Period Of Atrial Pacing Research Articles

Implantable Sensors for Heart Failure

Heart failure (HF) affects more than 5 million Americans, and acute decompensated heart failure (ADHF) has emerged as the leading cause of hospitalization among people over the age of 65 years.1 Importantly, HF is a leading public health concern, and hospitalization expenses related to management of ADHF impose a substantial financial burden on the health care system. Additionally, readmission rates after hospitalization for ADHF may be as high as 50% at 6 months,2 and insights from the ADHERE registry suggest that a majority of patients admitted with ADHF have a history of heart failure.1 These data demonstrate that the majority of patients admitted with ADHF are known to the medical system and to medical providers, thereby creating an opportunity for upstream strategies that may be capable of detecting early HF destabilization and implementing therapies to restabilize the patient and avert hospitalization. The anticipated changes in the health care system—with a focus on bundled payments for disease management—will necessitate robust disease management programs to optimize therapy and minimize recurrent admissions once patients have been diagnosed with HF. Perhaps even more importantly, averting repeat episodes of ADHF is likely to have a stabilizing effect on the progression of HF and may improve long-term morbidity and mortality. The transition from chronic HF to ADHF involves perturbations in multiple intersecting processes including neurohormonal circuits, inflammatory mediators, cardiorenal interactions, and myocardial performance. Concurrently, derangements in comorbid illnesses such as coronary disease, atrial and ventricular arrhythmias, and hypertension also contribute to the pathophysiology of ADHF.3 Ultimately, these multiple pathways lead to an elevation in ventricular filling pressures and signs of vascular congestion, which, in concert with symptoms from impaired cardiac output, lead to the clinical constellation of ADHF. This pathophysiologic paradigm highlights multiple opportunities for detecting early changes in the processes that …

Calpain in Atrial Fibrillation: Friend or Foe?

Atrial fibrillation (AF) is associated with the occurrence of substantial structural changes in atrial tissue. AF is known to induce a cellular calcium-overload due to an increased influx of calcium through L-type calcium channels. Therefore, alterations of intracellular calcium homeostasis with activation of calcium-dependent signalling pathways like calcineurin and calpain appear of particular importance. Whereas calcineurin-dependent signalling contributes to the development of atrial hypertrophy [1–3], activation of the calcium-dependent protease calpain I may lead to destruction of cellular proteins. The histopathology of fibrillating atria is thought to be similar to chronically ischemic ventricular myocardium. A study by Goette et al. [4] showed that patients with AF have increased expression and activity of calpain I in atrial tissue. The changes in calpain activity were accompanied by reduced amounts of TnT and morphological degradation of myofilaments in fibrillating atria. Aime-Sempe et al. [5] provided evidence of an increased rate of apoptosis in fibrillating human atria. Importantly, inflammatory infiltrates were not observed in that study either. This suggests that non-inflammatory pathways contribute for the described apoptotic cell death in atrial tissue. The present study by Yue Li et al. [6] shows that an inhibitor of calpain I (N-Acetyl-Leu-Leu-Met; ALLM) diminishes the extent of apoptotic cell death in an in vivo canine model of AF. They show that inhibition of calpain I is able to reduce the rate of apoptosis (apoptosis index) and caspase expression as otherwise found highly increased after the 3 week period of atrial pacing. Anti-apoptotic proteins like bcl2 recovered by ALLM therapy are indicative of calpain activity being upstream of mitochondrial apoptotic pathways. Thus, the present paper provides first evidence using an in vivo model that inhibition of calpain I prevents pacinginduced apoptosis. This finding may have important implications since increased rate of apoptosis might affect the electrical and mechanical properties of fibrillating atrial tissue. Nevertheless, it still has to be proven that the demonstrated molecular effects of ALLM influence directly the occurrence/persistence of AF or the mechanical atrial function. Thus, it appears too early to state that ALLM is useful as upstream therapy in AF. Calpain I cleaves a variety of proteins to promote apoptosis with caspase-7 being just one recent example [7]. However, there is apparent crosstalk between apoptotic and necrotic pathways and activation of calpain promotes apoptosis even during caspase inhibition. In the heart, caspase-independent induction of apoptosis has been recently shown to occur via release of apoptosis-inducing U. Lendeckel Institute of Medical Biochemistry and Molecular Biology, Ernst-Moritz-Arndt University, Greifswald, Germany

Control of cardiac rate, contractility, and atrioventricular conduction by medullary raphé neurons in anesthetized rats

The sympathetic actions of medullary raphé neurons on heart rate (HR), atrioventricular conduction, ventricular contractility, and rate of relaxation were examined in nine urethane-anesthetized (1-1.5 g/kg iv), artificially ventilated rats that had been adrenalectomized and given atropine methylnitrate (1 mg/kg iv). Mean arterial pressure (MAP), ECG, and left ventricular pressure were recorded. The peak rates of rise and fall in the first derivative of left ventricular (LV) pressure (dP/dtmax and dP/dtmin, respectively) and the stimulus-R ($-R) interval were measured during brief periods of atrial pacing at 8.5 Hz before and after ventral medullary raphé neurons were activated by dl-homocysteic acid (DLH, 0.1 M) or inhibited by GABA (0.3 M) in local microinjections (90 nl). LV dP/dtmax values were corrected for the confounding effect of MAP, determined at the end of the experiments after giving propranolol (1 mg/kg iv) to block sympathetic actions on the heart. DLH microinjections into the ventral medullary raphé region increased HR by 44 +/- 2 beats/min, LV dP/dtmax by 1,055 +/- 156 mmHg/s, and the negative value of LV dP/dtmin by 729 +/- 204 mmHg/s (all, P < 0.001) while shortening the $-R interval by 2.8 +/- 0.8 ms (P < 0.01). GABA microinjections caused no significant change in HR, LV dP/dtmax, or $-R interval but reduced LV dP/dtmin from -5,974 +/- 93 to -5,548 +/- 171 mmHg/s and MAP from 115 +/- 4 to 105 +/- 5 mmHg (both, P < 0.01). Rises in tail skin temperature confirmed that GABA injections effectively inhibited raphé neurons. When activated, the neurons in the ventral medullary raphé region thus enhance atrioventricular conduction, ventricular contractility, and relaxation in parallel with HR, but they provide little or no tonic sympathetic drive to the heart.

Sequential Alterations in Myocardial Lactate Metabolism, S‐T Segments, and Left Ventricular Function During Angina Induced by Atrial Pacing

SUMMARYMyocardial lactate metabolism was monitored before, during, and after a period of atrial pacing with a continuous automated sampling technic. The electrocardiogram was recorded, and left ventricular function was evaluated by relating left ventricular end‐diastolic pressure to left ventricular stroke work. Seventeen of 21 patients with coronary artery disease experienced angina during pacing, and 13 of these showed lactate production by the myocardium during angina. The abnormalities in lactate metabolism developed early in the pacing period, along with S‐T segment depression and impairment of left ventricular function, all of which usually occurred before the onset of pain. In the patients with angina, the mean lactate extraction was 14.1% during the control period and —15.1% during the pacing period. Abnormalities in myocardial lactate metabolism have been demonstrated with greater regularity during pacing‐induced angina than during angina precipitated by exercise or isoproterenol. This investigation has demonstrated the sequences of changes in lactate metabolism during and after a period of angina and their relation to electrocardiographic and hemodynamic events.

Continuous recording of coronary sinus oxygen saturation during atrial pacing in patients with coronary artery disease or with syndrome X.

Coronary sinus oxygen saturation was measured continuously during incremental atrial pacing in 34 patients undergoing cardiac catheterisation. In eleven patients with normal coronary arteriograms, negative exercise tests, and no ST segment depression on the electrocardiogram, an increase in the rate of atrial pacing transiently decreased coronary sinus oxygen saturation but within 20 s oxygen saturation returned to the control value. In six patients with coronary artery disease ST segment depression developed during atrial pacing. The coronary sinus oxygen saturation fell and remained reduced until pacing was discontinued. The size of the fall of coronary sinus oxygen saturation increased with increasing heart rate. In seven patients with coronary artery disease the ST segments were unaltered during atrial pacing and coronary sinus oxygen saturation did not fall. Ten patients with syndrome X were studied. In six ST segment depression developed on atrial pacing. In five, three of whom developed ST segment depression, the changes in coronary sinus oxygen saturation during atrial pacing were similar to those observed in patients without any evidence of coronary artery disease. In three, all of whom developed ST segment depression, coronary sinus oxygen saturation gradually increased throughout the period of atrial pacing. In two patients coronary sinus oxygen saturation fell in a manner similar to that observed in patients with obstructive coronary artery disease who developed ST segment depression on pacing. Thus regulation of coronary blood flow in normal persons in response to an increase of heart rate is rapid. Oxygen extraction across the coronary bed can increase by up to 30% and a persistent increase in oxygen extraction is an indicator of myocardial ischaemia. The term "syndrome X" does not describe a homogeneous group of patients but in the majority coronary sinus oxygen saturation does not fall despite symptoms and changes on the electrocardiogram, indicating that inadequate coronary blood flow is not the dominant mechanism.

Alterations in Myocardial Uptake of Glutamate and Release of Alanine After Propranolol, Nifedipine, and Glyceryl Trinitrate in Coronary Artery Disease

We examined the effects of antianginal drugs on myocardial uptake of glutamate and release of alanine in patients with chronic effort angina. Thirty-three patients underwent two periods of atrial pacing, the second preceded either by no medication (controls) (n = 8), 0.1 mg/kg i.v. propranolol (n = 8), 30 mg nifedipine sublingually (n = 9) or 0.75 mg glyceryl trinitrate sublingually (n = 8). Before, during, and after each pacing period, coronary sinus blood flow (CSBF), oxygen uptake, and arteriocoronary sinus differences (ACs) of plasma glutamate and alanine were determined. In all groups of patients, arterial alanine concentration fell during the second test. Except for this fall, no metabolic change was seen in controls. Propranolol increased circulating arterial concentration and ACs values of glutamate throughout the test. Nifedipine did not change arterial glutamate concentration but decreased ACs glutamate before and after pacing. Glyceryl trinitrate decreased CSBF, oxygen uptake, and net myocardial uptake of glutamate before pacing despite unchanged arterial level and ACs values. Alterations of myocardial glutamate uptake after drugs may reflect metabolic effects of propranolol primarily exerted on extracardial sites and of nifedipine exerted on the myocardium itself, whereas changes after glyceryl trinitrate seem to be secondary to its cardiac unloading effect. Alterations in myocardial release of alanine were too small and inconsistent to be taken as drug effects.

The effect of verapamil on myocardial exchange of free fatty acids, citrate, lactate and glucose in coronary artery disease.

Twelve patients with coronary artery stenosis (greater than 50% diameter reduction) underwent two identical periods of atrial pacing before and after i.v. verapamil (0.1 mg/kg). Myocardial exchanges of free fatty acids (FFA), citrate, lactate and glucose were evaluated from measurements of arterio-coronary sinus differences (n = 12) and coronary sinus blood flow (CSBF) (n = 9). Before verapamil 11 patients developed angina. Verapamil abolished pain in seven and improved pacing time to angina in four patients. After verapamil, aortic pressure decreased (P less than 0.05), while the rate pressure product remained unchanged during rest and pacing. Verapamil decreased CSBF by 20% (P less than 0.05) during pacing, and increased oxygen extraction both during pacing and recovery. During pacing verapamil increase net FFA extraction (P less than 0.01) and uptake (1 to 8 mumol/min P less than 0.05), and decreased glucose extraction (P less than 0.05) and uptake (22 to 11 mumol/min P less than 0.02. Verapamil increased myocardial citrate release during pacing (P less than 0.05), suggesting a citrate inhibition of glycolysis as a possible mechanism of the inhibited glucose uptake. During pacing, verapamil reduced lactate release in seven patients (P less than 0.05) and decreased lactate extraction in five patients (P less than 0.05). The results suggest that verapamil mediates its beneficial effect on pacing-induced angina, in part by changing substrate utilization of the ischaemic myocardium in man towards that of normal heart.

Sequential alterations in myocardial lactate metaboli, S-T segments, and left ventricular function during angina induced by atrial pacing.

Myocardial lactate metabolism was monitored before, during, and after a period of atrial pacing with a continuous automated sampling technic. The electrocardiogram was recorded, and left ventricular function was evaluated by relating left ventricular end-diastolic pressure to left ventricular stroke work. Seventeen of 21 patients with coronary artery disease experienced angina during pacing, and 13 of these showed lactate production by the myocardium during angina. The abnormalities in lactate metabolism developed early in the pacing period, along with S-T segment depression and impairment of left ventricular function, all of which usually occurred before the onset of pain. In the patients with angina, the mean lactate extraction was 14.1% during the control period and —15.1% during the pacing period. Abnormalities in myocardial lactate metabolism have been demonstrated with greater regularity during pacing-induced angina than during angina precipitated by exercise or isoproterenol. This investigation has demonstrated the sequences of changes in lactate metabolism during and after a period of angina and their relation to electrocardiographic and hemodynamic events.