Development of a comprehensive cardiac atlas on a 1.5 Tesla Magnetic Resonance Linear Accelerator.

Background and purpose: The 1.5 Tesla (T) Magnetic Resonance Linear Accelerator (MRL) provides an innovative modality for improved cardiac imaging when planning radiation treatment. No MRL based cardiac atlases currently exist, thus, we sought to comprehensively characterize cardiac substructures, including the conduction system, from cardiac images acquired using a 1.5 T MRL and provide contouring guidelines. Materials and methods: Five volunteers were enrolled in a prospective protocol (NCT03500081) and were imaged on the 1.5 T MRL with Half Fourier Single-Shot Turbo Spin-Echo (HASTE) and 3D Balanced Steady-State Free Precession (bSSFP) sequences in axial, short axis, and vertical long axis. Cardiac anatomy was contoured by (AS) and confirmed by a board certified cardiologist (JR) with expertise in cardiac MR imaging. Results: A total of five volunteers had images acquired with the HASTE sequence, with 21 contours created on each image. One of these volunteers had additional images obtained with 3D bSSFP sequences in the axial plane and additional images obtained with HASTE sequences in the key cardiac planes. Contouring guidelines were created and outlined. 15-16 contours were made for the short axis and vertical long axis. The cardiac conduction system was demonstrated with eleven representative contours. There was reasonable variation of contour volume across volunteers, with structures more clearly delineated on the 3D bSSFP sequence. Conclusions: We present a comprehensive cardiac atlas using novel images acquired prospectively on a 1.5 T MRL. This cardiac atlas provides a novel resource for radiation oncologists in delineating cardiac structures for treatment with radiotherapy, with special focus on the cardiac conduction system.

Profibrotic COVID-19 subphenotype exhibits enhanced localized ER-dependent HSP47+ expression in cardiac myofibroblasts in situ.

We recently described a subgroup of autopsied COVID-19 subjects (∼40%), termed 'profibrotic phenotype,' who exhibited clusters of myofibroblasts (Mfbs), which were positive for the collagen-specific chaperone heat shock protein 47 (HSP47+) in situ. This report identifies increased, localized (hot spot restricted) expression of αSMA, COLα1, POSTN and FAP supporting the identity of HSP47+ cells as myofibroblasts and characterizing a profibrotic extracellular matrix (ECM) phenotype. Coupled with increased GRP78 in COVID-19 subjects, these data could reflect induction of the unfolded protein response for mitigation of proteostasis (i.e., protein homeostasis) dysfunction in discrete clusters of cells. ECM shifts in selected COVID-19 subjects occur without significant increases in either global trichrome positive staining or myocardial injury based quantitively on standard H&E scoring. Our findings also suggest distinct mechanism(s) for ECM remodeling in the setting of SARS-CoV-2 infection. The ratio of CD163+/CD68+ cells is increased in hot spots of profibrotic hearts compared with either controls or outside of hot spots in COVID-19 subjects. In sum, matrix remodeling of human COVID-19 hearts in situ is characterized by site-restricted profibrotic mediated (e.g., HSP47+ Mfbs, CD163+ Mφs) modifications in ECM (i.e., COLα1, POSTN, FAP), with a strong correlation between COLα1 and HSP47+cells within hot spots. Given the established associations of viral infection (e.g., human immunodeficiency virus; HIV), myocardial fibrosis and sudden cardiac death, early screening tools (e.g., plasma biomarkers, noninvasive cardiac magnetic resonance imaging) for diagnosis, monitoring and treatment of fibrotic ECM remodeling are warranted for COVID-19 high-risk populations.

Collagen-Specific HSP47+ Myofibroblasts and CD163+ Macrophages Identify Profibrotic Phenotypes in Deceased Hearts With SARS-CoV-2 Infections.

Background Cardiac fibrosis complicates SARS-CoV-2 infections and has been linked to arrhythmic complications in survivors. Accordingly, we sought evidence of increased HSP47 (heat shock protein 47), a stress-inducible chaperone protein that regulates biosynthesis and secretion of procollagen in heart tissue, with the goal of elucidating molecular mechanisms underlying cardiac fibrosis in subjects with this viral infection. Methods and Results Using human autopsy tissue, immunofluorescence, and immunohistochemistry, we quantified Hsp47+ cells and collagen α 1(l) in hearts from people with SARS-CoV-2 infections. Because macrophages are also linked to inflammation, we measured CD163+ cells in the same tissues. We observed irregular groups of spindle-shaped HSP47+ and CD163+ cells as well as increased collagen α 1(I) deposition, each proximate to one another in "hot spots" of ≈40% of hearts after SARS-CoV-2 infection (HSP47+ P<0.05 versus nonfibrotics and P<0.001 versus controls). Because HSP47+ cells are consistent with myofibroblasts, subjects with hot spots are termed "profibrotic." The remaining 60% of subjects dying with COVID-19 without hot spots are referred to as "nonfibrotic." No control subject exhibited hot spots. Conclusions Colocalization of myofibroblasts, M2(CD163+) macrophages, and collagen α 1(l) may be the first evidence of a COVID-19-related "profibrotic phenotype" in human hearts in situ. The potential public health and diagnostic implications of these observations require follow-up to further define mechanisms of viral-mediated cardiac fibrosis.

Onset of the COVID-19 pandemic reduced active time in patients with implanted cardiac devices.

BACKGROUND: Physical inactivity and sedentary behavior are modifiable risk factors for chronic disease and all-cause mortality that may have been negatively impacted by the COVID-19 shutdowns. METHODS: Accelerometry data was retrospectively collected from 332 permanent pacemaker (PPM) and 244 implantable cardiac defibrillation (ICD) patients for 6 time points: March 15-May 15, 2020 (pandemic period), January 1-March 14, 2020, October 1-December 31, 2019, March 15-May 15, 2019, January 1-March 14, 2019, and October 1-December 31, 2018. Paired t-tests, with Bonferroni correction, were used to compare time periods. RESULTS: Activity significantly decreased during the pandemic period compared to one year prior by an average of 0.53 ± 1.18h/day (P < 0.001) for PPM patients and 0.51 ± 1.2h/day (P < 0.001) for ICD patients. Stratification of subjects by active time (< 2 versus ≥ 2h/day) showed patients with < 2h, particularly those with ICDs, had modestly greater activity reductions with the pandemic onset. Logistical regression analyses suggest a trend toward a greater reduction in active time at the onset of the pandemic and an increased risk of hospital or emergency department (ED) admission for PPM patients, but not ICD patients. CONCLUSION: The onset of the pandemic in the United States was associated with a significant drop in PPM and ICD patient active hours that was modestly more pronounced in less active patients and cannot be explained by one year of aging or seasonal variation. If sustained, these populations may experience excess cardiovascular morbidity.

Value CMR: Towards a Comprehensive, Rapid, Cost-Effective Cardiovascular Magnetic Resonance Imaging.

Cardiac magnetic resonance imaging (CMR) is considered the gold standard for measuring cardiac function. Further, in a single CMR exam, information about cardiac structure, tissue composition, and blood flow could be obtained. Nevertheless, CMR is underutilized due to long scanning times, the need for multiple breath-holds, use of a contrast agent, and relatively high cost. In this work, we propose a rapid, comprehensive, contrast-free CMR exam that does not require repeated breath-holds, based on recent developments in imaging sequences. Time-consuming conventional sequences have been replaced by advanced sequences in the proposed CMR exam. Specifically, conventional 2D cine and phase-contrast (PC) sequences have been replaced by optimized 3D-cine and 4D-flow sequences, respectively. Furthermore, conventional myocardial tagging has been replaced by fast strain-encoding (SENC) imaging. Finally, T1 and T2 mapping sequences are included in the proposed exam, which allows for myocardial tissue characterization. The proposed rapid exam has been tested in vivo. The proposed exam reduced the scan time from >1 hour with conventional sequences to <20 minutes. Corresponding cardiovascular measurements from the proposed rapid CMR exam showed good agreement with those from conventional sequences and showed that they can differentiate between healthy volunteers and patients. Compared to 2D cine imaging that requires 12-16 separate breath-holds, the implemented 3D-cine sequence allows for whole heart coverage in 1-2 breath-holds. The 4D-flow sequence allows for whole-chest coverage in less than 10 minutes. Finally, SENC imaging reduces scan time to only one slice per heartbeat. In conclusion, the proposed rapid, contrast-free, and comprehensive cardiovascular exam does not require repeated breath-holds or to be supervised by a cardiac imager. These improvements make it tolerable by patients and would help improve cost effectiveness of CMR and increase its adoption in clinical practice.

Cardiac Magnetic Resonance for Early Detection of Radiation Therapy-Induced Cardiotoxicity in a Small Animal Model.

BACKGROUND: Over half of all cancer patients receive radiation therapy (RT). However, radiation exposure to the heart can cause cardiotoxicity. Nevertheless, there is a paucity of data on RT-induced cardiac damage, with limited understanding of safe regional RT doses, early detection, prevention and management. A common initial feature of cardiotoxicity is asymptomatic dysfunction, which if left untreated may progress to heart failure. The current paradigm for cardiotoxicity detection and management relies primarily upon assessment of ejection fraction (EF). However, cardiac injury can occur without a clear change in EF. OBJECTIVES: To identify magnetic resonance imaging (MRI) markers of early RT-induced cardiac dysfunction. METHODS: We investigated the effect of RT on global and regional cardiac function and myocardial T1/T2 values at two timepoints post-RT using cardiac MRI in a rat model of localized cardiac RT. Rats who received image-guided whole-heart radiation of 24Gy were compared to sham-treated rats. RESULTS: The rats maintained normal global cardiac function post-RT. However, a deterioration in strain was particularly notable at 10-weeks post RT, and changes in circumferential strain were larger than changes in radial or longitudinal strain. Compared to sham, circumferential strain changes occurred at the basal, mid-ventricular and apical levels (p<0.05 for all at both 8-weeks and 10-weeks post-RT), most of the radial strain changes occurred at the mid-ventricular (p=0.044 at 8-weeks post-RT) and basal (p=0.018 at 10-weeks post-RT) levels, and most of the longitudinal strain changes occurred at the apical (p=0.002 at 8-weeks post-RT) and basal (p=0.035 at 10-weeks post-RT) levels. Regionally, lateral myocardial segments showed the greatest worsening in strain measurements, and histologic changes supported these findings. Despite worsened myocardial strain post-RT, myocardial tissue displacement measures were maintained, or even increased. T1/T2 measurements showed small non-significant changes post-RT compared to values in non-irradiated rats. CONCLUSIONS: Our findings suggest MRI regional myocardial strain is a sensitive imaging biomarker for detecting RT-induced subclinical cardiac dysfunction prior to compromise of global cardiac function.

Tachyarrhythmia discriminator for implantable cardioverter-defibrillators in bundle branch block.

BACKGROUND: Inaccurate arrhythmia classification by implantable cardioverter-defibrillators (ICDs) contributes to inappropriate shocks and increased health care utilization. OBJECTIVE: The purpose of this study was to evaluate the ability of a novel discriminator using far-field (FF) and near-field (NF) right ventricular lead electrograms (EGMs) to differentiate ventricular tachycardia (VT) from supraventricular tachycardia (SVT) in patients with underlying conducted narrow QRS, right bundle branch block (RBBB), and left bundle branch block (LBBB). METHODS: ICD interrogations were reviewed, identifying subjects with tachycardia events at least 5 beats in duration with stable morphology and cycle length. FF to NF (FF-NF) EGM intervals during tachycardia and baseline conducted rhythm were measured using digital calipers. Events with uncertain tachycardia rhythm mechanism were excluded. RESULTS: Ninety-five subjects were included. Mean FF-NF interval during tachycardia was significantly lower during SVT than VT (25.8 ± 12.0 ms vs 91.0 ± 37.2 ms; P <.001). Participants with LBBB (n = 22) and RBBB (n = 21) had significantly lower mean FF-NF intervals during SVT compared with VT (LBBB 25.6 ± 7.26 ms vs 93.1 ± 41.5 ms; P <.001; RBBB 30.0 ± 16.6 ms vs 101.7 ± 34.3 ms; P <.001). In this cohort, FF-NF interval cutoff of 100 ms was 100% specific for VT discrimination regardless of underlying QRS morphology, with sensitivity of 46%, 50%, and 38% for LBBB, RBBB, and narrow QRS, respectively. CONCLUSION: Prolonged FF-NF interval on intracardiac EGM during tachycardia is a highly specific discriminator for VT, regardless of baseline QRS morphology.

Assessing the Risks Associated with MRI in Patients with a Pacemaker or Defibrillator.

BACKGROUND: The presence of a cardiovascular implantable electronic device has long been a contraindication for the performance of magnetic resonance imaging (MRI). We established a prospective registry to determine the risks associated with MRI at a magnetic field strength of 1.5 tesla for patients who had a pacemaker or implantable cardioverter-defibrillator (ICD) that was "non-MRI-conditional" (i.e., not approved by the Food and Drug Administration for MRI scanning). METHODS: Patients in the registry were referred for clinically indicated nonthoracic MRI at a field strength of 1.5 tesla. Devices were interrogated before and after MRI with the use of a standardized protocol and were appropriately reprogrammed before the scanning. The primary end points were death, generator or lead failure, induced arrhythmia, loss of capture, or electrical reset during the scanning. The secondary end points were changes in device settings. RESULTS: MRI was performed in 1000 cases in which patients had a pacemaker and in 500 cases in which patients had an ICD. No deaths, lead failures, losses of capture, or ventricular arrhythmias occurred during MRI. One ICD generator could not be interrogated after MRI and required immediate replacement; the device had not been appropriately programmed per protocol before the MRI. We observed six cases of self-terminating atrial fibrillation or flutter and six cases of partial electrical reset. Changes in lead impedance, pacing threshold, battery voltage, and P-wave and R-wave amplitude exceeded prespecified thresholds in a small number of cases. Repeat MRI was not associated with an increase in adverse events. CONCLUSIONS: In this study, device or lead failure did not occur in any patient with a non-MRI-conditional pacemaker or ICD who underwent clinically indicated nonthoracic MRI at 1.5 tesla, was appropriately screened, and had the device reprogrammed in accordance with the prespecified protocol. (Funded by St. Jude Medical and others; MagnaSafe ClinicalTrials.gov number, NCT00907361 .).

The relationship between defibrillation threshold and total mortality.

BACKGROUND: The relationship between the defibrillation threshold (DFT) and total mortality is unclear. METHODS: A university hospital prospectively maintained implantable defibrillator (ICD) database identified 508 patients who underwent ICD implantation and had DFT testing performed at implant. Patients were placed in one of three groups based on the implant DFT (high (≥20 J), moderate (19-11 J), or low DFT (≤10 J)). RESULTS: Sixty-seven patients had a high DFT, 216 had a moderate DFT, and 225 had a low DFT. The mean left ventricular ejection fraction (LVEF) was 0.25, 0.28, and 0.30 in the high, moderate, and low DFT groups, respectively, (p = 0.04). There were significantly more patients with a subcutaneous electrode in the high DFT group (p < 0.001), more patients taking amiodarone (p < 0.001), and more patients on oral anticoagulation (p = 0.04). There were a total of 140 deaths during the follow-up period (mean 3.2 ± 1.7 years). There were 24 deaths in the high DFT group (35.8%), 62 in the moderate DFT group (28.7%), and 54 in the low DFT group (24.0%) (p = 0.05). Implant DFT was a significant predictor of mortality (p = 0.01), as was age, LVEF (p < 0.001), CAD (p = 0.01), amiodarone use (p = 0.02), and hematoma at implant (p = 0.01). An elevated DFT was an independent predictor of mortality after controlling for all significant univariate variables (p = 0.004). CONCLUSIONS: A high-implant DFT predicts an adverse prognosis, even when an adequate ICD safety margin is present.

Effectiveness of VF induction with DC fibber versus conventional induction methods in patients on chronic amiodarone therapy.

BACKGROUND: Amiodarone therapy, especially chronic, can result in difficult ventricular fibrillation (VF) inductions during implantable cardioverter defibrillator (ICD) testing. The efficacy of various VF induction methods on patients treated with amiodarone has not been well described. This prospective analysis evaluated the impact of direct current (DC) fibber, burst fibber, and synchronized T-wave shock VF induction methods. METHODS: Data were collected from one study and two enrolling centers totaling 14 ICD patients (92.9 % male, age 64.3 years (range 23.6-81.2)). A minimum of two successful VF inductions from each patient were required to be included in the study analysis. Each VF induction method was attempted in each patient. Non-sustained VF resulting in an aborted shock was considered an induction failure. All 14 patients were on chronic amiodarone therapy. RESULTS: From a total of 42 attempted inductions, 25 (59.5 %) were successful at inducing VF. The success rates of effective induction of VF during the first attempt using DC, burst, and Shock-on-T are 100, 50, and 28.6 %, respectively. DC fibber had significantly higher VF induction rates than Shock-on-T (p = 0.004) or burst fibber (p = 0.02). There was no difference between Shock-on-T and burst fibber (p = 0.45). CONCLUSION: The success rate of VF induction using DC fibber method is significantly higher than either Shock-on-T or burst fibber induction methods for patients on chronic amiodarone therapy. This may facilitate defibrillation threshold testing in such patients.

A comparison of cardiac magnetic resonance imaging peri-infarct border zone quantification strategies for the prediction of ventricular tachyarrhythmia inducibility.

BACKGROUND: Peri-infarct border zone (BZ) as quantified by late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (MRI) has been proposed as a risk stratification tool, and is associated with increased mortality. BZ has been measured by various methods in the literature. We assessed which BZ analysis best predicts inducible arrhythmia during electrophysiological study (EPS). METHODS: LGE was performed in 47 patients with coronary artery disease referred for EPS to assess for ventricular tachycardia (VT). LGE data was analyzed for BZ quantification by 3 previously published methods. Method I (BZ-I) used pixels 2-3 standard deviations over the mean of normal tissue, expressed as % of left ventricular mass, Method II (BZ-II, as described by Yan) and Method III (BZ-III, as described by Schmidt). EPS results were classified as negative (non-inducible) or positive (monomorphic VT - MVT). RESULTS: There were 47 subjects-age 61.7 years, 72% male. During EPS, 20 patients were non-inducible and 18 had induced MVT. Ejection fraction was not significantly different between non-inducible patients and those with MVT (34.1% vs. 28.5%, p = 0.13). BZ-I was significantly different (1.4% vs. 2.6%, p = 0.001), but not BZ-II (7.9% vs. 6.9%, p = 0.68) or BZ-III (2.7 g vs. 2.1 g, p = 0.88). Multivariate analysis demonstrated that only BZ-I was an independent predictor of EPS outcome after controling for infarct size (OR 1.97 per % change, 95% CI 1.04-3.73, p = 0.04). CONCLUSIONS: This study demonstrates significant variability between the published methods for measuring BZ. Also, BZ-I is a stronger predictor of inducible MVT during EPS than ejection fraction and infarct size. BZ may be another LGE marker of elevated risk of arrhythmia.

Atrial Fibrillation in Acute Coronary Syndrome.

Atrial fibrillation (AF) is a common cardiac arrhythmia occurring in an estimated 2.7 to 6.1 million people in the United States. The risk factors for the development of AF are very similar to those for developing coronary artery disease, and AF is often associated with acute coronary syndrome (ACS) and acute myocardial infarction (MI). Overall, AF complicates approximately 10% of acute infarcts and the incidence rate is comparable between the thrombolytic and percutaneous coronary intervention (PCI) eras. Prior to widespread use of thrombolysis, the incidence of AF during acute MI was as high as 18%. Moreover, AF is a marker for increased long term mortality post infarct. Over the past 20 years, the relative mortality risk for patients with AF post MI has remained around 2.5 times that for patients without AF. The treatment of AF in the setting of MI and ACS is similar to without; however there is often an increased urgency to limiting rapid heart rates which may exacerbate acute ischemia. Cardioversion and IV amiodarone may be utilized more liberally in this setting than otherwise. Anticoagulation is usually required both for the treatment of MI and possible PCI, as well as for cerebral vascular accident prevention from AF-induced thromboembolism. Often patients require triple-therapy for optimal treatment of both conditions, and special considerations for bleeding risk must be analyzed.

Atrioventricular junction ablation and pacemaker implantation for heart failure associated with atrial fibrillation: potential issues and therapies in the setting of acute heart failure syndrome.

Atrial fibrillation is the most common arrhythmia and is especially clinically important in patients with heart failure. Prolonged atrial fibrillation with high ventricular rate response may lead to development or worsening of left ventricular function. If adequate heart rate control cannot be obtained medically, often patients will undergo pacemaker implant and catheter ablation of the atrioventricular junction. This intervention can have profound effects on the course of heart failure. This article reviews the technique, complications, outcome data, and alternatives to this management strategy. The potential role of this therapeutic modality in those hospitalized with acute heart failure syndromes is discussed.

Diurnal heart rate patterns in inappropriate sinus tachycardia.

BACKGROUND: Inappropriate sinus tachycardia (IAST) is a supraventricular tachycardia originating from the sinus node. Proposed etiologies for this symptom complex include autonomic dysfunction, abnormal automaticity, or hypersensitivity of the sinus node. METHODS: Patients with IAST were identified by symptomatic tachycardia, with P-wave morphology consistent with origination from a sinus location. A matched set of control subjects was included. Hourly heart rate (HR) was measured as the average HR during each one hour period on an ambulatory 24-hour Holter monitor. Patients were further divided into two subgroups based on average daily HR < or = 80 and >80 bpm. Harmonic analysis was used to evaluate diurnal variation. RESULTS: The mean HR was 86.0 +/- 12.8 beats per minute (bpm) in the IAST group and 73.9 +/- 8.6 bpm in the control group (P = 0.056). There was an increased overall heart rate for the IAST group, which appeared to be more prominent in the morning hours. In the IAST subgroup with average daily HR < or = 80, hourly HR appears similar to controls for the period 8 pm-8 am. However, in the late AM, the IAST group had an increase in HR not seen in the control subjects. In the IAST subgroup with average HR > 80, there appeared to be a fixed difference in HR compared to the control group, without hourly change. CONCLUSIONS: Patients with IAST and elevated average daily HR exhibit normal diurnal variation around a higher mean HR. In contrast, patients with IAST and lower average daily HR had an exaggerated morning rise in HR. These diurnal patterns may be useful to classify the pathophysiology of IAST.

A novel method for sinus node modification and phrenic nerve protection in resistant cases.

This is a case report of inappropriate sinus tachycardia in a patient who had a previous unsuccessful endocardial ablation, which had been limited due to concerns of phrenic nerve injury. The patient required a repeat ablation that utilized a novel combined epicardial and endocardial approach for sinus node modification and simultaneous protection of the phrenic nerve via an epicardial balloon.

The use of periinfarct contrast-enhanced cardiac magnetic resonance imaging for the prediction of late postmyocardial infarction ventricular dysfunction.

BACKGROUND: Although ejection fraction (EF) both perimyocardial infarction (MI) and late post-MI are important prognostic factors, only implantable cardioverter-defibrillator trials of post-MI patients with depressed late EF have shown improved survival. This may relate to imprecision of early EF because of post-MI stunning. We sought to determine if peri-MI infarct size, as measured by cardiac magnetic resonance (CMR), is superior to early EF to predict late post-MI EF. METHODS: Seventy-three patients with ST-elevation MI had infarct size and EF quantified using CMR early (<1 week) and late (>3 months) post-MI. RESULTS: Late EF was significantly correlated with early EF (R = 0.734, P < .001), and with infarct size (R = -0.661, P < .001), and both early EF and infarct size were significant predictors of late EF. Subgroup analyses showed that low late EF (35%. There was no difference in early EF between the subgroup with a late EF >35% compared to the subgroup with late EF