Protective or Inhibitory Effect of Pharmacological Therapy on Cardiac Ischemic Preconditioning: A Literature Review.

Ischemic preconditioning (IP) is an innate phenomenon, triggered by brief, non-lethal cycles of ischemia/reperfusion applied to a tissue or organ that confers tolerance to a subsequent more prolonged ischemic event. Once started, it can reduce the severity of myocardial ischemia associated with some clinical situations, such as percutaneous coronary intervention (PCI) and intermittent aortic clamping during coronary artery bypass graft surgery (CABG). Although the mechanisms underlying IP have not been completely elucidated, several studies have shown that this phenomenon involves the participation of cell triggers, intracellular signaling pathways, and end-effectors. Understanding this mechanism enables the development of preconditioning mimetic agents. It is known that a range of medications that activate the signaling cascades at different cellular levels can interfere with both the stimulation and the blockade of IP. Investigations of signaling pathways underlying ischemic conditioning have identified a number of therapeutic targets for pharmacological manipulation. This review aims to present and discuss the effects of several medications on myocardial IP.

Type 2 diabetes mellitus and myocardial ischemic preconditioning in symptomatic coronary artery disease patients.

BACKGROUND: The influence of diabetes mellitus on myocardial ischemic preconditioning is not clearly defined. Experimental studies are conflicting and human studies are scarce and inconclusive. OBJECTIVES: Identify whether diabetes mellitus intervenes on ischemic preconditioning in symptomatic coronary artery disease patients. METHODS: Symptomatic multivessel coronary artery disease patients with preserved systolic ventricular function and a positive exercise test underwent two sequential exercise tests to demonstrate ischemic preconditioning. Ischemic parameters were compared among patients with and without type 2 diabetes mellitus. Ischemic preconditioning was considered present when the time to 1.0 mm ST deviation and rate pressure-product were greater in the second of 2 exercise tests. Sequential exercise tests were analyzed by 2 independent cardiologists. RESULTS: Of the 2,140 consecutive coronary artery disease patients screened, 361 met inclusion criteria, and 174 patients (64.2 ± 7.6 years) completed the study protocol. Of these, 86 had the diagnosis of type 2 diabetes. Among diabetic patients, 62 (72 %) manifested an improvement in ischemic parameters consistent with ischemic preconditioning, whereas among nondiabetic patients, 60 (68 %) manifested ischemic preconditioning (p = 0.62). The analysis of patients who demonstrated ischemic preconditioning showed similar improvement in the time to 1.0 mm ST deviation between diabetic and nondiabetic groups (79.4 ± 47.6 vs 65.5 ± 36.4 s, respectively, p = 0.12). Regarding rate pressure-product, the improvement was greater in diabetic compared to nondiabetic patients (3011 ± 2430 vs 2081 ± 2139 bpm x mmHg, respectively, p = 0.01). CONCLUSIONS: In this study, diabetes mellitus was not associated with impairment in ischemic preconditioning in symptomatic coronary artery disease patients. Furthermore, diabetic patients experienced an improvement in this significant mechanism of myocardial protection.

Hypotheses, rationale, design, and methods for evaluation of ischemic preconditioning assessed by sequential exercise tests in diabetic and non-diabetic patients with stable coronary artery disease--a prospective study.

BACKGROUND: Ischemic preconditioning is a powerful mechanism of myocardial protection and in humans it can be evaluated by sequential exercise tests. Coronary Artery Disease in the presence of diabetes mellitus may be associated with worse outcomes. In addition, some studies have shown that diabetes interferes negatively with the development of ischemic preconditioning. However, it is still unknown whether diabetes may influence the expression of ischemic preconditioning in patients with stable multivessel coronary artery disease. METHODS/DESIGN: This study will include 140 diabetic and non-diabetic patients with chronic, stable coronary artery disease and preserved left ventricular systolic function. The patients will be submitted to two sequential exercise tests with 30-minutes interval between them. Ischemic parameters will be compared between diabetic and non-diabetic patients. Ischemic preconditioning will be considered present when time to 1.0 mm ST-segment deviation is greater in the second of two sequential exercise tests. Exercise tests will be analyzed by two independent cardiologists. DISCUSSION: Ischemic preconditioning was first demonstrated by Murry et al. in dog's hearts. Its work was reproduced by other authors, clearly demonstrating that brief periods of myocardial ischemia followed by reperfusion triggers cardioprotective mechanisms against subsequent and severe ischemia. On the other hand, the demonstration of ischemic preconditioning in humans requires the presence of clinical symptoms or physiological changes difficult to be measured. One methodology largely accepted are the sequential exercise tests, in which, the improvement in the time to 1.0 mm ST depression in the second of two sequential tests is considered manifestation of ischemic preconditioning.Diabetes is an important and independent determinant of clinical prognosis. It's a major risk factor for coronary artery disease. Furthermore, the association of diabetes with stable coronary artery disease imposes worse prognosis, irrespective of treatment strategy. It's still not clearly known the mechanisms responsible by these worse outcomes. Impairment in the mechanisms of ischemic preconditioning may be one major cause of this worse prognosis, but, in the clinical setting, this is not known. The present study aims to evaluate how diabetes mellitus interferes with ischemic preconditioning in patients with stable, multivessel coronary artery disease and preserved systolic ventricular function.

Effect of hypoglycemic agents on ischemic preconditioning in patients with type 2 diabetes and symptomatic coronary artery disease.

OBJECTIVE: To assess the effect of two hypoglycemic drugs on ischemic preconditioning (IPC) patients with type 2 diabetes and coronary artery disease (CAD). RESEARCH DESIGN AND METHODS: We performed a prospective study of 96 consecutive patients allocated into two groups: 42 to group repaglinide (R) and 54 to group vildagliptin (V). All patients underwent two consecutive exercise tests (ET1 and ET2) in phase 1 without drugs. In phase 2, 1 day after ET1 and -2, 2 mg repaglinide three times daily or 50 mg vildagliptin twice daily was given orally to patients in the respective group for 6 days. On the seventh day, 60 min after 6 mg repaglinide or 100 mg vildagliptin, all patients underwent two consecutive exercise tests (ET3 and ET4). RESULTS: In phase 1, IPC was demonstrated by improvement in the time to 1.0 mm ST-segment depression and rate pressure product (RPP). All patients developed ischemia in ET3; however, 83.3% of patients in group R experienced ischemia earlier in ET4, without significant improvement in RPP, indicating the cessation of IPC (P < 0.0001). In group V, only 28% of patients demonstrated IPC cessation, with 72% still having the protective effect (P < 0.0069). CONCLUSIONS: Repaglinide eliminated myocardial IPC, probably by its effect on the KATP channel. Vildagliptin did not damage this protective mechanism in a relevant way in patients with type 2 diabetes and CAD, suggesting a good alternative treatment in this population.

Electrovectorcardiographic diagnosis of left septal fascicular block: anatomic and clinical considerations.

Several publications considering anatomical, histological, pathological, electrocardiographic, vectorcardiographic, and electrophysiologic studies have shown that the left bundle branch splits into three fascicles or in a "fan-like interconnected network" in the vast majority of human hearts. The left His system is trifascicular with a left anterior, a left posterior, and a left septal fascicle (LSF). Consequently, the classic term "hemiblock," to describe the block of one of the fascicles, established several decades ago by the Rosembaum's school, should be updated. Electrovectorcardiographic changes resulting from conduction abnormalities of the left anterior and left posterior fascicles are commonly diagnosed, mainly by their changes in the frontal plane. However, the existence of conduction defects of the LSF remains controversial. The ECG/VCG hallmark of LSF block is prominent anterior QRS forces (PAF) on the horizontal plane. This ECG/VCG phenomena should be distinguished from other conditions that also produce anterior QRS shift in the HP as: normal variants, right ventricular enlargement, misplaced precordial leads, lateral myocardial infarction, right bundle branch block, Wolff-Parkinson-White, obstructive and nonobstructive forms of hypertrophic cardiomyopahty, diastolic left ventricular enlargement, endomiocardial fibrosis, Duchenne muscular dystrophy, and dextroposition. The two highly frequent etiologies of LSFB are ischemia (coronary artery disease (CAD) with critical proximal obstruction of the left anterior descending coronary artery) and, in Latin America, Chagas' cardiomyopathy. The aims of this review are to revise the evidence of the existence of a trifascicular left Hissian system and to help in the ECG/VCG recognition of the LSFB.

Propofol infusion syndrome and Brugada syndrome electrocardiographic phenocopy.

This anesthetic drug may cause a rare condition named propofol infusion syndrome, characterized by unexplained lactic acidosis, lipemia, rhabdomyolysis, cardiovascular collapse and Brugada-like electrocardiographic pattern or Brugada electrocardiographic phenocopy changes following high-dose propofol infusion over prolonged periods of time. Several articles have contributed to our understanding of the cause of the syndrome, and the growing number of case reports has made it possible to identify several risk factors. Uncertainty remains as to whether a genetic susceptibility exists. The favorable recovery profile associated with propofol offers advantages over traditional anesthetics in clinical situations in which rapid recovery is important. Propofol is a safe anesthetic agent, but propofol infusion syndrome is a rare lethal complication.

Aspectos básicos da ergometria contemporânea / Basics of contemporary exercise testing

O teste ergométrico é um exame já bem estabelecido e vem sendo adotado na prática clínica por várias décadas. Ele é geralmente seguro, mas deve ser considerado de forma judiciosa, indicando-se de forma apropriada qual o tipo de paciente que deve ser submetido ao exame. A interpretação do teste ergométrico inclui capacidade funcional, aspectos clínicos, hemodinâmicos e a resposta eletrocardiográfica...

Exercise testing is a well-established procedure that has been in widespread clinical use for many decades. Exercise testing is generally a safe procedure, but good clinical judgment should therefore be used in deciding which patients should undergo exercise testing. Interpretation of the exercise test should include exercise capacity and clinical, hemodynamic, and electrocardiographic response...

Escore eletrocardiográfico para avaliação de isquemia miocárdica: aplicação em testes ergométricos sequenciais para avaliação do fenômeno do aquecimento / Electrocardiographic score for myocardial ischemia evaluation: application in sequential exercise tests for warm-up phenomenon evaluation

O tempo para 1,0mm de depressão do segmento ST (T-1,0mm) adotado para caracterizar o fenômeno do aquecimento, uma expressão do precondicionamento isquêmico (PCI), em testes ergométricos sequenciais é consistente e reprodutível, porém, possui várias limitações. O objetivo deste estudo foi aplicar um escore eletrocardiográfico de isquemia miocárdica em testes ergométricos sequenciais comparando com o clássico índice T-1,0mm. Avaliamos 61 pacientes, com idade média de 62,2+7,5 anos, 86,9% homens, portadores de diabetes mellitus tipo 2 e coronariopatia multiarterial. Foram analisados 151 exames, destes 116 de pacientes completaram as duas fases de avaliação. A primeira fase compreendia dois testes ergométricos sequenciais para documentação do PCI e a segunda fase, após 1 semana, mais dois testes sob efeito de repaglinida oral. Dois observadores aplicaram o escore de forma cega. Observou-se concordância perfeita inter e intraobservador (Kendall Tau-b = 0,96, p<0,0001, Kendall Tau-b=0,98, p<0,0001, respectivamente). Os valores de sensibilidade, especificidade, valor preditivo negativo, valor preditivo positivo e acurácia, foram respectivamente de 72,41%, 89,29%, 75,8%, 87,5% e 81%. Concluímos que o escore de isquemia é um método consistente e reprodutível para documentação do fenômeno do aquecimento, representando uma alternativa factível ao índice T-1,0mm.

The time to 1.0mm ST-segment depression (T-1.0mm), adopted to document the warm-up phenomenon, an expression of the ischemic preconditioning (IPC), during sequential exercise tests is considered reliable and reproductible, although with several limitations. The main goal of this study was to apply an electrocardiographic ischemic myocardium score to sequential exercise tests, comparing with the standard T-1.0mm. We evaluated 61 patients, mean age 62,2+7,5 years-old, 86.9% male, with type 2 diabetes mellitus and multivessel coronary disease. We analyzed 151 exercise tests, being 116 tests from patients who fulfilled the two phases of the study. The first phase enrolled the patients for two sequential exercise tests to document the IPC and the second phase, after 1 week, two additional sequential exercise tests were performed under repaglinide treatment. We observed a perfect concordance inter and intraobserver (Kendall Tau-b=0.96, p<0.0001; Kendall Tau-b=0,98, p<0,0001, respectively). The sensibility, specificity, positive predictive value and negative predictive value were also determined: 72.41%, 89.29%, 75.8%, 87.5% and 81%, respectively. In conclusion, the electrocardiographic ischemic score is a consistent and reproductible tool to document the warm-up phenomenon, representing a reliable alternative to the T-1.0mm.

The enigmatic sixth wave of the electrocardiogram: the U wave.

The U wave is the last, inconstant, smallest, rounded and upward deflection of the electrocardiogram. Controversial in origin, it is sometimes seen following the T wave with the TU junction along the baseline or fused with it and before P of the following cycle on the TP segment. In this review we will study its temporal location related to monophasic action potential, cardiac cycle and heart sounds, polarity, voltage or amplitude, frequency and shapecontour. We will analyze the clinical significance of negative, alternant, prominent U wave, and the difference between T wave with two peaks (T1-T2) and true U wave. Finally we will analyze the four main hypotheses about the source of U wave: repolarization of the intraventricular conducting system or Purkinje fibers system, delayed repolarization of the papillary muscles, afterpotentials caused by mechanoelectrical hypothesis or mechanoelectrical feedback, and the prolonged repolarization in the cells of the mid-myocardium ("M-cells").

Early repolarization variant: epidemiological aspects, mechanism, and differential diagnosis.

Early repolarization variant (ERV or ERPV) is a enigmatic electrocardiographic phenomenon, characterized by prominent J wave and ST-segment elevation in multiple leads. Recently, there has been renewed interest in ERV because of similarities to the arrhythmogenic Brugada syndrome (BrS). Not much is known about the epidemiology of ERV and several studies have reported that this condition is associated with a good prognosis. Both syndromes exhibit some similarities including the ionic underlying mechanism, the analogous responses to changes in heart rate and autonomic tone, sympathicomimetics (isoproterenol test) as well as in sodium channel and beta-blockers. These observations raise the hypothesis that ERV may be not as benign as traditionally believed. Additionally, there are documents showing that ST-segment height in the man is greatly influenced by central sympathetic nervous activity, both at baseline and during physiologic and pharmacological stress. Central sympathetic dysfunction regularly results in multilead ST-segment elevation or J wave that decreases or below isoelectric baseline during low dose isoproterenol infusion. In this review, we describe the characteristics of ERV and the main differences with acute pericarditis, acute myocardial infraction/injury and Brugada syndrome.

Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome.

Class III drugs prolong the QT interval by blocking mainly the delayed rectifier rapid potassium outward current (IKr), with little effect on depolarization. This K(+) channel in encoded by the human ether-a-go-go-related gene (hERG). Inhibition of hERG potassium currents by class III antiarrhythmic drugs causes lengthening of cardiac action potential, which produces a beneficial antiarrhythmic effect. Excessive prolongation of the action potential may lead to acquired long QT syndrome, which is associated with a risk of "torsade de pointes". Class III agents can block all types of potassium channels: IKs, IKr, IKur and IK1. The main representing class III agent is amiodarone. It is the gold standard in the prevention of recurrence of atrial fibrillation. Although it is highly effective in treating many arrhythmias, large number of adverse effects limits its clinical use. Dronedarone is a synthetic amiodarone analogue, iodine-free compound, with fewer adverse effects, and shares amiodarone's multichannel blocking effects, inhibiting transmembrane Na+, IKs, IKur, IK1, and slow Ca(++)L-type calcium currents. The main new generation class III drugs are: dofetilide, dronedarone, azimilide, and ibutilide. Oral dofetilide did not increase mortality in patients with a recent myocardial infarction or congestive heart failure. It is an alternative for the pharmacological conversion of atrial fibrillation and flutter. Azimilide blocks both rapid and slow potassium channels components. Azimilide is not a methanesulfonanilide compound. Trecitilide, tedisamil, ersentilide, ambasilide, chromanol and sematilide are class III miscellaneous agents. Old mixed agents are sotalol and bretylium. The present article reviews the main trials accomplished with these drugs.

The history of left septal fascicular block: chronological considerations of a reality yet to be universally accepted.

There are several papers in literature that prove in a conclusive and incontestable way, that the left branch of the His bundle, in most instances (85% of the cases) splits into three fascicles of variable morphological pattern, and not into two: left anterior fascicle (LAF), left posterior fascicle (LPF), and left septal fascicle (LSF). The abovementioned papers have anatomical, histological, anatomo-pathological, electrocardiographic, and vectocardiographic, body surface potential mapping or ECG potential mapping and electrophysiological foundation.Additionally, the mentioned papers have been performed both in animal models (dogs) and in the human heart.Several clinical papers have shown that the left septal fascicular block (LSFB) may occur intermittently or transitorily as a consequence of a temporary dromotropic alteration, constituting an aberrant ventricular conduction, rate-dependent or by the application of atrial extra-stimuli, or naturally during the acute phase of infarction when this involves the anterior descending artery, before the septal perforating artery that supplies the central portion of the septum, where the mentioned LSF runs.The ECG/VCG manifestation of LSFB consists in anterior shift of electromotive forces, known as Prominent Anterior Forces (PAF), which can hardly be diagnosed in the clinical absence of other causes capable of causing PAF, such as the normal variant by counterclockwise rotation of the heart on its longitudinal axis, in right ventricular enlargement, in the dorsal or lateral infarction of the new nomenclature, in type-A WPW, in CRBBB, and others. In this historical manuscript, we review in a sequential fashion, the main findings that confirmed the unequivocal existence of this unjustifiably "forgotten" dromotropic disorder.In the developed countries, its most important cause is coronary insufficiency, particularly the proximal involvement of the left anterior descending coronary artery, and in Latin America, Chagas disease.

The management of Brugada syndrome patients.

Brugada syndrome is a congenital electrical disorder characterised by the appearance of distinctive QRST-T patterns in the right precordial leads and an increased risk of sudden death (SCD) in young healthy adults. Although chamber enlargement is not apparent in most cases, autopsy and histological investigations have revealed structural abnormalities. The typical Brugada ECG manifestation is often concealed and may be revealed by Class IC anti-arrhythmic agents with the effect of blocking the fast component of sodium channel currents. The syndrome may also be unmasked or precipitated by a febrile state, vagotonic agents, alpha-adrenergic agonists, beta-adrenergic blockers, tricyclic or tetracyclic antidepressants, a combination of glucose and insulin and hypokalaemia, as well as by alcohol and cocaine toxicity. Since the typical Brugada ECG pattern can be normalised by Class IA agents to block transient outward currents (I(to)) or by isoproterenol and cilostazol to boost calcium channel currents, they have been considered pharmacological therapies aimed at rebalancing the ion channel currents during cardiac depolarisation and repolarisation. Case studies by intra-cardiac mappingguided ablation in the right ventricular outflow tract and Purkinje network have shown evidence of eliminating the substrate of ventricular tachycardia/fibrillation (VT/VF) in Brugada syndrome, which may be used as an adjunct to device therapy to abort electrical storms. At present the most effective therapy to prevent sudden cardiac death in Brugada syndrome is an implantable cardioverter defibrillator. (Cardiol J 2007; 14: 97-106).

O eletrocardiograma de alta resolução da ativação atrial em pacientes com ou sem fibrilação atrial paroxística / The signal-averaged electrocardiogram of atrial activation in patients with or without paroxysmal atrial fibrillation

OBJETIVO: Analisar os parâmetros do eletrocardiograma de alta resolução da onda P no domínio do tempo (ECGAR-P) e compará-los com: a duração da onda P no eletrocardiograma clássico (P no ECG), o diâmetro atrial esquerdo (AE) e a fração de ejeção do ventrículo esquerdo (FE) obtidos no ecocardiograma, para avaliar pacientes com fibrilação atrial paroxística (FAP). MÉTODOS: Foram estudados 181 pacientes: 117 com FAP comprovada e 64 sem FAP. Os parâmetros do ECGAR-P foram: a duração da onda P filtrada (DPF), as voltagens da raiz quadrada média dos últimos 40, 30 e 20 ms da onda P filtrada (RMS 40, RMS 30 e RMS 20), a voltagem da raiz quadrada média dos potenciais da onda P filtrada (RMS P), a integral dos potenciais da onda P filtrada (Integral P) e a duração dos potenciais tardios da onda P filtrada abaixo de 3 æV (PT<3). RESULTADOS: Os parâmetros que apresentaram diferenças estatisticamente significantes entre os grupos foram: DPF, RMS 40, 30 e 20, PT<3, P no ECG e AE. Os cálculos pela curva ROC mostraram, para cada parâmetro, o melhor valor de corte e os estimadores de desempenho: sensibilidade, especificidade, área sob a curva e p-value (p) ou nível descritivo. CONCLUSÃO: O ECGAR-P no domínio do tempo mostrou-se melhor que o eletrocardiograma clássico e o ecocardiograma para identificar pacientes com fibrilação atrial paroxística.

OBJECTIVE: To analyze the parameters of the time domain P-wave signal-averaged electrocardiogram (P-SAECG) and compare them with the P-wave duration on the conventional electrocardiogram (P on ECG) as well as the left atrium diameter (LAD) and left ventricular ejection fraction (EF) obtained on the echocardiogram in order to evaluate patients with paroxysmal atrial fibrillation (PAF). METHODS: One hundred and eighty-one patients were included in the study: 117 with confirmed PAF and 64 without PAF. The P-SAECG parameters used were: the filtered P-wave duration (FPD), the root mean square (RMS) voltages in the last 40, 30 and 20 ms of the filtered P-wave (RMS 40, RMS 30 and RMS 20), the root mean square voltage of the filtered P-wave potentials (RMS P), the integral of the potentials during the filtered P-wave (Integral P) and the filtered P-wave late potential durations below 3 æV (PL<3). RESULTS: The parameters that presented significant statistical differences between the groups were: FPD, RMS 40, 30 and 20, PL<3, P on ECG and LAD. The ROC curve calculations demonstrated the best cut-off points and performance estimates for each parameter: sensitivity, specificity, area under the curve and p-value (p). CONCLUSION: The time domain P-SAECG proved to be a superior method to identify patients with paroxysmal atrial fibrillation than the conventional electrocardiogram and echocardiogram.

The signal-averaged electrocardiogram of atrial activation in patients with or without paroxysmal atrial fibrillation.

OBJECTIVE: To analyze the parameters of the time domain P-wave signal-averaged electrocardiogram (P-SAECG) and compare them with the P-wave duration on the conventional electrocardiogram (P on ECG) as well as the left atrium diameter (LAD) and left ventricular ejection fraction (EF) obtained on the echocardiogram in order to evaluate patients with paroxysmal atrial fibrillation (PAF). METHODS: One hundred and eighty-one patients were included in the study: 117 with confirmed PAF and 64 without PAF. The P-SAECG parameters used were: the filtered P-wave duration (FPD), the root mean square (RMS) voltages in the last 40, 30 and 20 ms of the filtered P-wave (RMS 40, RMS 30 and RMS 20), the root mean square voltage of the filtered P-wave potentials (RMS P), the integral of the potentials during the filtered P-wave (Integral P) and the filtered P-wave late potential durations below 3 microV (PL<3). RESULTS: The parameters that presented significant statistical differences between the groups were: FPD, RMS 40, 30 and 20, PL<3, P on ECG and LAD. The ROC curve calculations demonstrated the best cut-off points and performance estimates for each parameter: sensitivity, specificity, area under the curve and p-value (p). CONCLUSION: The time domain P-SAECG proved to be a superior method to identify patients with paroxysmal atrial fibrillation than the conventional electrocardiogram and echocardiogram.