Implementation of pharmacogenetics: the University of Maryland Personalized Anti-platelet Pharmacogenetics Program.

Despite a substantial evidence base, implementation of pharmacogenetics into routine patient care has been slow due to a number of non-trivial practical barriers. We implemented a Personalized Anti-platelet Pharmacogenetics Program (PAP3) for cardiac catheterization patients at the University of Maryland Medical Center and the Baltimore Veterans Administration Medical Center Patients' are offered CYP2C19 genetic testing, which is performed in our Clinical Laboratory Improvement Amendment (CLIA)-certified Translational Genomics Laboratory. Results are returned within 5 hr along with clinical decision support that includes interpretation of results and prescribing recommendations for anti-platelet therapy based on the Clinical Pharmacogenetics Implementation Consortium guidelines. Now with a working template for PAP3, implementation of other drug-gene pairs is in process. Lessons learned as described in this article may prove useful to other medical centers as they implement pharmacogenetics into patient care, a critical step in the pathway to personalized and genomic medicine.

Recurrent Stent Thrombosis Following Myocardial Infarction Associated With VITT-Like Antibodies.

Early stent thrombosis is a rare complication of percutaneous intervention and is associated with significant 30-day mortality. We present a novel case of multiple recurrent early stent thrombosis consistent with spontaneous vaccine-induced thrombotic thrombocytopenia. We were successfully able to manage this unusual condition through an interdisciplinary collaboration.

CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings.

Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of CYP2C19-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.

Microvascular angina: assessment of coronary blood flow, flow reserve, and metabolism.

Microvascular angina (MVA) is an often overlooked cause of significant chest pain. Decreased myocardial perfusion secondary to dysregulated blood flow in the microvasculature can occur in the presence or absence of obstructive epicardial coronary artery disease. The corresponding myocardial ischemia and angina is now a well-established diagnosis, made by detection of decreased coronary flow reserve (CFR). Although low CFR and MVA are associated with poor prognosis, there is initial evidence for reversibility of this abnormal vascular regulation with aggressive medical therapy and control of associated risk factors. Current assessment of MVA is carried out predominantly during cardiac catheterization; however, noninvasive techniques to assess CFR are being developed, including PET, MRI, and CT modalities. Quantitative tracer techniques or imaging of metabolic disturbances reflecting ischemia will likely enhance diagnostic approaches for such patients as well as allow more frequent monitoring of response to therapy.

Transseptal Puncture Learning Curve for Transcatheter Edge-to-Edge Mitral Valve Repair.

OBJECTIVE: This study examined the learning curve for transseptal puncture (TSP) during transcatheter edge-to-edge mitral valve repair (TEER) performed by a dedicated mitral valve structural heart team. Effective TSP is mandatory for TEER but can be time-consuming and associated with complications including pericardial effusion and cardiac tamponade. METHODS: TSP was performed on 107 consecutive patients (76 ± 1 years, 52% male) undergoing TEER between 2014 and 2019. TSP was performed by each structural heart team member (1 cardiologist, 2 cardiac surgeons) on a rotating case-by-case basis. No team member had prior independent TSP experience. Data collected included total procedure time, TSP time (time elapsed between procedure start and septal crossing), and number of TSP attempts before successful puncture. Cumulative sum (CUSUM) of deviations from the mean across sequential cases were used to examine learning curves. RESULTS: Median total procedure time was 107 min, and the median TSP time was 14 min. Greater case number was significantly associated with both lower TSP time (r s = -0.22, P = 0.022) and lower total procedure time (r s = -0.29, P = 0.003). The majority of patients required only 1 TSP attempt (79%). There was a significant quadratic relationship between case number and the CUSUM for TSP time, with the learning curve peaking at 49 cases. CONCLUSIONS: TSP for TEER has a substantial learning curve, requiring >50 cases to achieve acceptable efficiency. Even once proficiency is demonstrated, TSP remains a time-consuming component of TEER. Improvements in transseptal access technology may significantly decrease the time needed to master TSP and may improve the safety and precision of the procedure.

Development of a Reproducible Swine Model of Chronic Ischemic Mitral Regurgitation: Lessons Learned.

BACKGROUND: Durability of mitral valve repair for ischemic mitral regurgitation (IMR) remains poor. We established a swine model of chronic IMR, and describe the methods and lessons learned from this model. METHODS: Thirty-five swine underwent percutaneous myocardial infarction with ethanol ablation of the circumflex or obtuse marginal (OM) arteries. Swine were followed with routine echocardiography for the development of severe IMR. Once severe IMR was established, swine underwent mitral valve operations on cardiopulmonary bypass. After operation, swine were survived up to 7 weeks. Angiographic and echocardiographic features of swine who developed severe IMR (IMR swine) and those who did not (non-IMR swine) were compared. RESULTS: The median number of OM arteries was 3, with 2 OM arteries infarcted. Acute survival after the myocardial infarction was 74% (26 of 35) with 3 (9%) early, postoperative deaths. Among the 23 swine with follow-up to determine IMR status, 14 of 23 (61%) developed significant IMR. Among IMR pigs, left ventricular (LV) ejection fraction decreased from 65% pre-myocardial infarction to 45% pre-mitral valve intervention (P < .001). Among non-IMR swine, LV ejection fraction decreased nonsignificantly from baseline (60%) to latest follow-up (55%) (P = .443). LV end-diastolic dimension (P = .039), wall motion score (P = .027), global circumferential strain (P = .014), and global longitudinal strain (P = .023) were significantly worse in IMR compared with non-IMR swine. CONCLUSIONS: A reproducible percutaneous model of severe IMR in swine is feasible with a guided anesthetic and perioperative approach. This model can serve as a platform to better understand the mechanism of IMR and subsequently to test novel repair techniques.

Hybrid coronary revascularization: which patients? When? How?

PURPOSE OF REVIEW: The aim of this review is to report on current indications and patient selection for hybrid coronary revascularization and to outline current techniques for a hybrid approach. RECENT FINDINGS: Hybrid coronary intervention is a revascularization strategy that combines surgical and catheter-based procedures for treatment of multivessel coronary artery disease. Most published studies report on application of this concept in patients with complex lesions of the left anterior descending artery and nonleft anterior descending lesions suited for percutaneous coronary intervention. Currently, the spectrum of surgical procedures in hybrid coronary revascularization ranges from left internal mammary artery bypass grafting via sternotomy and minithoracotomy to completely endoscopic robotic double vessel coronary artery bypass grafting. Percutaneous coronary intervention in hybrid procedures is performed as single or multiple coronary angioplasty with stenting using either bare metal or drug-eluting stents. Staged and simultaneous approaches can be applied. The latter are increasingly performed in the hybrid operating room. SUMMARY: Hybrid coronary intervention is an emerging interdisciplinary approach in the treatment of coronary artery disease and a potential viable alternative to open coronary bypass surgery or multivessel stenting.

Hybrid coronary revascularization: an overview of options for anticoagulation and platelet inhibition.

BACKGROUND: Hybrid coronary revascularization, in which coronary bypass grafting is combined with percutaneous coronary intervention, is a promising strategy for optimizing outcomes in the treatment of coronary artery disease. Balancing the risk of surgical bleeding with the risk of percutaneous coronary intervention-related thrombosis is a major challenge inherent in carrying out a successful procedure and requires careful selection of antiplatelet and anticoagulant agents. METHODS: Advantages and disadvantages of antiplatelet and anticoagulant agents in use today for hybrid coronary revascularization are reviewed. RESULTS: Currently available anticoagulants and platelet inhibitors have been used to provide safe and effective protection from thrombosis while limiting surgical bleeding in hybrid coronary revascularization, but there is no agreement on an optimal strategy, and each patient presents a unique pharmacologic and logistic puzzle. CONCLUSION: Knowledge of the salient features of the available medications will allow the cardiologist and surgeon to design the optimal strategy for each patient.

Nuclear cardiac stress testing in the era of molecular medicine.

The objective of cardiac stress testing is to detect coronary artery disease (CAD) and to prevent future adverse events, such as myocardial infarction or death. The progression from electrocardiographically based stress testing to current SPECT and PET technologies has brought improvements in diagnostic efficacy and resolution. Myocardial perfusion imaging facilitates management of CAD in elective and acute settings by providing valuable diagnostic and prognostic information. Hybrid PET/CT and SPECT/CT systems impart complementary information of coronary anatomy and its physiologic significance on blood flow reserve. In the current era, diagnosis and treatment of cardiovascular disease is increasingly defined by underlying molecular and genomic aberrations rather than by clinical signs and symptoms alone. Nuclear imaging is uniquely primed to exploit the targeting of expressed cell-surface molecules and intracellular processes of cardiovascular disease and to foster the development of innovative therapeutic interventions in the future.

Test-retest reliability of assessment for intraventricular dyssynchrony by tissue Doppler imaging echocardiography.

The purpose of this study was to evaluate the test-retest reliability of intraventricular dyssynchrony (IVD) assessment by tissue Doppler imaging (TDI) echocardiography. Limited response rates to cardiac resynchronization may improve with TDI screening for appropriate recipients. However, the clinical applicability of TDI will depend on the reliability of the test. Repeat TDI was prospectively performed (11 +/- 11 days apart) in 15 patients with QRS intervals >120 ms and left ventricular ejection fractions <35% and 25 normal controls using the same machine, sonographer, and blinded readers for the 2 tests. There was no change in clinical status or treatment between tests. Established and clinically feasible criteria for IVD were evaluated. These were based on differences of TDI-derived activation time between 2, 4, or 12 left ventricular segments. Reliability was assessed by linear correlation and Bland-Altman analysis for quantified measures, along with percentage agreement and kappa statistics for IVD diagnosis. Despite good intrareader (r = 0.98, p <0.0001) and interreader (2 segments: r = 0.96, p <0.0001; 4 segments: r = 0.85, p <0.0001) reliability, test-retest correlations were uniformly modest for the 2-segment (r = 0.26, p = 0.11), 4-segment (r = 0.36, p = 0.021), and 12-segment (r = 0.50, p = 0.0009) measures. Test-retest agreement for IVD diagnosis by either criterion was equally limited (2 segments: 83%, kappa = 0.27; 4 segments: 75%, kappa = 0.47; 12 segments: 68%, kappa = 0.35). Bland-Altman analysis demonstrated wide confidence intervals, exceeding the diagnostic cutoff values for the respective criteria. In conclusion, the accurate assessment of IVD by TDI may be limited by poor test-retest reliability.

Multisite Investigation of Strategies for the Implementation of CYP2C19 Genotype-Guided Antiplatelet Therapy.

CYP2C19 genotype-guided antiplatelet therapy following percutaneous coronary intervention is increasingly implemented in clinical practice. However, challenges such as selecting a testing platform, communicating test results, building clinical decision support processes, providing patient and provider education, and integrating methods to support the translation of emerging evidence to clinical practice are barriers to broad adoption. In this report, we compare and contrast implementation strategies of 12 early adopters, describing solutions to common problems and initial performance metrics for each program. Key differences between programs included the test result turnaround time and timing of therapy changes, which are both related to the CYP2C19 testing model and platform used. Sites reported the need for new informatics infrastructure, expert clinicians such as pharmacists to interpret results, physician champions, and ongoing education. Consensus lessons learned are presented to provide a path forward for those seeking to implement similar clinical pharmacogenomics programs within their institutions.

A double-blind placebo-controlled pilot study of controlled-release paroxetine on depression and quality of life in chronic heart failure.

BACKGROUND: Depression is frequently observed in patients with heart failure and is associated with poor quality of life and adverse prognosis. However, the prevalence of depression in heart failure could be overestimated because symptoms of depression overlap with those of heart failure. Similarly, the importance of depression may be overestimated if depression merely reflects worse heart failure. Because the response to depression treatment has not been evaluated in this patient population, we evaluated the efficacy of controlled-release paroxetine (paroxetine CR), a selective serotonin reuptake inhibitor, on depression and quality of life in chronic heart failure. METHODS: A double-blind, randomized, placebo-controlled design was used to evaluate reductions in depression following 12 weeks of treatment with paroxetine CR (n = 14, age 62.1 +/- 12.3 years) or placebo (n = 14, age = 61.9 +/- 9.0 years). Patients with symptomatic congestive heart failure and a score of at least 10 on the Beck Depression Inventory (BDI) were eligible. Beck Depression Inventory was obtained at baseline and 4, 8, and 12 weeks of follow-up. Quality of life was assessed using the Medical Outcomes Study Short Form and the Minnesota Living with Heart Failure Questionnaire. RESULTS: Controlled-release paroxetine resulted in significantly more recovery from depression (BDI <10) than placebo (69% vs 23%, P = .018) and resulted in lower continuous BDI scores throughout the intervention (P = .024). Controlled-release paroxetine was associated with higher general health levels compared with placebo on the Medical Outcomes Study 36-Item Short Form survey (38 +/- 10 vs 30 +/- 6, P = .016) at 12 weeks of follow-up. Reductions in depression were correlated with improvements in psychological aspects of quality of life (P < .05) but not with physical quality of life measures (P > .10). CONCLUSION: Antidepressant therapy with paroxetine CR results in significant reductions in depression among patients with heart failure. The reductions in depression with paroxetine CR are accompanied by improvements in psychological aspects of quality of life. Larger controlled trials are needed to further document the effectiveness of paroxetine CR and other selective serotonin reuptake inhibitors in patients with heart failure and to determine patient subgroups that are most likely to benefit from antidepressive interventions.

Cardiac risk assessment: matching intensity of therapy to risk.

Simple RSS allow for rapid decision making in the emergency department. The data presented in this article suggest that for patients at the highest risk and the lowest risk for complications of NSTEACS, the scoring systems work well and allow effective triage and treatment. For patients at intermediate risk (30%-40% of all patients who have ACS), however, it is not clear whether early aggressive treatment with cardiac catheterization or routine conservative management should be the standard of care. The consensus guidelines are vague, and the scoring systems discriminate less well for these patients. The authors think that patients at intermediate risk are best served by initial screening with an RSS like the TRS (with risk scores of 3-4), followed by a multimarker strategy to define risk better. They also think that the next step is to design clinical trials to test strategies of care defined prospectively by risk. This step would, in the authors' opinion, begin the next round of the cycle of clinical therapeutics [31]. The treatment of patients who have NSTE ACS has been characterized in the past 2 decades by care based on evidence from many excellent clinical tri-als. The consensus panels have convened and guide patient management. Quality-improvement initiatives such as CRUSADE and GRACE give feedback to improve compliance with guidelines. The understanding of risk is developing with the help of these scoring systems. Discovery is ongoing. The next decade of acute cardiac care will focus on early identification of patients at high risk and on matching the most intensive treatments to the patients most in need. Excessive testing and care promotes cost inefficiency and, perhaps, increased hazard for some patients. New trials are needed to move these new hypotheses back into practice.

Robotically assisted hybrid coronary revascularization: does sequence of intervention matter?

OBJECTIVE: Hybrid coronary revascularization (HCR) is a treatment strategy for the revascularization of multivessel coronary disease that combines the advantages of both minimally invasive surgical techniques and percutaneous coronary intervention (PCI). The optimal sequence by which revascularization should be accomplished has not been determined. We investigated clinical outcomes in a series of patients planned for HCR via robotically assisted totally endoscopic coronary artery bypass (TECAB) and standard PCI based on revascularization sequence. METHODS: A total of 238 patients planned for HCR between 2001 and 2011 were divided into three groups based on treatment sequence: (a) TECAB before PCI, (b) PCI before TECAB, and (c) same-session procedure. Multiple procedural and clinical end points before discharge and up to 2 years after the procedure were compared between the three groups in an intention-to-treat analysis. Demographic features were reviewed to determine baseline differences between each group. RESULTS: Of the 238 patients, 175 (73.5%) underwent TECAB before PCI, 38 patients (16.0%) underwent PCI before TECAB, and 25 (10.5%) underwent a simultaneous revascularization procedure. At baseline, the patients undergoing TECAB before PCI were significantly older. There was a significantly higher incidence of previous myocardial infarction in the PCI-first group (P < 0.001). There was a significant difference in intensive care unit (ICU) length of stay (LOS), with shorter ICU stays in the simultaneous revascularization group (P = 0.031) and shorter hospital LOS in the PCI before TECAB group (P = 0.021). CONCLUSIONS: In conclusion, revascularization sequence did not dramatically impact clinical outcomes in our observational study. The patients undergoing PCI-first and same-session interventions had shorter hospital and ICU LOS compared with the patients undergoing surgery first. Our findings suggest that no revascularization approach is arbitrarily superior and that revascularization sequence should be individualized on the basis of patient presentation and anatomical considerations.

Acute coronary syndromes: from the emergency department to the cardiac care unit.

Acute coronary syndromes result in a significant burden of morbidity and mortality in the United States. This spectrum of acute coronary thrombosis (including unstable angina, non-ST-segment elevation myocardial infarction, and ST-elevation myocardial infarction) has been well studied in large clinical trials. This review details the initial management of patients presenting with possible acute coronary syndromes in the context of care from the emergency department to the cardiac care unit. The importance of a rapid and focused evaluation, risk stratification, and appropriate therapies are discussed.

Evidence for early right ventricular and septal mechanical activation (interventricular dyssynchrony) in pulmonary hypertension.

This study sought to characterize mechanical activation in pulmonary arterial hypertension (PAH) using 2-dimensional echocardiography with tissue Doppler imaging. Whether pathologic alterations of the right ventricle in PAH affect interventricular dyssynchrony due to changes in mechanical activation of the septum and the right ventricle is unclear. We studied 20 patients with PAH (14 women, mean age 55 +/- 16 years) and 20 healthy controls (15 women, mean age 41 +/- 11 years) that underwent tissue Doppler imaging between July 2006 and May 2007. PAH was associated with accelerated right ventricular (RV) (p <0.0001) and septal (p = 0.022) activation times, but no differences were found in lateral wall activation times between groups (p = 0.35). Measures of ventricular dyssynchrony indicated that patients with PAH had significantly lower RV-lateral wall delays (patients 3.2 +/- 66.2 ms vs controls 56.7 +/- 52.0 ms, p = 0.007), reflecting a faster activation of the right ventricle relative to the lateral wall than controls. In conclusion, PAH is associated with interventricular dyssynchrony manifested by accelerated RV free wall and septal activation times. Whether such dyssynchrony should serve as a therapeutic target remains to be determined.