardial perfusion grade. In addition, safety and feasibility were tested in 8 patients after primary percutaneous coronary intervention. The contrast density differential between the proximal artery and the myocardium derived from the TDC correlated well with TIMI myocardial perfusion grade (R = 0.54, p <0.001). The arterial transit time derived from the TDC correlated with TIMI frame count (R = 0.435, p = 0.011). Using a cutoff of 2.4, the density/time ratio, a ratio of density differential to transit time, had sensitivity and specificity of 100% for coronary arterial occlusion. The positive and negative predictive values were 100%. The generation of a TDC was safe and feasible in 7 patients after acute myocardial infarctions, but the correlation between TDC-derived parameters and TIMI parameters did not reach statistical significance. In conclusion, this novel method of digital subtraction angiography with rapid, automated, quantitative assessment of myocardial perfusion in the cardiac catheterization laboratory correlates well with established angiographic measures of perfusion. Further studies to assess the prognostic value of this technique are warranted.

Emerging role for bone marrow derived mesenchymal stem cells in myocardial regenerative therapy.

Current treatments for ischemic cardiomyopathy are aimed toward minimizing the deleterious consequences of diseased myocardium. The possibility of treating heart failure by generating new myocardium and vascular tissue has been an impetus toward recent stem cell research. Mesenchymal stem cells (MSC), also referred to as marrow stromal cells, differentiate into a wide variety of lineages, including myocardial and endothelial cells. The multi-lineage potential of MSCs, their ability to elude detection by the host immune system, and their relative ease of expansion in culture make MSCs a very promising source of stem cells for transplantation. In addition, emerging experimental results with MSCs offer novel mechanistic insights into cardiac regenerative therapy in general. Here we review the characterization of MSCs, animal and human trials studying MSCs in cardiomyogenesis and vasculogenesis in postinfarct myocardium, routes of delivery, and potential mechanisms of stem cell repair.

Roads to polyploidy: the megakaryocyte example.

Polyploidy, recognized by multiple copies of the haploid chromosome number, has been described in plants, insects, and in mammalian cells such as, the platelet precursors, the megakaryocytes. Several of these cell types reach high ploidy via a different cell cycle. Megakaryocytes undergo an endomitotic cell cycle, which consists of an S phase interrupted by a gap, during which the cells enter mitosis but skip anaphase B and cytokinesis. Here, we review the mechanisms that lead to this cell cycle and to polyploidy in megakaryocytes, while also comparing them to those described for other systems in which high ploidy is achieved. Overall, polyploidy is associated with an orchestrated change in expression of several genes, of which, some may be a result of high ploidy and hence a determinant of a new cell physiology, while others are inducers of polyploidization. Future studies will aim to further explore these two groups of genes.