Immediate recruitment of dormant coronary collaterals can provide more than half of normal resting perfusion during coronary occlusion in patients with coronary artery disease.

BACKGROUND: Dormant coronary collaterals are highly prevalent and clinically beneficial in cases of coronary occlusion. However, the magnitude of myocardial perfusion provided by immediate coronary collateral recruitment during acute occlusion is unknown. We aimed to quantify collateral myocardial perfusion during balloon occlusion in patients with coronary artery disease (CAD). METHODS: Patients without angiographically visible collaterals undergoing elective percutaneous transluminal coronary angioplasty (PTCA) to a single epicardial vessel underwent two scans with 99mTc-sestamibi myocardial perfusion single-photon emission computed tomography (SPECT). All subjects underwent at least three minutes of angiographically verified complete balloon occlusion, at which time an intravenous injection of the radiotracer was administered, followed by SPECT imaging. A second radiotracer injection followed by SPECT imaging was performed 24 h after PTCA. RESULTS: The study included 22 patients (median [interquartile range] age 68 [54-72] years. The perfusion defect extent was 19 [11-38] % of the LV, and the collateral perfusion at rest was 64 [58-67]% of normal. CONCLUSION: This is the first study to describe the magnitude of short-term changes in coronary microvascular collateral perfusion in patients with CAD. On average, despite coronary occlusion and an absence of angiographically visible collateral vessels, collaterals provided more than half of the normal perfusion.

Human genetic risk of treatment with antiviral nucleoside analog drugs that induce lethal mutagenesis: The special case of molnupiravir.

This review considers antiviral nucleoside analog drugs, including ribavirin, favipiravir, and molnupiravir, which induce genome error catastrophe in SARS-CoV or SARS-CoV-2 via lethal mutagenesis as a mode of action. In vitro data indicate that molnupiravir may be 100 times more potent as an antiviral agent than ribavirin or favipiravir. Molnupiravir has recently demonstrated efficacy in a phase 3 clinical trial. Because of its anticipated global use, its relative potency, and the reported in vitro "host" cell mutagenicity of its active principle, ß-d-N4-hydroxycytidine, we have reviewed the development of molnupiravir and its genotoxicity safety evaluation, as well as the genotoxicity profiles of three congeners, that is, ribavirin, favipiravir, and 5-(2-chloroethyl)-2'-deoxyuridine. We consider the potential genetic risks of molnupiravir on the basis of all available information and focus on the need for additional human genotoxicity data and follow-up in patients treated with molnupiravir and similar drugs. Such human data are especially relevant for antiviral NAs that have the potential of permanently modifying the genomes of treated patients and/or causing human teratogenicity or embryotoxicity. We conclude that the results of preclinical genotoxicity studies and phase 1 human clinical safety, tolerability, and pharmacokinetics are critical components of drug safety assessments and sentinels of unanticipated adverse health effects. We provide our rationale for performing more thorough genotoxicity testing prior to and within phase 1 clinical trials, including human PIG-A and error corrected next generation sequencing (duplex sequencing) studies in DNA and mitochondrial DNA of patients treated with antiviral NAs that induce genome error catastrophe via lethal mutagenesis.

Scientific STAFF and MALT meetings - past, present, and future.

The scientific STAFF and MALT meetings were created around the turn of the century for scientists engaged in enhancing the role of the 12-lead ECG for detection and quantification of involved myocardium in patients with acute coronary syndrome. These meetings were initially focused on computer processing of data from two single-center databases. The STAFF database was collected in the mid-nineties on patients with prolonged total coronary occlusion; high-resolution 12-lead ECGs were collected before, during, and after 5 minutes of occlusion. The MALT database was created in the early years of this century on consecutive patients with chest pain admitted to a large teaching hospital. Delayed enhancement magnetic resonance imaging and electrocardiograms were recorded in these acutely ill patients. The paper highlights the first 2 decades of the STAFF and MALT meetings and details the meeting format.

The STAFF studies of the first 5 minutes of percutaneous coronary angioplasty balloon occlusion in man.

The Staff Studies comprise a database of 228 patients undergoing elective 5 minute coronary artery balloon occlusion angioplasty at a single center in the pre-stent era in whom standard and high-frequency electrocardiographic and nuclear information was obtained immediately before, during and after balloon occlusion. The data were then analyzed by multiple investigators at different international academic centers from different perspectives. Simulating in a clinical setting the first 5 minutes of a heart attack, this database, now in digital format, is the largest database to date documenting standard and high-frequency ECG changes from the onset and for 5 minutes during acute coronary artery occlusion, with resting and occlusion imaging in a subset of these patients. The history, methodology, and legacy of these studies are discussed in this paper.

Availability of a baseline Electrocardiogram changes the application of the Sclarovsky-Birnbaum Myocardial Ischemia Grade.

BACKGROUND AND AIMS: The electrocardiogram (ECG) based Sclarovsky-Birnbaum Ischemia Grade may be used to determine the prognosis of patients with ST-elevation myocardial infarction (STEMI). However, application of the method is based on assumption of the baseline QRS morphology. Thus, the aims of this study were to determine if the baseline QRS morphology was correctly assumed based on an ECG recorded during induced ischemia, and if reference to the baseline ECG altered the designated Ischemia Grade. METHODS: Sixty-three patients with chronic ischemic heart disease that underwent elective percutaneous transluminal coronary angioplasty were included. Baseline ECG and ECG during the procedure were recorded. In the latter, Ischemia Grade was classified according to assumed baseline QRS morphology. Then the baseline ECG was used as reference and Ischemia Grade was determined based on change from the baseline ECG. RESULTS: In 66.6% (42/63) of patients the criteria for STEMI were fulfilled; the incidence was similar between left anterior descending (LAD) and right coronary artery (RCA) occlusion. In LAD patients who fulfilled STEMI criteria, assumption of baseline QRS morphology in involved leads was accurate in only 35% (7/20) and this altered the Ischemia Grade in 10% (2/20) of patients. In RCA patients who fulfilled STEMI criteria, assumption of baseline QRS morphology in involved leads was accurate in 77.3% (17/22) and this altered the Ischemia Grade in 9.1% (2/22) of patients. CONCLUSION: Application of the Sclarovsky-Birnbaum Ischemia Grade with reference to a baseline ECG altered Ischemia Grade in approximately 10% of patients. All patients that were reclassified were assigned a higher Ischemia Grade. Future research is needed to determine the impact of availability of the baseline ECG on the clinical diagnostic and prognostic performances of the Sclarovsky-Birnbaum Ischemia Grade.

An electrocardiographic sign of ischemic preconditioning.

Ischemic preconditioning is a form of intrinsic cardioprotection where an episode of sublethal ischemia protects against subsequent episodes of ischemia. Identifying a clinical biomarker of preconditioning could have important clinical implications, and prior work has focused on the electrocardiographic ST segment. However, the electrophysiology biomarker of preconditioning is increased action potential duration (APD) shortening with subsequent ischemic episodes, and APD shortening should primarily alter the T wave, not the ST segment. We translated findings from simulations to canine to patient models of preconditioning to test the hypothesis that the combination of increased [delta (Δ)] T wave amplitude with decreased ST segment elevation characterizes preconditioning. In simulations, decreased APD caused increased T wave amplitude with minimal ST segment elevation. In contrast, decreased action potential amplitude increased ST segment elevation significantly. In a canine model of preconditioning (9 mongrel dogs undergoing 4 ischemia-reperfusion episodes), ST segment amplitude increased more than T wave amplitude during the first ischemic episode [ΔT/ΔST slope = 0.81, 95% confidence interval (CI) 0.46-1.15]; however, during subsequent ischemic episodes the T wave increased significantly more than the ST segment (ΔT/ΔST slope = 2.43, CI 2.07-2.80) (P < 0.001 for interaction of occlusions 2 vs. 1). A similar result was observed in patients (9 patients undergoing 2 consecutive prolonged occlusions during elective percutaneous coronary intervention), with an increase in slope of ΔT/ΔST of 0.13 (CI -0.15 to 0.42) in the first occlusion to 1.02 (CI 0.31-1.73) in the second occlusion (P = 0.02). This integrated analysis of the T wave and ST segment goes beyond the standard approach to only analyze ST elevation, and detects cellular electrophysiology changes of preconditioning.

Difference vectors to describe dynamics of the ST segment and the ventricular gradient in acute ischemia.

BACKGROUND: The ECG is important in the diagnosis and triage of the acute coronary syndrome (ACS), especially in the hyperacute phase, the "golden hours," during which myocardial salvage possibilities are largest. An important triaging decision to be taken is whether or not a patient requires primary PCI, for which, as mentioned in the guidelines, the presence of an ST elevation (STE) pattern in the ECG is a major criterion. However, preexisting non-zero ST amplitudes (diagnostic, but also non-diagnostic) can obscure or even preclude this diagnosis. METHODS: In this study, we investigated the potential diagnostic possibilities of ischemia detection by means of changes in the ST vector, ΔST, and changes in the VG (QRST integral) vector, ΔVG. We studied the vectorcardiograms (VCGs) synthesized of the ECGs of 84 patients who underwent elective PTCA. Mean±SD balloon occlusion times were 260±76s. The ECG ischemia diagnosis (ST elevation, STE, or non-ST-elevation, NSTE), magnitudes and orientations of the ST and VG vectors, and the differences ΔST and ΔVG with the baseline ECG were measured after 3min of balloon occlusion. RESULTS: Planar angles between the ΔST and ΔVG vectors were 14.9±14.0°. Linear regression of ΔVG on ΔST yielded ΔVG=324·ΔST (r=0.85; P<0.0001, ΔST in mV). We adopted ΔST>0.05mV, and the corresponding ΔVG>16.2mV·ms as ischemia thresholds. The classical criteria characterized the ECGs of 46/84 (55%) patients after 3min of occlusion as STE ECGs. Combined application of the ΔST and ΔVG criteria identified 73/84 (87%) of the patients as ischemic. CONCLUSION: Differential diagnosis by ΔST and ΔVG (requiring an earlier made non-ischemic baseline ECG) could dramatically improve ECG guided detection of patients who urgently require catheter intervention.

Assessment of autonomic control of the heart during transient myocardial ischemia.

INTRODUCTION: In the presence of coronary artery obstruction, complex cardiovascular reflexes may lead to changes in heart rate and even to the precipitation of malignant arrhythmias. The autonomic nervous system (ANS) has traditionally been considered to be "balanced" between continuously interacting sympathetic and parasympathetic outflows. The purpose of this study was to assess ANS control of the heart during prolonged coronary balloon occlusion procedures of one of the major coronary arteries. METHODS: R-R intervals were obtained from continuous electrocardiographic data of 90 patients undergoing selective percutaneous coronary interventions (PCI) with balloon inflation periods ranging from 3 to 10 minutes (4.7 ± 1.1 minutes). Three 3-minute stages were chosen: (1) preinflation (baseline), (2) from the start of occlusion (PCI), and (3) immediately post deflation. The dynamics of the ANS was evaluated by heart rate variability analysis using standard time and frequency domain indices and the short-term fractal-like index (α(1)). RESULTS: During PCI, time and frequency domain measures related to vagal control decreased significantly with respect to baseline (significantly in left anterior descending [LAD] artery occlusions). During the postdeflation stage, heart rate variability and high-frequency power increased (P < .01) in the group with right coronary artery occlusions, whereas a marked sympathetic increase, as assessed by an increase (P < .01) of normalized low-frequency power and the low/high-frequency ratio was observed in the LAD group after balloon deflation. Fractal index α(1) decreased during the PCI period but increased significantly after balloon deflation. CONCLUSIONS: Significant changes in autonomic control of heart rate that were a function of the affected artery occurred during and after coronary artery occlusions. Occlusion of the LAD resulted in a significant reduction of vagal activity and a decrease of the short-term fractal index during PCI and a marked sympathetic response after postdeflation. However, a marked increment of vagal activity between the occlusion stage and postdeflation period was found in the right coronary artery group. These results may relate the site of the occlusion and lack of blood supply to different parts of the left ventricle.

Identification of genes contributing to cardiovascular disease in overweight and obese individuals from West Virginia.

Excess weight is a known risk factor for coronary artery disease (CAD) and a large percentage of overweight and obese individuals ultimately develop CAD. The objective of this study was to identify human genes associated with CAD in a subgroup of overweight and obese individuals using population-based association methods. Logistic regression analyses were used to test the association between single nucleotide polymorphisms (SNPs) in 34 candidate genes and the CAD phenotype with age, gender, and BMI as covariates. Two SNPs in the Apolipoprotein B (Apo B) gene [rs1042031 and rs1800479], one in the Cholesterol Ester Transfer Protein (CETP) gene [rs5880], and one in the Low Density Lipoprotein Receptor (LDLR) gene [rs2569538] met the 0.01 significance level for association with CAD. Based on these findings, we conclude that variants within the CETP and Apo B genes conferred susceptibility to CAD in overweight individuals and that a variant with the LDLR gene conferred susceptibility in an obese group.

Accuracy of advanced versus strictly conventional 12-lead ECG for detection and screening of coronary artery disease, left ventricular hypertrophy and left ventricular systolic dysfunction.

BACKGROUND: Resting conventional 12-lead ECG has low sensitivity for detection of coronary artery disease (CAD) and left ventricular hypertrophy (LVH) and low positive predictive value (PPV) for prediction of left ventricular systolic dysfunction (LVSD). We hypothesized that a approximately 5-min resting 12-lead advanced ECG test ("A-ECG") that combined results from both the advanced and conventional ECG could more accurately screen for these conditions than strictly conventional ECG. METHODS: Results from nearly every conventional and advanced resting ECG parameter known from the literature to have diagnostic or predictive value were first retrospectively evaluated in 418 healthy controls and 290 patients with imaging-proven CAD, LVH and/or LVSD. Each ECG parameter was examined for potential inclusion within multi-parameter A-ECG scores derived from multivariate regression models that were designed to optimally screen for disease in general or LVSD in particular. The performance of the best retrospectively-validated A-ECG scores was then compared against that of optimized pooled criteria from the strictly conventional ECG in a test set of 315 additional individuals. RESULTS: Compared to optimized pooled criteria from the strictly conventional ECG, a 7-parameter A-ECG score validated in the training set increased the sensitivity of resting ECG for identifying disease in the test set from 78% (72-84%) to 92% (88-96%) (P < 0.0001) while also increasing specificity from 85% (77-91%) to 94% (88-98%) (P < 0.05). In diseased patients, another 5-parameter A-ECG score increased the PPV of ECG for LVSD from 53% (41-65%) to 92% (78-98%) (P < 0.0001) without compromising related negative predictive value. CONCLUSION: Resting 12-lead A-ECG scoring is more accurate than strictly conventional ECG in screening for CAD, LVH and LVSD.

Comparison of high-frequency QRS components and ST-segment elevation to detect and quantify acute myocardial ischemia.

OBJECTIVE: This study tests the ability of high-frequency components of the depolarization phase (HF-QRS) vs conventional ST-elevation criteria to detect and quantify myocardial ischemia. METHODS: Twenty-one patients admitted for elective percutaneous coronary intervention were included. Quantification of the ischemia was made by myocardial scintigraphy. High-resolution electrocardiogram before and during percutaneous coronary intervention was recorded and signal averaged. The HF-QRS were determined within the frequency band 150 to 250 Hz. ST-segment deviation was measured in the standard frequency range (<100 Hz). RESULTS: HF-QRS criteria were met by 76% of the patients, whereas 38% met the ST-elevation criteria (P = .008). Both HF-QRS reduction and ST elevation correlated significantly with the amount of ischemia (HF-QRS: r = 0.59, P = .005 for extent and r = 0.69, P = .001 for severity; ST elevation: r = 0.49, P = .023 for extent and r = 0.57, P = .007 for severity). CONCLUSIONS: This study suggests that HF-QRS analysis could provide valuable information both to detect acute ischemia and to quantify myocardial area at risk.

Redundant protective barriers: minimizing operator occupational risk.

BACKGROUND: The ubiquitous use of less invasive therapeutic angiographic procedures has created the milieu for long-term occupational risk of cancer and genetic defects. This study set out to determine the relative effectiveness of redundant radiation protective barriers and their impact on operator total-body-ionizing radiation exposure in the catheterization suite. METHODS: Thermolucent dosimeter x-irradiation was measured inside and outside personal and movable protective barriers used concurrently during 50 consecutive procedures by a single operator. Additionally, the entrance/exit doses were recorded on the back and chest for all patients to provide insight into radiation scatter patterns. RESULTS: The x-ray beam had an average 90.8% decrement in energy traversing the patient's chest when entrance and exit doses were compared, suggesting a 3.3-fold greater operator scatter radiation exposure below the table compared with that above the table. All 0.5-mm lead equivalent personal barriers reduced operator exposure by 72-95%, whereas the 1.0-mm leaded personal barrier (overlapping gown) reduced exposure by 96%. The 0.75-mm leaded glasses reduced exposure to the left eye by 67%. A leaded left-hand glove reduced exposure by only 20%. The effective calculated operator radiation exposure risk reduction provided by the use of personal and movable barriers reduced the theoretical risk of fatal or nonfatal cancer by 22-fold while decreasing potential severe genetic effect by 25-fold in comparison to movable barriers alone. CONCLUSIONS: The optimal use of combined personal and movable (redundant) lead barriers results in a significant reduction in total-body operator radiation exposure in the catheterization laboratory. The use of redundant barriers in the catheterization suite is associated with a dramatic theoretical long-term occupational risk reduction and should be encouraged.

Detection of stress-induced myocardial ischemia from the depolarization phase of the cardiac cycle--a preliminary study.

BACKGROUND: Electrocardiogram (ECG)-based detection of ischemia is typically dependent on identifying changes in repolarization. Analysis of high-frequency QRS (HFQRS) components, related to the depolarization phase of the cardiac action potential, has been reported to better identify ischemia. Our aim was to test the hypothesis that HFQRS analysis is both more sensitive and specific than standard ECG for detecting exercise-induced ischemia in patients undergoing exercise myocardial perfusion imaging (MPI). METHODS: Exercise MPI was performed in 133 consecutive patients (age, 63 +/- 12; 100 males) and used as the gold standard for ischemia. Patients with QRS duration more than 120 milliseconds (n = 20), technical problems (n = 8), or inconclusive MPI (n = 4) were excluded, leaving 101 patients for analysis. Conventional ECG was combined with high-resolution ECG acquisition that was digitized and analyzed using the HyperQ System (BSP, Tel Aviv, Israel). The relative HFQRS intensity change during exercise was used as an index of ischemia. RESULTS: Of the 101 patients who were included in the analysis, 19 exhibited MPI ischemia. The HFQRS index of ischemia was found to be more sensitive (79% vs 41%; P < .05) and more specific (71% vs 57%; P < .05) than conventional ST analysis. CONCLUSIONS: The HFQRS analysis was more sensitive and specific than conventional ECG interpretation in detecting exercise-induced ischemia and exhibited enhanced diagnostic performance in both women and men. Thus, it may aid in the noninvasive diagnosis of ischemic heart disease.

High-frequency QRS electrocardiogram analysis during exercise stress testing for detecting ischemia.

INTRODUCTION: ECG stress testing is an inexpensive and non-invasive detector of myocardial ischemia; addition of high-frequency QRS analysis (HFQRS) may improve accuracy. This study compared HFQRS during exercise in patients with and without ischemia as defined by multiple criteria. MATERIAL AND METHODS: High-resolution ECGs were recorded for 139 patients undergoing T99-sestamibi/T201-thallium stress testing. Twenty-three were positive by at least two and 37 were negative for ischemia by all three of the following criteria: nuclear scan, ST-segment analysis and typical angina. Sixty-four not meeting criteria for positive or negative, six with adenosine test and nine patients with ECG recording artifacts were excluded. Mean age of the study group was 62+/-10 years, 83% were male. Ischemic patients had a higher incidence of previous myocardial infarction and coronary intervention than non-ischemic patients (74% vs. 46%; P=0.03 and 70% vs. 43%; P=0.05, respectively), but had a lower body mass index (28.7+/-5 vs. 33.0+/-8; P=0.015). HFQRS analysis consisting of signal averaging (150-250 Hz) and calculation of root mean squared values for each lead at different time points was performed and was similar between the groups. The relative change in HFQRS (RCQ) was calculated for each lead: {(maxHFQRS-minHFQRS)/maxHFQRS}. For each patient an RCQ index was calculated by averaging the two leads with the greatest RCQ value. The RCQ index was greater in ischemic vs. non-ischemic patients (45% vs. 34%; P=0.0069). CONCLUSION: Maximum decrease in HFQRS, as quantified by RCQ index, was greater in ischemic vs. non-ischemic patients. Use of the RCQ index may improve the diagnosis of ischemia during exercise stress testing.

Nanobacteria-associated calcific aortic valve stenosis.

Calcific aortic valve stenosis is the most common valvular disease in developed countries, and the major reason for operative valve replacement. In the US, the current annual cost of this surgery is approximately 1 billion dollars. Despite increasing morbidity and mortality, little is known of the cellular basis of the calcifications, which occur in high-perfusion zones of the heart. The case is presented of a patient with calcific aortic valve stenosis and colonies of progressively mineralized nanobacteria in the fibrocalcific nodules of the aortic cusps, as revealed by transmission electron microscopy. Consistent with their outstanding bioadhesivity, nanobacteria might serve as causative agents in the development of calcific aortic valve stenosis.

Non-linear dynamic analysis of the cardiac rhythm during transient myocardial ischemia.

Coronary artery occlusions related to myocardial ischemia drive cardiac control system reactions that may lead to heart failure. The purpose of this study was to assess the autonomic nervous system (ANS) response during prolonged percutaneous transluminal coronary angioplasty (PTCA). Continuous ECG data were acquired from 50 patients before and during PTCA, with occlusions in the left anterior descending, left circumflex or right coronary artery. Heart rate variability (HRV) was analyzed for 3-min segments of the R-R interval signal obtained from ECG data. The ANS behavior was evaluated by HRV analysis using fractal-like indices. The fractal scalar exponent alpha(1) and power-law slope beta decreased considerably during PTCA. This indicates that significant reactions of autonomic control of the heart rate occurred during coronary artery occlusions, with a reduction in complexity of the ANS.

Abnormal intra-QRS potentials associated with percutaneous transluminal coronary angiography-induced transient myocardial ischemia.

This article introduces a novel concept of abnormal intra-QRS potentials (AIQPs) associated with myocardial ischemia. AIQPs are microvolt-level potentials--subtle alterations in the QRS of the high-resolution electrocardiogram (ECG)--isolated from the unfiltered signal-averaged ECG (SAECG) by a method of mathematical modeling. The aims of the study were (1) to determine the characteristics of potentials in the SAECG related to ischemically altered activation during percutaneous transluminal coronary angiography (PTCA), (2) to determine their relationship with standard 12-lead ECG variables, and (3) to investigate whether AIQPs have a specific pathophysiologic basis in myocardial ischemia. Continuous high-resolution ECG data were acquired from 12 patients before, during, and after PTCA. SAECGs were computed every 60 seconds using an enhanced method of signal averaging. AIQP, ST-segment deviation, and changes in standard ECG QRS duration were measured in each 1-minute SAECG. AIQP amplitudes increased significantly during balloon inflation, compared with the preinflation state. AIQPs exhibited a greater prevalence (12 of 12 patients) than ST-segment deviation changes of more than 100 microV (7 of 12 patients), or measurable changes in standard QRS duration (4 of 12 patients). In patients with significant changes in 12-lead ECG variables during balloon inflation, AIQPs were strongly correlated with both ST-segment and QRS-duration changes. AIQP timing was correlated with the artery occluded, suggesting a specific, ischemia-influenced origin of the signal. AIQPs show promise as a time-localized, sensitive new ECG marker of ischemically altered ventricular activation.