Modifiable Cardiometabolic Risk Factors in Survivors of Childhood Cancer: JACC: CardioOncology State-of-the-Art Review.

The growing community of childhood cancer survivors faces a heavy burden of late onset morbidities and mortality, with cardiovascular diseases being the leading noncancer cause. In addition to demographics and cancer treatment exposures, which cannot be altered, cardiometabolic risk factors (obesity, hypertension, diabetes, and dyslipidemia) and frailty potentiate the risk of morbidity and mortality associated with chronic health conditions. Important opportunities exist to target these risk factors and improve late health outcomes for survivors. Unfortunately, limited evidence exists on the optimal methods to prevent, screen, and treat cardiometabolic risk factors among survivors, resulting in significant underdiagnosis and undertreatment. In this review, we discuss the prevalence of, risk factors for, current survivor-specific recommendations, and gaps in knowledge to mitigate potentially modifiable cardiometabolic risk factors and frailty among survivors of childhood cancer.

Improved Cardiomyopathy Risk Prediction Using Global Longitudinal Strain and N-Terminal-Pro-B-Type Natriuretic Peptide in Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy.

PURPOSE: To leverage baseline global longitudinal strain (GLS) and N-terminal-pro-B-type natriuretic peptide (NT-proBNP) to identify childhood cancer survivors with a normal left ventricular ejection fraction (LVEF) at highest risk of future treatment-related cardiomyopathy. METHODS: St Jude Lifetime Cohort participants ≥5 years from diagnosis, at increased risk for cardiomyopathy per the International Guideline Harmonization Group (IGHG), with an LVEF ≥50% on baseline echocardiography (n = 1,483) underwent measurement of GLS (n = 1,483) and NT-proBNP (n = 1,052; 71%). Multivariable Cox regression models estimated hazard ratios (HRs) and 95% CIs for postbaseline cardiomyopathy (modified Common Terminology Criteria for Adverse Events ≥grade 2) incidence in association with echocardiogram-based GLS (≥-18) and/or NT-proBNP (>age-sex-specific 97.5th percentiles). Prediction performance was assessed using AUC in models with and without GLS and NT-proBNP and compared using DeLong's test for IGHG moderate- and high-risk individuals treated with anthracyclines. RESULTS: Among survivors (median age, 37.6; range, 10.2-70.4 years), 162 (11.1%) developed ≥grade 2 cardiomyopathy 5.1 (0.7-10.0) years from baseline assessment. The 5-year cumulative incidence of cardiomyopathy for survivors with and without abnormal GLS was, respectively, 7.3% (95% CI, 4.7 to 9.9) versus 4.4% (95% CI, 3.0 to 5.7) and abnormal NT-proBNP was 9.9% (95% CI, 5.8 to 14.1) versus 4.7% (95% CI, 3.2 to 6.2). Among survivors with a normal LVEF, abnormal baseline GLS and NT-proBNP identified anthracycline-exposed, IGHG-defined moderate-/high-risk survivors at a four-fold increased hazard of postbaseline cardiomyopathy (HR, 4.39 [95% CI, 2.46 to 7.83]; P < .001), increasing to a HR of 14.16 (95% CI, 6.45 to 31.08; P < .001) among survivors who received ≥250 mg/m2 of anthracyclines. Six years after baseline, AUCs for individual risk prediction were 0.70 for models with and 0.63 for models without GLS and NT-proBNP (P = .022). CONCLUSION: GLS and NT-proBNP should be considered for improved identification of survivors at high risk for future cardiomyopathy.

Dyslipidemia and cardiovascular disease among childhood cancer survivors: a St. Jude Lifetime Cohort report.

BACKGROUND: Childhood cancer survivors have increased risk of dyslipidemia and atherosclerotic cardiovascular disease (CVD). The aim of this study was to evaluate the prevalence and associated cardiovascular risks of specific lipid abnormalities among childhood cancer survivors. METHODS: Comprehensive lipid panel measurements were obtained from 4115 5-year survivors, with 3406 (mean age at evaluation = 35.2 years, SD = 10.4 years) not having previous dyslipidemia diagnosis, as well as 624 age, sex, and race and ethnicity matched community controls. RESULTS: Previously undiagnosed dyslipidemia with abnormal low-density lipoprotein (LDL) cholesterol (>160 mg/dL), non-high density lipoprotein (HDL) cholesterol (>190 mg/dL), HDL cholesterol (<40 mg/dL for men, <50 mg/dL for women), and triglycerides (>150 mg/dL) were identified in 4%, 6%, 30%, and 17%, respectively. Survivors without previous dyslipidemia diagnosis had higher LDL cholesterol and non-HDL cholesterol and lower HDL cholesterol than community controls. Cranial radiotherapy (relative risk [RR] = 2.2, 95% confidence interval [CI] = 1.6 to 3.0 for non-HDL cholesterol) and total body irradiation for hematopoietic cell transplantation (RR = 6.7, 95% CI = 3.5 to 13.0 for non-HDL cholesterol; RR = 9.9, 95% CI = 6.0 to 16.3 for triglycerides) were associated with greater risk of dyslipidemia. Diagnoses of low HDL cholesterol (hazard ratio [HR] = 2.9, 95% CI = 1.8 to 4.7) and elevated triglycerides (HR = 3.1, 95% CI = 1.9 to 5.1) were associated with increased risk for myocardial infarction, and diagnoses of high LDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), high non-HDL cholesterol (HR = 2.2, 95% CI = 1.3 to 3.7), low HDL cholesterol (HR = 3.9, 95% CI = 2.8 to 5.4), and elevated triglycerides (HR = 3.8, 95% CI = 2.7 to 5.5) were associated with increased risk for cardiomyopathy. CONCLUSIONS: Previously undiagnosed dyslipidemia among childhood cancer survivors was associated with increased risk for myocardial infarction and cardiomyopathy. Comprehensive dyslipidemia evaluation and treatment are needed to reduce cardiovascular morbidity in this population.

Prevalence of Diastolic Dysfunction in Adult Survivors of Childhood Cancer: A Report From SJLIFE Cohort.

Background: The prevalence of diastolic dysfunction has not been systematically evaluated in a large population of survivors of childhood cancer using established guidelines and standards. Objectives: This study sought to assess the prevalence and progression of diastolic dysfunction in adult survivors of childhood cancer exposed to cardiotoxic therapy. Methods: Comprehensive, longitudinal echocardiographic examinations of adult survivors of childhood cancer ≥18 years of age and ≥10 years from diagnosis in SJLIFE (St. Jude Lifetime Cohort Study) were performed. Diastolic dysfunction was defined based on 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging guidelines. Results: Among 3,342 survivors, the median (25th-75th percentiles [quartile (Q)1-Q3]) age at diagnosis was 8.1 years (Q1-Q3: 3.6-13.7 years), 30.1 years (Q1-Q3: 24.4-37.0 years) at the baseline echocardiography evaluation (Echo 1), and 36.6 years (Q1-Q3: 30.8-43.6 years) at the last follow-up echocardiography evaluation (1,435 survivors) (Echo 2). The proportion of diastolic dysfunction was 15.2% (95% CI: 14.0%-16.4%) at Echo 1 and 15.7% (95% CI: 13.9%-17.7%) at Echo 2, largely attributable to concurrent systolic dysfunction. Less than 5% of survivors with preserved ejection fraction had diastolic dysfunction (2.2% at Echo 1, 3.7% at Echo 2). Using global longitudinal strain assessment in adult survivors with preserved ejection fraction (defined with a cutpoint worse than -15.9%), the proportion of diastolic dysfunction increased to 9.2% at baseline and 9.0% at follow-up. Conclusions: The prevalence of isolated diastolic dysfunction is low among adults who received cardiotoxic therapies for childhood cancer. The inclusion of left ventricular global longitudinal strain significantly increased the identification of diastolic dysfunction.

A Review of Cardiac Amyloidosis: Presentation, Diagnosis, and Treatment.

Amyloidosis is a group of disorders that can affect almost any organ due to the misfolding of proteins with their subsequent deposition in various tissues, leading to various disease manifestations based on the location. When the heart is involved, amyloidosis can manifest with a multitude of presentations such as heart failure, arrhythmias, orthostatic hypotension, syncope, and pre-syncope. Diagnosis of cardiac amyloidosis can be difficult due to the non-specific nature of symptoms and the relative rarity of the disease. Amyloidosis can remain undiagnosed for years, leading to its high morbidity and mortality due to this delay in diagnosis. Newer imaging modalities, such as cardiac magnetic resonance imaging, advanced echocardiography, and biomarkers, make a timely cardiac amyloidosis diagnosis more feasible. Many treatment options are available, which have provided new hope for this patient population. This manuscript will review the pathology, diagnosis, and treatment options available for cardiac amyloidosis and provide a comprehensive overview of this complicated disease process.

Association between ibrutinib treatment and hypertension.

BACKGROUND: Ibrutinib is a tyrosine kinase inhibitor most commonly associated with atrial fibrillation. However, additional cardiotoxicities have been identified, including accelerated hypertension. The incidence and risk factors of new or worsening hypertension following ibrutinib treatment are not as well known. METHODS: We conducted a retrospective study of 144 patients diagnosed with B cell malignancies treated with ibrutinib (n=93) versus conventional chemoimmunotherapy (n=51) and evaluated their effects on blood pressure at 1, 2, 3 and 6 months after treatment initiation. Descriptive statistics were used to compare baseline characteristics for each treatment group. Fisher's exact test was used to identify covariates significantly associated with the development of hypertension. Repeated measures analyses were conducted to analyse longitudinal blood pressure changes. RESULTS: Both treatments had similar prevalence of baseline hypertension at 63.4% and 66.7%, respectively. There were no differences between treatments by age, sex and baseline cardiac comorbidities. Both systolic and diastolic blood pressure significantly increased over time with ibrutinib compared with baseline, whereas conventional chemoimmunotherapy was not associated with significant changes in blood pressure. Baseline hypertensive status did not affect the degree of blood pressure change over time. A significant increase in systolic blood pressure (defined as more than 10 mm Hg) was noted for ibrutinib (36.6%) compared with conventional chemoimmunotherapy (7.9%) at 1 month after treatment initiation. Despite being hypertensive at follow-up, 61.2% of patients who were treated with ibrutinib did not receive adequate blood pressure management (increase or addition of blood pressure medications). Within the ibrutinib group, of patients who developed more than 20 mm Hg increase in systolic blood pressure, only 52.9% had hypertension management changes. CONCLUSIONS: Ibrutinib is associated with the development of hypertension and worsening of blood pressure. Cardiologists and oncologists must be aware of this cardiotoxicity to allow timely management of blood pressure elevations.

Benign Metastasizing Leiomyoma in the Heart of a 45-Year-Old Woman.

We report a rare case of benign metastasizing leiomyoma in the heart of a 45-year-old woman 2 years after a uterine leiomyoma had been discovered during hysterectomy. Computed tomograms at presentation showed a large mixed cystic mass in the pelvis and bilateral lung nodules suggestive of metastatic disease. A large cardiac mass, attached to the chordae of the tricuspid valve and later shown to be histopathologically consistent with uterine leiomyoma, was successfully resected through a right atriotomy. This case suggests that benign metastasizing leiomyoma should be considered in the differential diagnosis of right-sided cardiac tumors.

Novel Use of Biphasic Cuirass Ventilation During Definitive Radiation Therapy: A Technical Report.

The use of biphasic cuirass ventilator supported radiation therapy has never been documented. We present the first technical report here. A 57-year-old man with obstructive sleep apnea presented with a T0N1M0 right sided, human papillomavirus related head and neck cancer diagnosed on excisional lymph node biopsy. On further workup, the cancer was found to have originated in the right tonsil and was staged as T1N1. The patient started definitive treatment with concurrent chemo-radiation therapy, but after 5 treatments was no longer able to lay in a supine position for treatment. Diagnostic imaging workup eventually revealed an idiopathic right sided hemi-diaphragm eventration. After consultation with cardiology, pulmonology, and head and neck surgery, recommendation was made for tracheostomy to tolerate supine radiotherapy position, but the patient refused. Instead, computed tomography simulation for radiotherapy replanning was performed using a combination of biphasic cuirass ventilation, home continuous positive airway pressure and oxygen. The patient then tolerated definitive treatment to a dose of 69.96 Gray in 33 fractions with concurrent chemotherapy and experienced no unexpected side effects. Although complex, daily treatment setup was consistent. Daily onboard imaging was precise and accurate. The patient continues to follow up with radiation oncology, medical oncology, and pulmonology. This is the first use of biphasic cuirass ventilator supported radiotherapy reported in the scientific literature. Although daily treatment setup is complex, its use could be considered in patients unable to tolerate radiation therapy treatment positioning as an alternative to tracheostomy.

Cardiovascular risk assessment and management of patients undergoing hematopoietic cell transplantation.

The purpose of this review is to provide a framework for the cardiovascular evaluation and management of patients undergoing hematopoietic cell transplantation (HCT). To accomplish this, we have performed an extensive literature review, critically analyzed the available evidence, and developed a set of recommendations to guide best practice. Herein, we discuss the cardiovascular risk profile of patients undergoing HCT along with putative mechanisms of HCT-induced cardiovascular injury. We then present an algorithm for cardiovascular testing and risk mitigation of potential recipients. Last, we address the management of the most prevalent cardiovascular conditions associated with HCT recipients.

Patterns of Anticoagulation Use in Patients With Cancer With Atrial Fibrillation and/or Atrial Flutter.

BACKGROUND: Atrial fibrillation (AF) is a common cardiovascular complication affecting patients with cancer, but management strategies are not well established. OBJECTIVES: The purpose of this retrospective cohort study was to evaluate cross-sectional patterns of anticoagulation (AC) use in patients with cancer with AF or atrial flutter (AFL) on the basis of their risk for stroke and bleeding. METHODS: Patients with cancer and electrocardiograms showing AF or AFL performed at Moffitt Cancer Center in either the inpatient or outpatient setting were included in this retrospective analysis. We described percentages of AC prescription by stroke and bleeding risk, as determined by individual CHA2DS2-VASc and HAS-BLED scores, respectively. Multivariable logistic regression evaluated clinical variables independently associated with anticoagulant prescription. RESULTS: The prevalence of electrocardiography-documented AF or AFL was 4.8% (n = 472). The mean CHA2DS2-VASc score was 2.8 ± 1.4. Among patients with CHA2DS2-VASc scores ≥2 and HAS-BLED scores <3, 44.3% did not receive AC, and of these, only 18.3% had platelet values <50,000/µl. In multivariable analysis, older age, hypertension, prior stroke, and history of venous thromboembolism were each directly associated with AC use, while current chemotherapy use, prior bleeding, renal disease, and thrombocytopenia were each inversely associated with AC use. CONCLUSIONS: Nearly one-half of patients with cancer, the majority with normal platelet counts, had an elevated risk for stroke but did not receive AC. In addition to known predictors, current chemotherapy use was independently associated with a lower odds of AC use. This study highlights the need to improve the application of AF treatment algorithms to cancer populations.

Cardiovascular Events Among Adults Treated With Chimeric Antigen Receptor T-Cells (CAR-T).

BACKGROUND: Chimeric antigen receptors redirect T cells (CAR-T) to target cancer cells. There are limited data characterizing cardiac toxicity and cardiovascular (CV) events among adults treated with CAR-T. OBJECTIVES: The purpose of this study was to evaluate the possible cardiac toxicities of CAR-T. METHODS: The registry included 137 patients who received CAR-T. Covariates included the occurrence and grade of cytokine release syndrome (CRS) and the administration of tocilizumab for CRS. Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction or an increase in serum troponin. Cardiovascular events were a composite of arrhythmias, decompensated heart failure, and CV death. RESULTS: The median age was 62 years (interquartile range [IQR]: 54 to 70 years), 67% were male, 88% had lymphoma, and 8% had myeloma. Approximately 50% were treated with commercial CAR-T (Yescarta or Kymriah), and the remainder received noncommercial products. CRS, occurring a median of 5 days (IQR: 2 to 7 days) after CAR-T, occurred in 59%, and 39% were grade ≥2. Tocilizumab was administered to 56 patients (41%) with CRS, at a median of 27 h (IQR: 16 to 48 h) after onset. An elevated troponin occurred in 29 of 53 tested patients (54%), and a decreased left ventricular ejection fraction in 8 of 29 (28%); each occurred only in patients with grade ≥2 CRS. There were 17 CV events (12%, 6 CV deaths, 6 decompensated heart failure, and 5 arrhythmias; median time to event of 21 days), all occurred with grade ≥2 CRS (31% patients with grade ≥2 CRS), and 95% of events occurred after an elevated troponin. The duration between CRS onset and tocilizumab administration was associated with CV events, where the risk increased 1.7-fold with each 12-h delay to tocilizumab. CONCLUSIONS: Among adults, cardiac injury and CV events are common post-CAR-T. There was a graded relationship among CRS, elevated troponin, and CV events, and a shorter time from CRS onset to tocilizumab was associated with a lower rate of CV events.

Arrhythmogenic Anticancer Drugs in Cardio-Oncology.

Multiple cancer therapies are associated with cardiac arrhythmias through a variety of pathophysiologic mechanisms. Atrial fibrillation and atrial flutter are common during cancer therapy but should rarely limit continued delivery of therapy. Ventricular arrhythmias are not common during cancer therapy and are more often secondary to other cardiac pathologies. QT interval monitoring is recommended for some agents, although it is often not a reliable predictor of ventricular arrhythmias. Bradyarrhythmias are common and rarely require intervention, but special attention must be paid to heart block in checkpoint inhibitor therapy.

Rates and Risk of Atrial Arrhythmias in Patients Treated With Ibrutinib Compared With Cytotoxic Chemotherapy.

There is increasing evidence that rates of atrial arrhythmias (AA), specifically atrial fibrillation and flutter are elevated in patients treated with the tyrosine kinase inhibitor, ibrutinib; however, the exact risk of ibrutinib-associated AA is not definitively established. We conducted a retrospective study of 137 patients diagnosed with B-cell malignancies treated with ibrutinib compared with 106 patients treated with chemotherapy for the same cancers in order to quantify the rates and risk of AA in a "real-world" sample of cancer patients. Fisher's exact test was used to evaluate for any statistically significant differences between groups. Logistic regression was used to generate odds ratios, adjusting for potential confounders. Incidence of AA was 14% (n = 17) in ibrutinib-treated patients compared with 3% (n = 3) in patients treated with chemotherapy (p = 0.009). Ibrutinib-treated patients were significantly older (mean age 67 vs 63 years, p = 0.003); however, there were no other significant differences in baseline characteristics. Ibrutinib use, age, hypertension, and previous use of ACE inhibitors, angiotensin receptor blocker use, ß blocker use, and aspirin use were independently associated with incident arrhythmias. In multivariable analysis, patients treated with ibrutinib were associated with a 5-fold increased risk of developing AA (odds ratio = 5.18, 95% confidence interval 1.42 to 18.89). In conclusion, the rates and risk of AA are higher in patients treated with ibrutinib compared with chemotherapy, and this study provides strong evidence that ibrutinib itself is an independent risk factor for the development of incident AA.

Anticoagulation of Cardiovascular Conditions in the Cancer Patient: Review of Old and New Therapies.

PURPOSE OF REVIEW: The anticoagulation strategies for various cardiac-specific pathologies including atrial fibrillation are changing. Applying these strategies in patients with concomitant active cancer requires additional considerations. Here, we review the most recent changes in the anticoagulation management of common cardiac diseases and their application in cancer patients. RECENT FINDINGS: There are a range of indications for therapeutic anticoagulation in cancer patients including venous thromboembolism (VTE), atrial fibrillation/flutter (AF/AFL), prosthetic heart valves, and intracardiac thrombi. Certain cancer therapeutics such as ibrutinib and anthracycline chemotherapy increase the risk of developing AF/AFL and pose unique challenges in anticoagulation management. Anticoagulation decisions for AF/AFL often utilize the CHADS2 or the CHA2DS2-VASc score with annualized stroke risk; however, these risk stratification models may be inadequate in cancer patients. Cancer type, stage, prognosis, and bleeding risk are all relevant when considering whether to initiate therapeutic anticoagulation. Moreover, thrombocytopenia may limit the ability to provide anticoagulation. Subsequent analyses of direct oral anticoagulants (DOACs) show fewer bleeding complications and thromboembolic events compared to warfarin in AF/AFL with apixaban and edoxaban particularly promising in this population for VTE, pulmonary embolism, and AF/AFL. There is a lack of data regarding ablation therapy and left atrial occlusion devices in this population. There is a growing experience of DOACs for intracardiac thrombi. Warfarin is still appropriate for patients with prosthetic heart valves and left ventricular assist devices. Anticoagulation management in the cancer patient can be challenging. DOACs are often a safe alternative to warfarin in cancer-associated DVT/PE and AF/AFL, and may be preferable in certain circumstances. Other cardiac indications for anticoagulation including the presence of a mechanical heart valve remain unchanged and dependent on warfarin or heparin-based products.

Cardiotoxicity of Novel Targeted Chemotherapeutic Agents.

PURPOSE OF REVIEW: With the continuing development of newer targeted therapies in oncology, it is necessary to understand their potential cardiovascular side effects. In this review, we discuss the association of novel targeted agents and left ventricular systolic dysfunction. RECENT FINDINGS: Within the last 5 years, multiple new agents have been developed to target specific cancer pathways and found to have off-targeted cardiotoxicity. The most recent example is the recognition of myocarditis caused by immune checkpoint inhibitors. The development of targeted cancer therapies has revolutionized oncology, but many of these agents are inherently toxic to the cardiovascular system. Nearly all vascular endothelial growth factor (VEGF) inhibitors cause cardiotoxicity to varying degrees. Epidermal growth factor receptor (EGFR) inhibitors developed since the discovery of trastuzumab are significantly less cardiotoxic than their predecessor, but still convene risk. BCR-ABL tyrosine kinase inhibitors (TKI), once thought to pose significant risk as a class effect, appear to only be cardiotoxic if they have anti-VEGF activity. The newer generation of proteasome inhibitors such as carfilzomib appears to have significant cardiotoxicity, with almost 5% of patients developing symptomatic heart failure (HF). Immune checkpoint inhibitors can very rarely cause rapidly fatal myocarditis. As of now, there are no sufficient guidelines to direct clinical care for patients on these new classes of agents, but this is likely to change as more data and clinical experience accumulate.

Prevalence, etiology, and clinical implications of reduced longitudinal systolic strain in renal transplant candidates.

AIMS: Reduced global longitudinal systolic strain (GLS) is a common finding in end-stage renal disease (ESRD) patients with normal ejection fraction (EF), and GLS is a stronger predictor of mortality than EF. We sought to determine what factors may be responsible for the decreased strain in this population. METHODS AND RESULTS: The study group was comprised of 139 renal transplant candidates with a normal EF who had echocardiography with assessment of GLS and basal longitudinal systolic strain (BLS). A GLS of less than -18 and a BLS less than -17 were defined as abnormal. Logistic regression was used to determine variables associated with abnormal GLS and BLS. Of the 139 patients, 49% had abnormal GLS and 70% had abnormal BLS. The univariate predictors of abnormal GLS (P<.05) were low-normal EF, increased interventricular septal thickness (IVS), diabetes, and dihydropyridine calcium channel blocker use. The univariate predictors of abnormal BLS (P<.05) were elevated systolic blood pressure, elevated diastolic blood pressure, elevated heart rate, decreased EF, increased IVS, increased left ventricular posterior wall thickness (LVPW), increased left ventricular mass index, regular dialysis, and clonidine use. On multivariate analysis, low-normal EF (P<.001), increased IVS (P=.024), and diabetes (P=.042) were independent predictors of abnormal GLS, while increased DBP (P=.018), increased LVPW (P=.001), and regular dialysis (P=.006) were independent predictors of abnormal BLS. CONCLUSIONS: Clinical variables and co-findings beyond EF are associated with abnormal strain measurements and may partially explain the large incidence of abnormal strain in renal transplant candidates.

Prognostic utility of blood pressure-adjusted global and basal systolic longitudinal strain.

Assessment of global longitudinal systolic strain (GLS) and longitudinal systolic strain of the basal segments (BLS) has shown prognostic value in cardiac disorders. However, strain is reduced with increased afterload. We assessed the prognostic value of GLS and BLS adjusted for afterload. GLS and BLS were determined in 272 subjects with normal ejection fraction and no known coronary disease, or significant valve disease. Systolic blood pressure (SP) and diastolic blood pressure (DP) obtained at the time of echocardiography were used to adjust GLS and BLS as follows: strain×SP (mmHg)/120 mmHg and strain×DP (mmHg)/80 mmHg. Patients were followed for cardiac events and mortality. The mean age was 53±15 years and 53% had hypertension. There were 19 cardiac events and 70 deaths over a mean follow-up of 26±14 months. Cox analysis showed that left ventricular mass index (P=0.001), BLS (P<0.001), and DP-adjusted BLS (P<0.001) were independent predictors of cardiac events. DP-adjusted BLS added incremental value (P<0.001) to the other two predictors and had an area under the curve of 0.838 for events. DP (P=0.001), age (P=0.001), ACE inhibitor use (P=0.017), and SP-adjusted BLS (P=0.012) were independent predictors of mortality. SP-adjusted BLS added incremental value (P=0.014) to the other independent predictors. In conclusion, DP-adjusted BLS and SP-adjusted BLS were independent predictors of cardiac events and mortality, respectively. Blood pressure-adjusted strain added incremental prognostic value to other predictors of outcome.

Small conductance calcium-activated potassium current is important in transmural repolarization of failing human ventricles.

BACKGROUND: The transmural distribution of apamin-sensitive small conductance Ca(2+)-activated K(+) (SK) current (IKAS) in failing human ventricles remains unclear. METHODS AND RESULTS: We optically mapped left ventricular wedge preparations from 12 failing native hearts and 2 rejected cardiac allografts explanted during transplant surgery. We determined transmural action potential duration (APD) before and after 100 nmol/L apamin administration in all wedges and after sequential administration of apamin, chromanol, and E4031 in 4 wedges. Apamin prolonged APD from 363 ms (95% confidence interval [CI], 341-385) to 409 (95% CI, 385-434; P<0.001) in all hearts, and reduced the transmural conduction velocity from 36 cm/s (95% CI, 30-42) to 32 cm/s (95% CI, 27-37; P=0.001) in 12 native failing hearts at 1000 ms pacing cycle length (PCL). The percent APD prolongation is negatively correlated with baseline APD and positively correlated with PCL. Only 1 wedge had M-cell islands. The percentages of APD prolongation in the last 4 hearts at 2000 ms PCL after apamin, chromanol, and E4031 were 9.1% (95% CI, 3.9-14.2), 17.3% (95% CI, 3.1-31.5), and 35.9% (95% CI, 15.7-56.1), respectively. Immunohistochemical staining of subtype 2 of SK protein showed increased expression in intercalated discs of myocytes. CONCLUSIONS: SK current is important in the transmural repolarization in failing human ventricles. The magnitude of IKAS is positively correlated with the PCL, but negatively correlated with APD when PCL is fixed. There is abundant subtype 2 of SK protein in the intercalated discs of myocytes.