PI3K Inhibitors in Cardiovascular Disease

Cardiovascular diseases, including atherosclerotic disease and its thrombotic complications are one main cause of hospitalization and mortality in the world. The family of phosphoinositide 3‐kinases (PI3Ks) play an important role in the pathogenesis of cardiovascular diseases by regulating essential cellular functions, such as cell migration, translational responses, and cell survival, and thereby, modulating several essential biologic processes, such as metabolism, vascular homeostasis and thrombogenicity. PI3Ks can be divided into three classes, of which the class I‐group is the best characterized. This group consists of four isoforms, named PI3Kα, β, δ, and γ. Each isoform has distinct functions under normal as well as pathophysiologic conditions. The development of several pharmacologic isoform‐selective, isoform‐preferring, and pan‐PI3K inhibitors enlarged and potentiated the knowledge about the effect of the different PI3K isoforms on specific biologic processes as well as their role under pathophysiologic conditions. Moreover, this offered the possibility for novel therapeutic strategies targeting PI3K isoforms in cardiovascular diseases. Therefore, this review will focus on the pathophysiologic role of class I PI3Ks in cardiovascular diseases as well as on the therapeutic potential of pharmacological PI3K inhibitors for the treatment of this scourge of humanity.     

Stroke Prevention Versus Bleeding Risk of Vitamin‐K Antagonists: A Double‐Edged Sword in Patients with Atrial Fibrillation Who Require Surgery

Patients with atrial fibrillation taking vitamin‐K antagonists and undergoing invasive interventions or large surgery procedures are at highest risk of bleeding complications. Therefore, the temporary interruption of vitamin‐K antagonists and bridging with heparin is a frequent clinical need, particularly in patients with high risk for stroke. The management of such patients is challenging because of the lack of randomized clinical trials assessing different periprocedural anticoagulation approaches and inconsistent recommendations from consensus groups. Recent non‐randomized trials have helped to estimate the risks of thromboembolism and bleeding with “bridging” anticoagulation involving either low‐molecular‐weight heparin or intravenous unfractioned heparin. Nevertheless, there is still a clear need for randomized double‐blinded controlled trials comparing efficacy and safety of the different “bridging” strategies, including unfractionated heparin and placebo comparators, in preventing thromboembolism for specific patients and procedures.     

Thiazide-induced hyponatraemia: epidemiology and clues to pathogenesis

Thiazide diuretics are one of the most widely used and cost-effective classes of antihypertensive agents worldwide. Thiazides however have a significant side effect profile and are frequently insufficient to normalize blood pressure alone. Thiazide-induced hyponatraemia (TIH) is a major adverse effect, affecting up to one in seven patients receiving these drugs. TIH is more common in females, the elderly and those of low body weight and may cause symptoms such as confusion, falls and seizures. It is a common cause of hospital admission in the elderly. Although TIH occurs at least as frequently as hypokalaemia, much less is understood about the mechanism by which this occurs. Thiazides lower blood pressure by reducing the reabsorption of sodium from the distal nephron by inhibition of the NaCl cotransporter. The molecular mechanism by which this occurs together with the little known role of thiazides in regulating water reabsorbtion from the collecting ducts is discussed and the relevance to TIH evaluated. TIH is highly reproducible by thiazide rechallenge suggesting there may be a genetic predisposition. Both targeted resequencing of candidate genes and genome wide association techniques offer promising strategies by which such genetic contributions may be investigated. The rewards for uncovering the molecular mechanisms underlying TIH and the regulation of distal nephron sodium and water absorption are significant; not only could it inform the design of better tolerated, more efficacious thiazide-like antihypertensive agents but it may also facilitate the pharmacogenomic profiling of hypertensive patients to avoid thiazides in those likely to suffer adverse effects.     

Risk stratification of sudden cardiac death and malignant ventricular arrhythmias in right ventricular dysplasia-cardiomyopathy

Arrhythmogenic right ventricular dysplasia-cardiomyopathy is in most cases a benign cause of ventricular arrhythmias in young patients. The major reason of mortality is sudden arrhythmic death with an annual rate of 2-3% as the first manifestation of the disease in most cases. Little is known about risk factors of sudden arrhythmic death so far. The purpose of the retrospective study was to classify risk factors from invasive and non-invasive examinations. METHODS: In a cohort of 121 consecutive patients sampled from 1986 to 1998 the value of right ventricular dilatation, left ventricular involvement analysed by angiocardiography or echocardiography and standard ECG parameters such as precordial T wave inversions, right precordial ST elevation, precordial QRS dispersion, left precordial JT interval prolongation and complete right bundle branch block were determined. The whole cohort of patients were divided into two groups with high arrhythmic risk (aborted or non-aborted sudden death, recurrent ventricular tachycardia despite medical treatment, recurrent syncopes) and low risk (frequent ventricular premature beats, non sustained ventricular tachycardia, uneventful course under medical therapy). RESULTS: From angiocardiography or echocardiography in a quantitative approach right ventricular dilatation (p<0.0001) and additional left ventricular abnormalities (p<0.0001) could be identified as major risk factors. From an ECG point of view increased precordial QRS dispersion > or =50 ms (p<0.01) with complete right bundle branch block and right ventricular dilatation in most cases and precordial T wave inversions beyond V3 (p<0.0001) and the phenomenon of left precordial JT interval prolongation (JT dispersion > or =30 ms) in cases of additional left ventricular abnormalities represented non-invasive predictors of recurrent arrhythmic events. Right precordial ST segment elevation could be excluded as risk factor of sudden arrhythmic death. CONCLUSIONS: Right ventricular dilatation with ECG depolarisation abnormalities and additional left ventricular involvement with striking ECG repolarisation abnormalities could be identified as strong risk factors of recurrent arrhythmic events in ARVD with unfavorable prognosis.     

Andersen-tawil syndrome associated with aborted sudden cardiac death: atrial pacing was effective for ventricular arrhythmias

ABSTRACT:: A 37-year-old Japanese woman experienced aborted sudden cardiac death from ventricular fibrillation and was diagnosed with Andersen-Tawil syndrome by genetic analysis that revealed 2 mutations in the KCNJ2 gene. Although she received an implantation of implantable cardioverter defibrillator and beta-blocker therapy, the frequency of premature ventricular contraction and bidirectional ventricular tachycardia did not decrease. Her ventricular arrhythmias increased after a full stomach test and a neostigmine provocation test, and reduced after cibenzoline administration, which indicates the relation with vagal tone. Moreover, increasing the pacing rate significantly decreased them. These findings indicate that the arrhythmia was bradycardia-dependent in this case.     

Myofiberbreak-up: a marker of ventricular fibrillation in sudden cardiac death

BACKGROUND: Electrophysiologically, ventricular fibrillation is defined as a "chaotic, random, asynchronous electrical activity of the ventricles due to repetitive re-entrant excitation and/or rapid focal discharge". To this point its morphological equivalent has not been defined. MATERIAL AND METHOD: Several groups of different diseases and types of accidental death in normal subjects were studied. A complete autopsy was performed and the hearts were examined in 432 cases. A total of 16 myocardial samples per heart were processed for histological examination and sections were stained by haematoxylin and eosin or by specific stains. The frequency, location and extent of myocellular segmentation (stretching and/or rupture) of intercalated discs and associated changes of myocardial bundles and single myocells were investigated. A quantitative analysis was performed and the data were processed for statistical evaluation. RESULTS: The frequency of MFB was maximal in coronary (88%) and Chagas (76%) groups followed by the intracranial brain haemorrhage group (52%). The extent of myofiberbreak-up was maximal in coronary/Chagas groups followed by intracranial haemorrhage and transplant groups. CONCLUSIONS: No correlation was seen between gender, age, heart weight, degree of coronary atherosclerosis, myocardial fibrosis, survival and MFB. If our postulate is correct, finding MFB in the myocardium might allow the diagnosis of a malignant arrhythmia followed by cardiac arrest due to ventricular fibrillation even in the absence of clinical information (sudden death out-of-hospital).     

Cardiac arrhythmias and sudden cardiac death in women

Zusammenfassung. Hintergrund: Geschlechtsspezifische Unterschiede bei Herzrhythmusstörungen sind seit Jahrzehnten bekannt. Einflüsse von Sexualsteroiden auf das autonome Nervensystem und die zelluläre Elektrophysiologie des Erregungsbildungs- und -leitungssystems werden ebenso diskutiert wie direkte genetische Dispositionen auf zellulärer, funktioneller oder metabolischer Ebene. Zudem gilt es, die alters- und geschlechtsspezifischen Unterschiede im Hinblick auf unterschiedliche kardiale Grunderkrankungen zu berücksichtigen, die ihrerseits Häufigkeit, Form und Schwere maßgeblich mitbestimmen. Herzrhythmusstörungen bei Frauen: Eine im Vergleich zu Männern höhere Ruhefrequenz und ein längeres QTc-Intervall, beginnend nach der Pubertät, sind die auffälligsten EKG-Veränderungen bei Frauen und weisen eine enge Beziehung zu konstitutionellen und hormonellen Einflüssen auf. Supraventrikuläre Herzrhythmusstörungen, bei Frauen prädestiniert Sinus- und AV-Knoten-Reentry-Tachykardien, seltener Wolff-Parkinson-White-Tachykardien, können zyklusabhängigen Häufigkeitsschwankungen unterliegen. Vorhofflimmern ist bei Frauen ebenfalls häufiger als bei Männern, meist typischerweise symptomatisch, und die Therapie erweist sich als problematischer. Ventrikuläre Herzrhythmusstörungen, in der gesunden Allgemeinbevölkerung gleich häufig, weisen bei Männern eine enge und prognostisch bedeutsame Beziehung zur KHK auf, während diese bei Frauen weniger ausgeprägt ist und arrhythmogene Kofaktoren eine größere Rolle spielen. Frauen leiden häufiger an erworbenem und kongenitalem Long-QT-Syndrom, in deren Folge häufiger Torsade de pointes-Tachykardien auftreten (u. a. durch ausgeprägtere medikamentös induzierte QT-Verlängerung, häufigere Kurz-Lang-Sequenzen, Unterschiede der Ikr-Sensitivität), die allerdings seltener als bei Männern in Kammerflimmern degenerieren. Frauen sind von einem plötzlichen Herztod etwa dreimal seltener betroffen. Er ereignet sich etwa zehn Jahre später; die zugrunde liegende Ursache ist deutlich heterogener als bei Männern, und die Prognose, ein solches Ereignis zu überleben, ist deutlich schlechter. Frauen sind in Studien zu Primär- und Sekundärprävention deutlich unterrepräsentiert, wenngleich der Nutzen dieser Therapie sogar den bei Männern zu übersteigen scheint. Schlussfolgerungen: Auch wenn die Genese der geschlechtsspezifischen Unterschiede von kardialen Arrhythmien in einer Reihe von Punkten noch offen ist, implizieren die dargestellten Befunde die besondere Notwendigkeit eines entsprechend ausgerichteten Forschungsansatzes, da sich nur so geschlechtsspezifische Risikostratifikations- und Therapieansätze für die Zukunft entwickeln lassen.     

Implications of obstructive sleep apnea for atrial fibrillation and sudden cardiac death

Obstructive sleep apnea (OSA) is a sleep-related breathing disorder with important cardiovascular consequences, including arrhythmogenesis. The unique pathophysiology of OSA results in multiple intermediate mechanisms that may promote atrial fibrillation, ventricular arrhythmias, and sudden cardiac death. These mechanisms may act acutely to trigger nocturnal dysrhythmias, or chronically by affecting the electrical and myocardial substrates. Burgeoning epidemiological data have identified an increased risk for atrial fibrillation and sudden cardiac death related to OSA. Currently, few data exist to support the efficacy of OSA therapy, namely continuous positive airway pressure, as an adjunct for arrhythmia prevention or management.     

Importance of a non-dominant right coronary artery occlusion presenting as sudden cardiac death with prolonged right ventricular dysfunction and malignant arrhythmias

We report a case of a patient who presented with sudden cardiac death secondary to a subtotal occlusion of a small non-dominant right coronary system. Catheterization several weeks following the initial episode revealed persistent severe right ventricular dysfunction with moderate hemodynamic compensation. Continued unstable arrhythmogenic potential at this point led to placement of an AICD device. The case highlights the potential hazard and often complacency involved in dealing with benign appearing lesions as this one. © 1995 Wiley-Liss, Inc.     

Prostacyclin prevents ventricular fibrillation in a canine model of sudden cardiac death

Summary The antifibrillatory, antithrombotic and hemodynamic properties of intraventricular prostacyclin (PGI₂) application were studied in a conscious canine model of sudden cardiac death. In anesthetized dogs, a wire electrode was implanted into the left circumflex coronary artery (LCX) and acute myocardial ischemia was produced by 90 min occlusion of the left anterior descending coronary artery (LAD) followed by reperfusion. An intracardiac pressure transducer measured ventricular pressure, heart rate, filling pressure and dP/dt. The ECG was obtained from subcutaneous chest needles. Six days later while in ambulatory state, a 180 A DC current was applied for 4 h to the LCX intimal lining in Tris-HCl (n=10) and PGI₂-treated dogs (50 and 100 ng/kg/min, 11 and 12 dogs, respectively).Myocardial injury and coronary thrombosis induced by electrical stimulation produced ventricular fibrillation in all vehicle-treated dogs at 145±33 min (mean±S.D.). In PGI₂-treated hearts only 2 animals fibrillated at 150±29 min and 180±52 min following 50 and 100 ng/kg/min of the prostanoid, respectively. Thus, 18/23 PGI₂-treated dogs survived 4h electrical stimulation of the artery.Within the LAD perfusion zone infarction was observed of equal volumes in vehicle and PGI₂-treated animals. No ischemia occurred distal to the LCX coronary thrombosis. Ventricular pressure fell in all groups. Heart rate increased in the controls and those animals treated with 50 ng/kg/min PGI₂ while 100 ng/kg/min PGI₂ increased heart rate by 22±5% (p<0.05). Filling pressure increased in controls but fell in the PGI₂-treated hearts.The results indicate that PGI₂ can prevent ventricular fibrillation resulting from acute ischemia at a site distant to previous myocardial ischemia with superimposed intimal injury and coronary thrombosis. The PGI₂ properties are due to prevention of coronary thrombosis and the occlusion of the artery. Antifibrillatory effects of the prostanoids are suggested.     

Left ventricular hypertrophy, arrhythmias and sudden death in systemic hypertension

Left ventricular (LV) hypertrophy is a significant independent risk factor for mortality from coronary heart disease, including sudden death. The proportion of sudden death to total death due to coronary heart disease remains high, at about 50% to 60%, despite the continuing downward trend in coronary heart disease mortality observed in the U.S. during the last decade. Prevalence of LV hypertrophy, determined by electrocardiogram in hypertensive patients (diastolic blood pressure greater than or equal to 90 mm Hg), including tall R wave and evidence of repolarization abnormality, is around 5%. The prevalence of LV hypertrophy by echocardiography is estimated at 44% to 48%. LV hypertrophy on electrocardiogram underestimates the magnitude of the problem of LV hypertrophy in hypertensive patients. Its overall sensitivity is less than 60%. The incidence of LV hypertrophy in hypertensive patients is lower when hypertension is treated successfully than when the patient is left either untreated or inadequately treated; successful treatment of hypertension causes regression of LV hypertrophy. However, hypertensive patients with LV hypertrophy have a poor prognosis despite treatment. The available evidence derived from the results of large clinical trials suggests that hypertensive patients should be treated before there is electrocardiographic evidence of LV hypertrophy.     

Late recurrent arrhythmias after ablation of atrial fibrillation: Incidence, mechanisms, and treatment

OBJECTIVES: The aim of the study was to determine the incidence of atrial flutter and other arrhythmia recurrences (other than atrial fibrillation [AF]) during long-term follow-up after left atrial substrate modification by percutaneous radiofrequency (RF) ablation of AF. BACKGROUND: RF ablation is an effective treatment for patients with AF. However, late recurrent arrhythmias may complicate the patient's course. METHODS: One hundred fifty consecutive patients with paroxysmal or persistent AF were included in this prospective study. The incidence of arrhythmia recurrences after AF ablation was analyzed during long-term follow-up using repetitive 7-day ECG recording. RESULTS: In 28 of 150 patients (18.7%), stable regular arrhythmias other than AF were detected during follow-up. Left atrial flutter observed in 10 patients (6.7%) was treated by recompletion of the ablation lines in all 10 patients. Left atrial flutter was associated with recurrence of AF in all 10 patients. Nine of 10 patients (90%) were free from atrial flutter and 6 of 10 patients were free from AF after the second intervention. Typical right atrial flutter occurred in 10 patients (6.7%) and was treated successfully by percutaneous RF ablation without recurrence in all patients. Additionally, atrial flutter was documented during follow-up in 7 patients (4.7%); however, invasive electrophysiologic evaluation was not performed due to various reasons. CONCLUSIONS: Left atrial flutter is a relevant complication after RF catheter ablation of AF and was always associated with AF recurrence in our study population. Prevention of left atrial flutter can be achieved by induction of ablation lines as continuous and transmural as possible. However, left atrial flutter that does occur late after ablation is amenable to interventional treatment with good prospects of success.     

REVIEW: New Approaches to Atrial Fibrillation Management: Treat the Patient,not the ECG

Atrial fibrillation causes a significant burden on patients and the health care system. The main goals of atrial fibrillation therapy are to improve symptoms and reduce morbidity. There have been significant recent developments in both stoke prophylaxis and rhythm/rate control. The results of the ACTIVE W study emphasize the importance of effective oral anticoagulant therapy in patients with moderate‐to‐high risk for stroke. The RE‐LY study showed superiority of dabigatran, an oral direct thrombin inhibitor, over warfarin in the prevention of stroke, or systemic embolism. Dronedarone, a new antiarrhythmic drug with multiple class effects, has been recently approved by the US Food and Drug Administration for the treatment of atrial fibrillation. Dronedarone has moderate rhythm and rate control efficacy; however, dronedarone significantly reduced cardiovascular hospitalization, cardiovascular death, and stroke in the large ATHENA trial. There is also an important shift in the paradigm of the goals of atrial fibrillation therapy. Instead of focusing solely on the electrocardiographic outcomes of treatment and considering “rhythm versus rate control,” one needs to consider “symptom control” as well as patient well‐being. This review will suggest that patient based outcomes rather than ECG‐based outcomes should be the primary goals of treatment. Original reports and reviews on specific topics were identified through Medline. Randomized controlled trials were selected as the primary source of information. Analysis included critical review of the evidence available to date.