Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial.

BACKGROUND: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina. METHODS: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery. RESULTS: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months. CONCLUSIONS: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

Contemporary experience with the Commando procedure for anterior mitral anular calcification.

Objective: Anterior mitral anular calcification, particularly in radiation heart disease, and previous valve replacement with destroyed intervalvular fibrosa are challenging for prosthesis sizing and placement. The Commando procedure with intervalvular fibrosa reconstruction permits double-valve replacement in these challenging conditions. We referenced outcomes after Commando procedures to standard double-valve replacements. Methods: From January 2011 to January 2022, 129 Commando procedures and 1191 aortic and mitral double-valve replacements were performed at the Cleveland Clinic, excluding endocarditis. Reasons for the Commando were severe calcification after radiation (n = 67), without radiation (n = 43), and others (n = 19). Commando procedures were referenced to a subset of double-valve replacements using balancing-score methods (109 pairs). Results: Between balanced groups, Commando versus double-valve replacement had higher total calcium scores (median 6140 vs 2680 HU, P = .03). Hospital outcomes were similar, including operative mortality (12/11% vs 8/7.3%, P = .35) and reoperation for bleeding (9/8.3% vs 5/4.6%, P = .28). Survival and freedom from reoperation at 5 years were 54% versus 67% (P = .33) and 87% versus 100% (P = .04), respectively. Higher calcium score was associated with lower survival after double-valve replacement but not after the Commando. The Commando procedure had lower aortic valve mean gradients at 4 years (9.4 vs 11 mm Hg, P = .04). After Commando procedures for calcification, 5-year survival was 60% and 59% with and without radiation, respectively (P = .47). Conclusions: The Commando procedure with reconstruction of the intervalvular fibrosa destroyed by mitral anular calcification, radiation, or previous surgery demonstrates acceptable outcomes similar to standard double-valve replacement. More experience and long-term outcomes are required to refine patient selection for and application of the Commando approach.

Sex Bias in Prediction and Diagnosis of Cardiac Surgery Associated Acute Kidney Injury.

Background: Female sex has been recognized as a risk factor for cardiac surgery associated acute kidney injury (CS-AKI). The current study sought to evaluate whether female sex is a risk factor for CS-AKI, or modifies the association of peri-operative change in serum creatinine with CS-AKI. Methods: Observational study of adult patients undergoing cardiac surgery between 2000 and 2019 in a single U.S. center. The main variable of interest was registered patient sex, identified from electronic medical records. The main outcome was CS-AKI within 2 weeks of surgery. Results: Of 58526 patients, 19353 (33%) were female; 12934 (22%) incurred AKI based on ≥ 0.3 mg/dL or ≥ 50% rise in serum creatinine (any AKI), 3320 (5.7%) had moderate to severe AKI, and 1018 (1.7%) required dialysis within 2 weeks of surgery. Female sex was associated with higher risk for AKI in models that were based on preoperative serum creatinine (OR, 1.35; 95% CI, 1.29-1.42), and lower risk with the use of estimated glomerular filtration, (OR, 0.90; 95% CI, 0.86-0.95). The risk for moderate to severe CS-AKI for a given immediate peri-operative change in serum creatinine was higher in female compared to male patients (p < .0001 and p < .0001 for non-linearity), and the association was modified by pre-operative kidney function (p < .0001 for interaction). Conclusions: The association of patient sex with CS-AKI and its direction was dependent on the operational definition of pre-operative kidney function, and differential outcome misclassification due to AKI defined by absolute change in serum creatinine.

Identifying and mitigating risk of postcardiotomy cardiogenic shock in patients with ischemic and nonischemic cardiomyopathy.

OBJECTIVES: To identify preoperative predictors of postcardiotomy cardiogenic shock in patients with ischemic and nonischemic cardiomyopathy and evaluate trajectory of postoperative ventricular function. METHODS: From January 2017 to January 2020, 238 patients with ejection fraction <30% (206/238) or 30% to 34% with at least moderately severe mitral regurgitation (32/238) underwent conventional cardiac surgery at Cleveland Clinic, 125 with ischemic and 113 with nonischemic cardiomyopathy. Preoperative ejection fraction was 25 ± 4.5%. The primary outcome was postcardiotomy cardiogenic shock, defined as need for microaxial temporary left ventricular assist device, extracorporeal membrane oxygenation, or vasoactive-inotropic score >25. RandomForestSRC was used to identify its predictors. RESULTS: Postcardiotomy cardiogenic shock occurred in 27% (65/238). Pulmonary artery pulsatility index <3.5 and pulmonary capillary wedge pressure >19 mm Hg were the most important factors predictive of postcardiotomy cardiogenic shock in ischemic cardiomyopathy. Cardiac index <2.2 L·min-1 m-2 and pulmonary capillary wedge pressure >21 mm Hg were the most important predictive factors in nonischemic cardiomyopathy. Operative mortality was 1.7%. Ejection fraction at 12 months after surgery increased to 39% (confidence interval, 35-40%) in the ischemic group and 37% (confidence interval, 35-38%) in the nonischemic cardiomyopathy group. CONCLUSIONS: Predictors of postcardiotomy cardiogenic shock were different in ischemic and nonischemic cardiomyopathy. Right heart dysfunction, indicated by low pulmonary artery pulsatility index, was the most important predictor in ischemic cardiomyopathy, whereas greater degree of cardiac decompensation was the most important in nonischemic cardiomyopathy. Therefore, preoperative right heart catheterization will help identify patients with low ejection fraction who are at greater risk of postcardiotomy cardiogenic shock.

Hemodynamic Determinants of Cardiac Surgery-Associated Acute Kidney Injury.

OBJECTIVES: Examine the: 1) relative role of hemodynamic determinants of acute kidney injury (AKI) obtained in the immediate postcardiac surgery setting compared with established risk factors, 2) their predictive value, and 3) extent mediation via central venous pressure (CVP) and mean arterial pressure (MAP). DESIGN: Retrospective observational study. The main outcome of the study was moderate to severe AKI, per kidney disease: improving global outcomes, within 14 days of surgery. SETTING: U.S. academic medical center. PATIENTS: Adult patients undergoing cardiac surgery between January 2000 and December 2019 (n = 40,426) in a single U.S.-based medical center. Pulmonary artery catheter measurements were performed at a median of 102 minutes (11, 132) following cardiopulmonary bypass discontinuation. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The median age of the cohort was 67 years (58, 75), and 33% were female; 70% had chronic hypertension, 29% had congestive heart failure, and 3% had chronic kidney disease. In a multivariable model, which included comorbidities and traditional intraoperative risk factors, CVP (p < 0.0001), heart rate (p < 0.0001), cardiac index (p < 0.0001), and MAP (p < 0.0001), were strong predictors of AKI, and superseded factors such as surgery type and cardiopulmonary bypass duration. The cardiac index had a significant interaction with heart rate (p = 0.026); a faster heart rate had a differentiating effect on the relationship of cardiac index with AKI, where a higher heart rate heightened the risk of AKI primarily in patients with low cardiac output. There was also significant interaction observed between CVP and MAP (p = 0.009); where the combination of elevated CVP and low MAP had a synergistic effect on AKI incidence. CONCLUSIONS: Hemodynamic factors measured within a few hours of surgery showed a strong association with AKI. Furthermore, determinants of kidney perfusion, namely CVP and arterial pressure are interdependent; as are constituents of stroke volume, that is, cardiac output and heart rate.

Coronary Artery Surgery: Past, Present, and Future.

Coronary artery bypass grafting (CABG) is the most commonly performed and studied major cardiac operation worldwide. An understanding of the evolution of CABG, including the early days of cardiac surgery, the first bypass operation, continuous improvements in techniques, and streamlining of the operation, is important to inform current trends and future innovations. This article will examine how CABG evolved (from techniques to conduits), describe current trends in the field, and explore what lies on the horizon for the future of CABG.

Complete Coronary Revascularization and Outcomes in Patients Who Underwent Coronary Artery Bypass Grafting: Insights from The REGROUP Trial.

There is growing evidence in support of coronary complete revascularization (CR). Nonetheless, there is no universally accepted definition of CR in patients who undergo coronary bypass grafting surgery (CABG). We sought to investigate the outcomes of CR, defined as surgical revascularization of any territory supplied by a suitable coronary artery with ≥50% stenosis. We performed a preplanned subanalysis in the Randomized Trial of Endoscopic or Open Saphenous Vein Graft Harvesting (REGROUP) clinical trial cohort. Of 1,147 patients who underwent CABG, 810 (70.6%) received CR. The primary outcome was a composite of major adverse cardiac events (MACEs), including death from any cause, nonfatal myocardial infarction, or repeat revascularization over a median 4.7 years of follow-up. MACE occurred in 175 patients (21.6%) in the CR group and 86 patients (25.5%) in the incomplete revascularization (IR) group (hazard ratio [HR] 0.87, 95% confidence interval [CI] 0.67 to 1.13, p = 0.29). A total of 97 patients (12.0%) in the CR group and 48 patients (14.2%) in the IR group died (HR 0.93, 95% CI 0.65 to 1.32, p = 0.67); nonfatal myocardial infarction occurred in 49 patients (6.0%) in the CR group and 30 patients (8.9%) in the IR group (HR 0.76, 95% CI 0.48 to 1.2, p = 0.24), and repeat revascularization occurred in 62 patients (7.7%) in the CR group and 39 patients (11.6%) in the IR group (HR 0.64; 95% CI 0.42 to 0.95, p = 0.027). In conclusion, in patients with a great burden of co-morbidities who underwent CABG in the REGROUP trial over a median follow-up period of a median 4.7 years, CR was associated with similar MACE rates but a reduced risk of repeat revascularization. Longer-term follow-up is warranted.

Multiarterial vs Single-Arterial Coronary Surgery: 10-Year Follow-up of 1 Million Patients.

BACKGROUND: Although many options exist for multivessel coronary revascularization, controversy persists over whether multiarterial grafting (MAG) confers a survival advantage over single-arterial grafting (SAG) with saphenous vein in coronary artery bypass grafting (CABG). This study sought to compare longitudinal survival between patients undergoing MAG and those undergoing SAG. METHODS: All patients undergoing isolated CABG with ≥2 bypass grafts in The Society of Thoracic Surgeons Adult Cardiac Surgery Database (2008-2019) were linked to the National Death Index. Risk adjustment was performed using inverse probability weighting and multivariable modeling. The primary end point was longitudinal survival. Subpopulation analyses were performed and volume thresholds were analyzed to determine optimal benefit. RESULTS: A total of 1,021,632 patients underwent isolated CABG at 1108 programs (100,419 MAG [9.83%]; 920,943 SAG [90.17%]). Median follow-up was 5.30 years (range, 0-12 years). After risk adjustment, all characteristics were well balanced. At 10 years, MAG was associated with improved unadjusted (hazard ratio, 0.59; 95% CI 0.58-0.61) and adjusted (hazard ratio, 0.86; 95% CI, 0.85-0.88) 10-year survival. Center volume of ≥10 MAG cases/year was associated with benefit. MAG was associated with an overall survival advantage over SAG in all subgroups, including stable coronary disease, acute coronary syndrome, and acute infarction. Survival was equivalent to that with SAG for patients age ≥80 years and those with severe heart failure, renal failure, peripheral vascular disease, or obesity. Only patients with a body mass index ≥40 kg/m2 had superior survival with SAG. CONCLUSIONS: Multiarterial CABG is associated with superior long-term survival and should be the surgical multivessel revascularization strategy of choice for patients with a body mass index of less than 40 kg/m2.

Programmatic approach to patients with advanced ischemic cardiomyopathy: Integrating microaxial support into strategies for the modern era.

Patients with advanced ischemic cardiomyopathy manifesting as left ventricular dysfunction exist along a spectrum of severity and risk, and thus decision-making surrounding optimal management is challenging. Treatment pathways can include medical therapy as well as revascularization through percutaneous coronary intervention or coronary artery bypass grafting. Additionally, temporary and durable mechanical circulatory support, as well as heart transplantation, may be optimal for select patients. Given this spectrum of risk and the complexity of treatment pathways, patients may not receive appropriate therapy given their perceived risk, which can lead to sub-satisfactory outcomes. In this review, we discuss the identification of high-risk ischemic cardiomyopathy patients, along with our programmatic approach to patient evaluation and perioperative optimization. We also discuss our strategies for therapeutic decision-making designed to optimize both short- and long-term patient outcomes.

What determines outcomes in multivalve reoperations? Effect of patient and surgical complexity.

OBJECTIVE: Patient characteristics, risks, and outcomes associated with reoperative multivalve cardiac surgery are poorly characterized. Effect of patient variables and surgical components of each reoperation were evaluated with regard to operative mortality. METHODS: From January 2008 to January 2022, 2324 patients with previous cardiac surgery underwent 2352 reoperations involving repair or replacement of multiple cardiac valves at Cleveland Clinic. Mean age was 66 ± 14 years. Number of surgical components representing surgical complexity (valve procedures, aortic surgery, coronary artery bypass grafting, and atrial fibrillation procedures) ranged from 2 to 6. Random forest for imbalanced data was used to identify risk factors for operative mortality. RESULTS: Surgery was elective in 1327 (56%), urgent in 1006 (43%), and emergency in 19 (0.8%). First-time reoperations were performed in 1796 (76%) and 556 (24%) had 2 or more previous operations. Isolated multivalve operations comprised 54% (1265) of cases; 1087 incorporated additional surgical components. Two valves were operated on in 80% (1889) of cases, 3 in 20% (461), and 4 in 0.09% (2). Operative mortality was 4.2% (98 out of 2352), with 1.7% (12 out of 704) for elective, isolated multivalve reoperations. For each added surgical component, operative mortality incrementally increased, from 2.4% for 2 components (24 out of 1009) to 17% for ≥5 (5 out of 30). Predictors of operative mortality included coronary artery bypass grafting, surgical urgency, cardiac, renal dysfunction, peripheral artery disease, New York Heart Association functional class, and anemia. CONCLUSIONS: Elective, isolated reoperative multivalve surgery can be performed with low mortality. Surgical complexity coupled with key physiologic factors can be used to inform surgical risk and decision making.

Increasing surgeon experience and cumulative institutional experience drive decreasing hospital mortality after reoperative cardiac surgery.

OBJECTIVE: The study objective was to identify the effects of surgeon experience and age, in the context of cumulative institutional experience, on risk-adjusted hospital mortality after cardiac reoperations. METHODS: From 1951 to 2020, 36 surgeons performed 160,338 cardiac operations, including 32,871 reoperations. Hospital death was modeled using a novel tree-bagged, generalized varying-coefficient method with 6 variables reflecting cumulative surgeon and institutional experience up to each cardiac operation: (1) number of total and (2) reoperative cardiac operations performed by a surgeon, (3) cumulative institutional number of total and (4) reoperative cardiac operations, (5) year of surgery, and (6) surgeon age at each operation. These were adjusted for 46 patient characteristics and surgical components. RESULTS: There were 1470 hospital deaths after cardiac reoperations (4.5%). At the institutional level, hospital death decreased exponentially and became less variable, leveling at 1.2% after approximately 14,000 cardiac reoperations. For all surgeons as a group, hospital death decreased rapidly over the first 750 reoperations and then gradually decreased with increasing experience to less than 1% after approximately 4000 reoperations. Surgeon age up to 75 years was associated with ever-decreasing hospital death. CONCLUSIONS: Surgeon age and experience have been implicated in adverse surgical outcomes, particularly after complex cardiac operations, with young surgeons being novices and older surgeons having declining ability. However, at Cleveland Clinic, outcomes of cardiac reoperations improved with increasing primary surgeon experience, without any suggestion to mid-70s of an age cutoff. Patients were protected by the cumulative background of institutional experience that created a culture of safety and teamwork that mitigated adverse events after cardiac surgery.

The ISCHEMIA trial revisited: setting the record straight on the benefits of coronary bypass surgery and the misinterpretation of a landmark trial.

OBJECTIVES: The ISCHEMIA trial is a landmark study that has been the subject of heated debate within the cardiovascular community. In this analysis of the ISCHEMIA trial, we aim to set the record straight on the benefits of coronary artery bypass grafting (CABG) and the misinterpretation of this landmark trial. We sought to clarify and reorient this misinterpretation. METHODS: We herein analyse the ISCHEMIA trial in detail and describe how its misinterpretation has led to an erroneous guideline recommendation downgrading for prognosis-altering surgical therapy in these at-risk patients. RESULTS: The interim ISCHEMIA trial findings align with previous evidence where CABG reduces the long-term risks of myocardial infarction and mortality in advanced coronary artery disease. The trial outcomes of a significantly lower rate of cardiovascular mortality and a higher rate of non-cardiovascular mortality with the invasive strategy are explained according to landmark evidence. CONCLUSIONS: The ISCHEMIA trial findings are aligned with previous evidence and should not be used to downgrade recommendations in recent guidelines for the indisputable benefits of CABG.

Branched stented anastomosis frozen elephant trunk repair: Early results from a physician-sponsored investigational device exemption study.

BACKGROUND: Multisegment thoracic aortic disease typically requires total aortic arch replacement, affects a heterogenous population, and carries a high risk even at centers of excellence. Risk has been associated with the duration of operation and complexity of repair. A novel branched stented anastomosis frozen elephant trunk repair (B-SAFER) technique has been developed at our center and is currently being studied as a physician-sponsored investigation device exemption (PS-IDE). OBJECTIVE: This study aimed to assess the early safety of using this investigational technique to treat the proximal aorta in subjects with aortic disease involving multiple segments. METHODS: This prospective, single center, nonrandomized study enrolled patients undergoing B-SAFER for acute aortic syndrome (n = 73), aortic aneurysm with chronic aortic dissection (n = 68), degenerative aortic aneurysm (n = 33), or congenital aortic arch disease (n = 4). Devices are delivered antegrade under hypothermic circulatory arrest, and the arch reconstruction is performed as a single anastomosis single stent (SASS; n = 70), single anastomosis multiple stent (SAMA; n = 68), multiple anastomosis single stent (MASS; n = 21), or multiple anastomosis multiple stent (MAMS; n = 16) reconstruction. The primary safety endpoints were operative mortality, disabling stroke, and paraparesis/paralysis. RESULTS: Between May 27, 2021, and December 31, 2022, 178 patients underwent B-SAFER in the configurations and for the indications as described above. The median patient age was 65 years (range, 21 to 85 years), and 52 (29%) were female. The median cardiopulmonary bypass time was 188 minutes (interquartile range [IQR], 155 to 226 minutes), and 97% of the patients underwent repair with antegrade brain perfusion for a median of 46 minutes (IQR, 38 to 61 minutes). Operative mortality occurred in 10 patients (5.6%, including 6 [8.2%] with acute dissection, 2 [2.9%] with chronic dissection, 2 [6.1%] with degenerative aneurysm, and 0 with a congenital disorder), disabling stroke in 5 patients (2.9%), and paraparesis in 1 patient. Other serious complications included respiratory failure (n = 20; 11.4%) and acute kidney injury (n = 18; 10%). Thirty-two patients (18%) had undergone second-stage repairs (28 endovascular and 4 open), with 1 operative mortality after that procedure due to distal rupture. Estimated survival was 95% at 30 days, 88% at 90 days, 84% at 6 months, and 79% at 1 year. One-year survival differed by indication (72% for acute dissection, 91% for chronic dissection, 71% for degenerative aneurysm, and 100% for congenital disorders). CONCLUSIONS: The B-SAFER technique for total arch replacement in a complex cohort of patients with various indications for surgery is a safe and reproducible operation, as demonstrated by the early results from a very inclusive PS-IDE study. Further follow-up and analysis will help refine the technique. Novel devices to perform this procedure should be developed.

Coronary artery bypass grafting in left ventricular dysfunction: when and how.

PURPOSE OF REVIEW: The surgical management of patients undergoing coronary artery bypass grafting (CABG) with low ejection fraction presents unique challenges that require meticulous attention to details and good surgical technique and judgement. This review details the latest evidence and best practices in the care of such patients. RECENT FINDINGS: CABG in patients with low ejection fraction carries a significant risk of perioperative mortality and morbidity related to the development of postcardiotomy shock. Preoperative optimization with pharmacological or mechanical support is required, especially in patients with cardiogenic shock. Rapid and complete revascularization is what CABG surgeons aim to achieve. Multiple arterial revascularization should be reserved to selected patients. Off-pump CABG, on-pump breathing heart CABG, and new cardioplegic solutions remain of uncertain benefit compared with traditional CABG. SUMMARY: Tremendous advancements in CABG allowed surgeons to offer revascularization to patients with severe left ventricular dysfunction and multivessel disease with acceptable risk. Despite that, there is a lack of comprehensive and robust studies particularly on long-term outcomes. Individualized patient assessment and a heart team approach should be used to determine the optimal surgical strategy for each patient.

Pathophysiology and management of saphenous vein graft disease.

INTRODUCTION: The saphenous vein graft (SVG) is the most used conduit in CABG. With standardization of its use as a conduit came an understanding of its accelerated atherosclerosis, known as saphenous vein graft disease (SVGD). Given its extensive use, a review of the pathophysiology and management of SVGD is important as we optimize its use. AREAS COVERED: For this review, an extensive literature search was completed to identify and examine the evolution of SVG in CABG, mechanisms driving SVGD, and methods developed to prevent and manage it. This includes a review of relevant major papers and trials in this space. EXPERT OPINION: Eras of evolution in SVG usage in CABG include an experimental era, era of SVG dominance in CABG, and the current era of mixed venous and arterial grafting. As SVGD was studied, the mechanisms behind it became more understood, and prevention and management methods were developed. As advances in surgical techniques and pharmacotherapy continue to reduce occurrence and severity of SVGD, long-term patency of SV grafts continues to improve and remain excellent in optimized settings. With continued innovation and improvement in operative techniques, the SVG conduit is and will remain an important player in the field of coronary bypass.