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Peter R Kowey

Publications and source records attributed to Peter R Kowey.

At least 19 recordsLinked to original sources
PubMed2006

L-type calcium current reactivation contributes to arrhythmogenesis associated with action potential triangulation.

INTRODUCTION: The morphology of the mammalian cardiac action potential (AP) is an important factor in the susceptibility to drug-induced early afterdepolarizations (EADs) that may initiate torsade de pointes (TdP). AP triangulation has been shown to be an important predictor of drug-induced TdP. METHODS AND RESULTS: APs from guinea pig and rabbit left ventricular single myocytes were recorded using a microelectrode-recording technique. I(Ca-L) currents were recorded in ventricular myocytes of guinea pig and rabbit using patch-clamping technique. At a stimulus frequency of 0.5 Hz, guinea pig ventricular myocytes displayed a square-like AP, whereas rabbit ventricular myocytes exhibited a triangle-like AP. Dofetilide-induced EADs were observed only in rabbit ventricular myocytes. Under the guinea pig AP clamping condition, the normalized I(Ca-L) instant reactivation currents in guinea pig and rabbit myocytes at voltages of -40 mV were 0.13 +/- 0.01 and 0.14 +/- 0.01, respectively. However, when rabbit AP served as the first clamping voltage, the normalized I(Ca-L) reactivation currents at -40 mV in guinea pig and rabbit myocytes were 0.20 +/- 0.01, 0.21 +/- 0.01, respectively, indicating that the I(Ca-L) recovery from inactivation in the rabbit triangular AP condition was significantly faster than in the guinea pig square AP condition. Comparison of the voltage clamp using the triangular waveform with the square waveform further confirmed that triangulation accelerates I(Ca-L) recovery from inactivation. CONCLUSIONS: In rabbit ventricular myocardium, AP triangulation accelerates I(Ca-L) channel recovery from inactivation, leading to instability of the cell membrane potential during repolarization, which is capable of initiating TdP.

Action Potentials↗
PubMed2006

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias.

BACKGROUND: The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP. METHODS AND RESULTS: Thirteen compounds were tested for their potential for TdP using the rabbit left ventricular wedges. All investigators were blinded to the names, concentrations and molecular weights of the drugs. The compounds were prepared by the study sponsor and sent to the investigator as 4 sets of 13 stock solutions with the order within each set being assigned by a random number generator. Each compound was scored semi-quantitatively for its relative potential for TdP based on its effect on ventricular repolarization measured as QT interval, dispersion of repolarization measured as T(p-e)/QT ratio and early afterdepolarizations. Disclosure of the names and concentrations after completion of the study revealed that all compounds known to be free of TdP risk received a score of less or equal to 0.25, whereas those with known TdP risk received a score ranging from 1.00 to 7.25 at concentrations less than 100X their free therapeutic plasma C(max). CONCLUSIONS: Our study provides a blinded evaluation of the isolated arterially-perfused rabbit wedge preparation demonstrating both a high sensitivity and specificity in the assessment of 13 agents with varying propensity for causing TdP.

Action Potentials↗
PubMed2006

Predictors of adverse outcome among patients with hypertension and coronary artery disease.

OBJECTIVES: We sought to determine predictors for adverse outcomes in hypertensive patients with coronary artery disease (CAD). BACKGROUND: Factors leading to adverse outcomes in hypertensive patients with CAD are poorly understood. The INternational VErapamil-trandolapril STudy (INVEST) compared outcomes in hypertensive patients with CAD that were assigned randomly to either a verapamil sustained-release (SR)- or an atenolol-based strategy for blood pressure (BP) control. Trandolapril and hydrochlorothiazide were used as added agents. During follow-up (61,835 patient-years), BP control and the primary outcome (death, nonfatal myocardial infarction, and nonfatal stroke) were not different between strategies. METHODS: We investigated risk for adverse outcome associated with baseline factors, follow-up BP, and drug treatments using Cox modeling. RESULTS: Previous heart failure (adjusted hazard ratio [HR] 1.96), as well as diabetes (HR 1.77), increased age (HR 1.63), U.S. residency (HR 1.61), renal impairment (HR 1.50), stroke/transient ischemic attack (HR 1.43), smoking (HR 1.41), myocardial infarction (HR 1.34), peripheral vascular disease (HR 1.27), and revascularization (HR 1.15) predicted increased risk. Follow-up systolic BP <140 mm Hg or diastolic BP <90 mm Hg (HRs 0.82 or 0.70, respectively) and trandolapril with verapamil SR (HRs 0.78 and 0.79) were associated with reduced risk. CONCLUSIONS: In hypertensive patients with CAD, increased risk for adverse outcomes was associated with conditions related to the severity of CAD and diminished left ventricular function. Lower follow-up BP and addition of trandolapril to verapamil SR each were associated with reduced risk.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2006

Antiarrhythmic drug therapy.

The use of antiarrhythmic drugs can be challenging to physicians. They are effective in treating various types of arrhythmias, yet their potential to cause adverse events, in particularly proarrhythmia, can be intimidating. When the decision to use antiarrhythmic therapy has been made, physicians are confronted with several issues: choosing the right drug, preventing complications, and selecting the setting in which the drug is to be given (in-hospital vs outpatient). In determining the best antiarrhythmic agent for each patient, one should have a basic understanding of their mechanisms of action and indications. Once this decision has been made, attention turns to avoiding complications and assessing for efficacy. Clinicians should be aware of the common drug interactions of each antiarrhythmic agent and avoid these whenever possible. In addition, patients need meticulous follow-up, including serial electrocardiograms and assessment for cardiovascular side effects. For several of the antiarrhythmic drugs, this can be accomplished in the outpatient setting in appropriate patients.

Journal Article↗
PubMed2006

Sudden death secondary to cardiac arrhythmias: mechanisms and treatment strategies.

PURPOSE OF REVIEW: This article reviews mechanisms and available therapeutic options for arrhythmias leading to sudden cardiac death in patients with coronary artery disease. RECENT FINDINGS: Intensive efforts have led to a better understanding of the pathophysiology and various treatments of sudden cardiac death. Antiarrhythmic medications have not demonstrated a survival benefit. Beta-adrenergic blocking agents have been revalidated in recent studies to improve survival and reduce risk of sudden cardiac death in patients with myocardial infarction. Angiotensin-converting enzyme inhibitors and aldosterone antagonists should also be used in these patients. Data from randomized trials demonstrate significant survival benefit with an implantable cardioverter-defibrillator and indications have expanded. Patients with established ischemic cardiomyopathy do not require electrophysiologic studies for induction of tachyarrhythmias based on these trials. One recent trial did not demonstrate mortality reduction with implantable defibrillators in patients with recent myocardial infarction. Devices may not provide survival benefit in patients with advanced New York Heart Association class IV heart failure. SUMMARY: The incidence of arrhythmia-related sudden death in the general population remains relatively high. Better risk stratification tools are needed to identify high-risk patients in the general population and in those with known coronary disease and to exclude low-risk patients.

Adrenergic beta-Antagonists↗
PubMed2006

Fast-track training of nonelectrophysiologists to implant defibrillators: is it needed?

Standard training pathways in cardiac electrophysiology are being short-circuited for a "fast-track" approach to train nonelectrophysiologists (not necessarily cardiologists) to implant defibrillators in patients. This approach has been undertaken by a professional society (The Heart Rhythm Society), a society that cannot police, or properly credential. They have support from the American College of Cardiology and, perhaps, even the Combined Medicare and Medicaid Services. This issue is particularly disturbing as there are no data to support the approach taken with regard to the safety and benefit for patients. This process disrupts the standard training pathways and will have long-term implications for the field of clinical cardiac electrophysiology and for the availability of highly trained individuals qualified to implant defibrillators. This issue has broad implications with regard to medical training pathways. We discuss these issues in detail and provide the results of two surveys, including a survey from members of the Heart Rhythm Society, most of whom disagree with the "fast-track" approach. A survey of cardiologist faculty members of the American College of Cardiology yielded similar results. We are particularly concerned about the disruption of training pathways in medicine and how this can affect patient care and can influence established training pathways in medicine.

Cardiology↗
PubMed2005

Hospitalizations for new heart failure among subjects with diabetes mellitus in the RENAAL and LIFE studies.

We sought to study the risk factors for heart failure (HF) and the relation between antihypertensive treatment with losartan and the first hospitalization for HF in patients with diabetes mellitus in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) studies. We evaluated 1,195 patients with hypertension, left ventricular hypertrophy, and diabetes from the LIFE study and 1,513 patients with type 2 diabetes and nephropathy from the RENAAL study. The comparative treatments were atenolol in the LIFE study and placebo in the RENAAL study. Patients with a history of HF were excluded from this analysis. Losartan significantly reduced the incidence of first hospitalizations for HF versus placebo in the RENAAL study (hazard ratio 0.74, p=0.037) and versus atenolol in the LIFE study (hazard ratio 0.57, p=0.019). Patients enrolled in the RENAAL study were at a higher risk of developing HF (hazard ratio for RENAAL vs LIFE diabetics 3.0, p<0.0001). The significant, independent baseline risk factors for the development of HF in the RENAAL study were urinary albumin/creatinine ratio, age, peripheral vascular disease, the Cornell product, body mass index, and previous angina; in the LIFE study they were the Cornell product, previous myocardial infarction, peripheral vascular disease, baseline atrial fibrillation, alcohol use (inverse relation), and urinary albumin/creatinine ratio. The beneficial effect of losartan on the reduction of risk for hospitalization for new HF was demonstrated in patients who were at high renal and/or high cardiovascular risk.

Adrenergic beta-Antagonists↗
PubMed2005

First experience with a Mobile Cardiac Outpatient Telemetry (MCOT) system for the diagnosis and management of cardiac arrhythmia.

Recently, a mobile cardiac outpatient telemetry (MCOT) system has become available that monitors the electrocardiogram continuously, recognizes arrhythmias automatically, and transmits abnormal rhythms instantaneously. MCOT does not require activation by the patient. We report data from the first 100 consecutive patients monitored by this new technology.

Adolescent↗
PubMed2005

Losartan and end-organ protection--lessons from the RENAAL study.

BACKGROUND: The Reduction in ENdpoints with the Angiotensin Antagonist Losartan (RENAAL) study reported that losartan delayed the progression of renal disease in patients with type 2 diabetes and nephropathy. Diabetic or renally impaired patients are at high cardiovascular risk, a risk potentially increased in patients with both conditions. HYPOTHESIS: This post hoc analysis examined whether baseline proteinuria was predictive of cardiovascular outcomes, and whether losartan modifies the risk of cardiovascular outcomes in these patients given its renal-protective effects. METHODS: The RENAAL study compared losartan with placebo (in addition to conventional antihypertensive medications) in type 2 diabetic patients with proteinuria. Morbidity and mortality due to cardiovascular causes were ascertained, and the relationship between baseline proteinuria and cardiovascular outcome was determined. The effect of treatment with losartan was examined using three time-to-event analyses of composite cardiorenal outcomes as described below. RESULTS: Increasing baseline proteinuria was associated with significantly increased risk of myocardial infarction (MI) and all-cause or cardiovascular death, but not stroke. Losartan significantly reduced the risk for the combined endpoint of end-stage renal disease (ESRD), MI, stroke, or death by 21% (p < or = 0.005), irrespective of whether all-cause or cardiovascular death was included in the analysis. In addition, losartan reduced the risk for the composite of ESRD or cardiovascular death by 19.2% (p < 0.05). CONCLUSION: In patients with type 2 diabetes and nephropathy, there is an increased risk of MI and cardiovascular or all-cause mortality. Treatment with losartan is associated with a reduction in proteinuria, a delay in the onset of ESRD, and no increased risk of cardiovascular events in this pre-ESRD population.

Adult↗
PubMed2005

Real-world algorithms for the optimal use of drugs and devices in the patient post myocardial infarction and the future of post myocardial infarction management.

Patients with left ventricular dysfunction (LVD) are at increased risk for dying suddenly of cardiac causes. The most common causes of LVD are coronary artery disease (CAD) and myocardial infarction (MI). Aggressive intervention following MI is essential for minimizing the myocardial damage that leads to LVD and the subsequent risk for heart failure and sudden cardiac death. This article describes practical algorithms for managing the patient post MI to minimize such risks. The degree of LVD is a key factor for determining clinical management strategies in the patient post MI. Risk factor reduction and selective neurohormonal blockade, especially with angiotensin-converting enzyme inhibitors, are usually recommended in the presence or absence of LVD, along with early use of a beta blocker. In patients with LVD, more aggressive intervention includes extended use of a beta blocker. In cases of LVD progressed to heart failure, the mixed beta and alpha blocker carvedilol has improved outcomes significantly. In clinical trials, carvedilol has been demonstrated to have antiarrhythmic activity, a property that offers protection against sudden arrhythmic death in high-risk patients with LVD. Addition of an aldosterone antagonist is also advised in patients with heart failure. In selected patients with reduced ejection fractions, use of surgical/catheter treatment and device therapy offers further benefits.

Adrenergic beta-Antagonists↗
PubMed2005

A randomized, double-blind, placebo-controlled study of the safety and efficacy of intravenous MCC-135 as an adjunct to primary percutaneous coronary intervention in patients with acute myocardial infarction: rationale and design of the evaluation of MCC-135 for left ventricular salvage in acute MI (EVOLVE) study.

As a consequence of acute ischemia and reperfusion in patients with acute ST elevation myocardial infarction, calcium overload inside myocytes not only affects myocardial contraction, relaxation, and myocyte recovery following reperfusion, but also may be related to myocyte necrosis and fatal arrhythmia. MCC-135 is the first in a new class of agents that reduce intracellular calcium overload. Pre-clinical and early clinical studies yielded promising results for patients with ST elevation myocardial infarction. The Evaluation of MCC-135 for Left Ventricular Salvage in Acute MI (EVOLVE) study is a Phase 2a, multicenter, randomized, double-blind, placebo-controlled clinical trial of 2 new doses of MCC-135 (4.5 mg/kg/48 hours and 9.0 mg/kg/48 hours) as adjunct therapy for preservation of left ventricular function and reduction of infarct size in patients undergoing primary percutaneous coronary intervention (PCI) for electrocardiographically moderate-large ST elevation myocardial infarction. The primary endpoint will be left ventricular ejection fraction on Day 5 post myocardial infarction as determined by single photon emission computed tomography (SPECT). Secondary endpoints will include SPECT and echocardiographic assessments, serum cardiac markers, clinical outcomes, and safety measures at specific time points through Day 30 post myocardial infarction. Follow-up clinical and safety assessments will be continued until Day 180. The rationale, design, and methods of the EVOLVE study are described in this paper, along with 2 sub-studies, involving a comparison of pre- and post-PCI measurements with either SPECT or echocardiography, to examine myocardial salvage and the time course of changes in myocardial infarction size and left ventricular function. MINIABSTRACT: The Evaluation of MCC-135 for Left Ventricular Salvage in Acute MI (EVOLVE) study is a Phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial of two doses of MCC-135, first in a new class of agents that reduce intracellular calcium overload, as adjunct therapy for preservation of left ventricular function and reduction of infarct size in patients with moderate-large STEMI undergoing primary PCI. The rationale, design, and methods of the EVOLVE study, along with two sub-studies, are described in this paper.

Acute Disease↗
PubMed2005

The QT and Tp-e intervals in left and right chest leads: comparison between patients with systemic and pulmonary hypertension.

BACKGROUND: Action potential duration in the right ventricle is normally shorter than that in the left. We tested the hypothesis that there may be intrinsic differences in the QT and Tp-e (an interval from the peak to the end of the T wave) intervals between the left and right chest leads that can be exaggerated by systemic hypertension but attenuated by pulmonary hypertension in humans. METHODS: Electrocardiograms in the left (V4L-V6L) and right (V4R-V6R) chest leads were obtained in 40 healthy individuals, 29 patients with systemic hypertension and left ventricular hypertrophy, and 15 patients with pulmonary hypertension. RESULTS: In healthy individuals, the corrected QT (QTc) and corrected Tp-e [T(p-e)c] intervals were 421+/-5 and 86+/-3 milliseconds in V4L through V6L, respectively, significantly longer than those recorded from V4R through V6R (383+/-5 and 62+/-4 milliseconds, respectively; P<.01). Left ventricular hypertrophy prolonged the QTc interval in V4L through V6L (456+/-5 milliseconds), exaggerating the difference in the QTc interval between the left and right chest leads (61+/-4 vs 40+/-3 milliseconds in healthy control subjects; P<.01). Left ventricular hypertrophy also resulted in a small but significant increase in the T(p-e)c interval in V4L through V6L (97+/-3 vs 86+/-3 milliseconds in control subjects; P<.05) but exerted no significant effect on the T(p-e)c interval in the right. In contrast, pulmonary hypertension lengthened the QTc interval in the right chest leads, reducing the difference in the QTc interval between the left and right chest leads (3+/-8 vs 40+/-3 milliseconds in control subjects; P<.01). CONCLUSIONS: There are intrinsic differences in the QT and Tp-e intervals between V4L-V6L and V4R-V6R that are significantly amplified by systemic hypertension but markedly attenuated by pulmonary hypertension.

Action Potentials↗
PubMed2005

Assessment of the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide in experimental models of torsades de pointes.

BACKGROUND: This study examined the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide. METHODS AND RESULTS: The electrophysiological and proarrhythmic effects of AZD7009 and dofetilide were assessed in the arterially perfused canine and rabbit left ventricular wedge preparation. The proarrhythmic potential of AZD7009, dofetilide, and azimilide was further assessed in the methoxamine-sensitized rabbit model of torsades de pointes (TdP) in vivo. AZD7009 lengthened the action potential duration (APD) and the QT interval in a bell-shaped manner (15.9 +/- 1.3% in canine wedge and 46.1 +/- 2.9% in rabbit wedge) occurring at 3 and 1 microM. In contrast, dofetilide did not show the bell-shaped concentration response and the QT interval was lengthened more extensively (27.7 +/- 1.6% and 100.8 +/- 10.0%). Furthermore, whereas dofetilide prolonged the midmyocardial and endocardial APD predominantly, resulting in an increased transmural dispersion of repolarization (TDR), AZD7009 prolonged the APD more homogenously in all cell layers. At 1 microM, AZD7009 produced phase 2 early afterdepolarizations (EADs) in 1/4 rabbit preparations but without ventricular R-on-T extrasystoles or TdP. In contrast, starting at 0.03 microM, dofetilide-induced EADs, R-on-T extrasystoles and TdP in 6/6, 5/6, and 4/6 preparations. Following intravenous infusion of AZD7009 (210 nmol/kg/minute), dofetilide (2 nmol/kg/minute) or azimilide (3.33 micromol/kg/minute), TdP was induced in 0/8, 5/8, and 5/8 rabbits (P = 0.026 vs AZD7009), respectively. In 5/5 rabbits, AZD7009 promptly suppressed TdP induced by dofetilide. CONCLUSIONS: In animal models of TdP, AZD7009 delays ventricular repolarization in a self-limited way associated with a low risk of repolarization-related proarrhythmia.

Action Potentials↗
PubMed2005

ECG repolarization waves: their genesis and clinical implications.

The electrocardiographic (ECG) manifestation of ventricular repolarization includes J (Osborn), T, and U waves. On the basis of biophysical principles of ECG recording, any wave on the body surface ECG represents a coincident voltage gradient generated by cellular electrical activity within the heart. The J wave is a deflection with a dome that appears on the ECG after the QRS complex. A transmural voltage gradient during initial ventricular repolarization, which results from the presence of a prominent action potential notch mediated by the transient outward potassium current (I(to)) in epicardium but not endocardium, is responsible for the registration of the J wave on the ECG. Clinical entities that are associated with J waves (the J-wave syndrome) include the early repolarization syndrome, the Brugada syndrome and idiopathic ventricular fibrillation related to a prominent J wave in the inferior leads. The T wave marks the final phase of ventricular repolarization and is a symbol of transmural dispersion of repolarization (TDR) in the ventricles. An excessively prolonged QT interval with enhanced TDR predisposes people to develop torsade de pointes. The malignant "R-on-T" phenomenon, i.e., an extrasystole that originates on the preceding T wave, is due to transmural propagation of phase 2 reentry or phase 2 early afterdepolarization. A pathological "U" wave as seen with hypokalemia is the consequence of electrical interaction among ventricular myocardial layers at action potential phase 3 of which repolarization slows. A physiological U wave is thought to be due to delayed repolarization of the Purkinje system.

Action Potentials↗