Intracellular calcium and ventricular function. Effects of nisoldipine on global ischemia in the isovolumic, coronary-perfused heart.

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([Ca2+]i). The present study was designed to determine the effects of the Ca2+ antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with a buffer containing 10(-8) M nisoldipine. From left ventricular developed pressure, time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i, from 0.35 to 0.81 microM, and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function. Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM, and in systolic [Ca2+]i to 0.77 microM, and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.

Intracoronary nifedipine in human beings: magnitude and time course of changes in left ventricular contraction/relaxation and coronary sinus blood flow.

Eight patients, all men, having at least 75% stenosis of the proximal, middle or both segments of the left anterior descending coronary artery, underwent intracoronary drug studies at the time of cardiac catheterization after saphenous vein bypass grafting. Nifedipine, 0.1 mg dissolved in saline solution, was infused into a left anterior descending graft that was the primary blood supply to each patient's anterior left ventricular wall and septum. High fidelity left ventricular pressure and its first derivative, dP/dt, and aortic pressure were sampled synchronously with coronary sinus blood flow by the thermodilution technique. The time constant of isovolumic pressure decay (T) was derived. In five patients, percent systolic shortening and mean shortening velocity were determined from myocardial markers implanted into the midwall of the myocardium at the time of cardiac surgery. In response to nifedipine, left ventricular systolic pressure decreased and end-diastolic pressure increased up to 60 seconds. Both positive and negative dP/dt also decreased up to 60 seconds, whereas coronary sinus blood flow increased up to 5 minutes. T was increased at 1 minute but returned to baseline by 3 minutes. Percent systolic shortening and mean shortening velocity were decreased at 1 minute but returned to control level by 3 minutes. Thus, although both left ventricular systolic and diastolic function were depressed by intracoronary administration of nifedipine, coronary sinus blood flow was augmented and remained increased long after changes in left ventricular contraction and relaxation had subsided. These temporal differences are consistent with animal studies showing a differential depressant effect of nifedipine on calcium uptake in smooth muscle and cardiac muscle.

Late increase in luminal diameter of aortocoronary venous bypass grafts associated with an increase in the vascular region under supply.

In a previous study, a significant inverse relation was found between the luminal size of aortocoronary venous bypass grafts and the vascular resistance of the coronary region that was perfused by the bypass graft in late stages after bypass surgery. This observation suggested that changes in the graft-dependent vascular area could influence the luminal size of the vein graft, even when they occurred several years after operation. Whereas it is well established today that aortocoronary vein grafts often decrease in luminal diameter after implantation, an increase in the bypass lumen has so far not been reported. Therefore, changes in luminal diameter of 27 vein grafts in 21 patients who underwent at least two postoperative angiographic studies (first study 8 +/- 5 months after surgery, second study 58 +/- 32 months after surgery) were compared with the size of the vascular region supplied by the bypass. The graft diameter was found to be unchanged between the two studies (3.3 +/- 0.6 versus 3.4 +/- 0.7 mm, p = NS) when the dependent vascular area was unchanged. A significant increase in graft diameter from 2.8 +/- 0.8 to 3.9 +/- 0.9 mm (p less than 0.001) was observed in nine patients in whom the area of perfusion had increased between the two studies because of the development of occlusion or obstruction of major coronary branches that were now perfused from the grafted vessel by way of collateral vessels. These data support the contention that the luminal size of aortocoronary vein grafts can adapt to the needs of the dependent myocardial vascular region even late after operation rather than being the result of a nonreversible degenerative process as commonly assumed.

Role of thrombolysis and thrombin in patients with acute coronary occlusion during percutaneous transluminal coronary angioplasty.

In a series of 447 patients with single vessel angioplasty, 27 (6.0%) had acute thrombotic occlusion early after the procedure. They were treated with combined intracoronary (20 mg)/intravenous (50 mg) thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) and repeat mild balloon inflations. Reopening of the vessel was achieved in 22 patients (81.5%). Follow-up coronary angiography 24 to 36 h later revealed reocclusion in 12 patients (54.5%). Thrombin levels measured as thrombin-antithrombin-III complex in patients with successful thrombolysis and persistent patency decreased from 8.5 +/- 11.4 micrograms/liter at baseline to 3.5 +/- 1.4 micrograms/liter 120 min after the start of thrombolysis; these levels increased from 9.4 +/- 15.0 micrograms/liter at baseline to 15.7 +/- 13.5 micrograms/liter 120 min after the start of thrombolysis in the patients with unsuccessful thrombolysis or early reocclusion (p less than 0.05). When a borderline value for thrombin-antithrombin-III complex level of 6 micrograms/liter was selected to separate the two groups of patients, patients with an unfavorable clinical course were identified 120 min after the start of thrombolysis by levels greater than 6 micrograms/liter (sensitivity 100%, specificity 92.8%). Thus, after abrupt thrombotic vessel closure during coronary angioplasty, the short-term results of thrombolysis seem to be governed by the release of thrombin. In two thirds of patients, however, the thrombin release cannot be suppressed by concomitant aspirin and heparin therapy. Even after successful reopening of the vessel these patients should therefore undergo immediate aortocoronary bypass grafting.

Percutaneous transluminal angioplasty of aortocoronary venous bypass grafts and effect of the caliber of the grafted coronary artery on graft stenosis.

The influence of morphologic parameters on the recurrence of stenosis after percutaneous transluminal coronary angioplasty of 49 stenoses in aortocoronary venous bypass grafts of 41 patients was investigated. Vessel dimensions were measured quantitatively. Angioplasty was successful in 46 stenoses (94%) of 38 patients (93%). In 35 patients (92% of successfully treated patients) with 42 stenoses, control angiography was performed after a mean interval of 189 +/- 186 days. In 9 patients (26%), 9 stenoses (21%) had recurred. The diameter of the grafted coronary artery distal to the anastomosis was significantly smaller in grafted arteries with than without recurrent stenoses (1.92 +/- 0.52 vs 2.45 +/- 0.50 mm; p less than 0.01). Recurrence also correlated with the ratio between graft diameter and coronary artery diameter greater than 1.35 (p less than 0.02) and with the stenosis length greater than 10 mm before angioplasty (p less than 0.01). Graft age, graft diameter and stenosis location in the graft had no significant influence on recurrence. Thus, the diameter of the grafted coronary artery and the length of the critical stenosis are parameters for recurrence after angioplasty of graft stenoses and should be considered in the selection of patients for this intervention.

Nisoldipine versus isosorbide dinitrate in coronary heart disease: results of a double-masked study.

The efficacy and tolerability of a twice-daily dose of 5 mg of nisoldipine versus 40 mg of sustained-release isosorbide dinitrate (ISDN) were compared in a randomized, double-masked study in 91 patients. During the 21-day treatment period, the mean time taken during bicycle ergometry to the appearance of an ST segment depression of at least 0.1 mV compared with the resting value increased from 287 +/- 129 seconds to 391 +/- 150 seconds in the nisoldipine group and from 254 +/- 140 seconds to 350 +/- 191 seconds in the ISDN group. The mean value at the end of treatment calculated by using analysis of covariance was 383 seconds in both groups. The difference between the two treatment groups was not statistically significant. The mean ST segment depression at individually maximal workload decreased from 0.19 +/- 0.07 mV to 0.12 +/- 0.08 mV in the nisoldipine group and from 0.18 +/- 0.07 mV to 0.14 +/- 0.08 mV in the ISDN group. The mean total duration of exercise increased from 420 +/- 161 seconds to 497 +/- 140 seconds in the nisoldipine group and from 425 +/- 167 seconds to 456 +/- 168 seconds in the ISDN group. In the nisoldipine group, 9 patients reported 12 adverse events that were considered to be possibly or probably related to the test medication; in the ISDN group, 13 patients reported 26 adverse events. Although the anti-ischemic effect of the two treatments was comparable, nisoldipine was descriptively superior to ISDN in terms of tolerability.

Posttraumatic myocardial infarction with severe coronary intimal dissection documented by intravascular ultrasound.

We present a case of posttraumatic myocardial infarction after blunt chest trauma in a previously healthy man. Coronary angiography showed an eccentric occlusion in the midportion of the left anterior descending artery. Subsequent intracoronary ultrasound imaging revealed a severe intimal dissection. The outcome after intracoronary stent placement was excellent. This rare but potentially harmful complication of blunt chest trauma should be kept in mind and coronary angiography performed immediately when coronary occlusion is suspected. Intravascular ultrasound imaging is a helpful tool in the assessment of coronary artery occlusion caused by intimal dissection.

Differential patterns of cocaine-induced organ toxicity in murine heart versus liver.

To determine cocaine's toxicity in different organs, BALB/c mice were intraperitoneally injected daily for 15 days with either saline or cocaine: 10 mg/kg, 30 mg/kg, or 60 mg/kg. Cardiac function, hepatic pathophysiology, heart and liver apoptosis, and tumor necrosis factor (TNF-alpha) levels were analyzed. After administration of cocaine, cardiac function decreased. Inflammatory cell infiltration and eosinophilic contraction bands were visible in the hearts of mice treated with 60mg/kg cocaine. Moreover, histopathology demonstrated that cocaine caused hepatic necrosis. TdT-mediated dUTP nick end-labeling (TUNEL) staining and DNA ladder analysis indicated that cocaine caused apoptosis in both the heart and liver. Moreover, immunoassay showed that TNF-alpha levels significantly increased in the heart and liver with cocaine administration. However, our RT-PCR study showed that there was no significant difference in either the heart or liver in the levels of mRNA for TNF-alpha between cocaine-treated and saline control mice. The present study demonstrated that cocaine is toxic to multiple organs, and at low dose can induce hepatic damage without gross pathological injury to the heart. The results suggest that the liver is more sensitive than the heart to cocaine toxicity, and induction of apoptosis or TNF-alpha elevation may be a common mechanism responsible for cocaines toxicity.

Method for non-invasively recording electrocardiograms in conscious mice.

BACKGROUND: The rapid increase in the development of mouse models is resulting in a growing demand for non-invasive physiological monitoring of large quantities of mice. Accordingly, we developed a new system for recording electrocardiograms (ECGs) in conscious mice without anesthesia or implants, and created Internet-accessible software for analyzing murine ECG signals. The system includes paw-sized conductive electrodes embedded in a platform configured to record ECGs when 3 single electrodes contact 3 paws. RESULTS: With this technique we demonstrated significantly reduced heart rate variability in neonates compared to adult mice. We also demonstrated that female mice exhibit significant ECG differences in comparison to age-matched males, both at baseline and in response to beta-adrenergic stimulation. CONCLUSIONS: The technology we developed enables non-invasive screening of large numbers of mice for ECG changes resulting from genetic, pharmacological, or pathophysiological alterations. Data we obtained non-invasively are not only consistent with what have been reported using invasive and expensive methods, but also demonstrate new findings regarding gender-dependent and age-dependent variations in ECGs in mice.

[Progression of coronary sclerosis after smoking cessation]. / Progression der Koronarsklerose nach Einstellen des Zigarettenrauchens.

Cigarette smoking is an established risk factor for the development of coronary artery disease, but whether cessation of heavy smoking influences progression of coronary artery disease is unclear. In 390 patients (359 men, 31 women; 52.4 +/- 6.7 SD years) with coronary artery disease, two coronary angiograms were performed at an interval of 62.4 +/- 23.5 months. Smoking habits were obtained by questionnaires. Progression of coronary artery disease was defined as the sum of new stenoses, progression of existing stenoses and new coronary occlusions. Multivariate classification analyses of risk factor profile revealed cigarette smoking (amount per day and length of time) as the most relevant factor for progression of coronary artery disease. Non-smokers had a progression score of 0.96 (95% confidence interval: 0.63-1.28) over the observation period. Former smokers (20.2 +/- 11.8 cigarettes/day for 19.4 +/- 7.6 years) who quit about 10 years before the first angiogram showed a progression of 2.20 (95% confidence interval: 1.77-2.63; p < 0.01) compared to non-smokers. Those smokers (23.8 +/- 9.2 cigarettes/day for 31.3 +/- 7.0 years) who quit at the time of the first angiogram showed a progression of 2.47 (95% confidence interval: 1.97-2.97; p < 0.001). Current smokers (20.5 +/- 9.7 cigarettes/day for 34.8 +/- 8.5 years) had a progression of 3.17 (95% confidence interval: 2.35-3.99; p < 0.001). The data indicate that former heavy cigarette smoking continues to act as a significant risk factor for progression of coronary artery disease even after cessation. This does not mean that current cigarette smokers should not stop.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of three different principles in the assessment of coronary flow reserve from digital angiograms.

In 70 patients without coronary disease we have compared three different principles to assess coronary flow reserve during diagnostic heart catheterization. Digital angiograms with ECG-triggered bolus injections of 4 to 8 ml of contrast medium at rest and after stimulation by dipyridamole (0,5 mg/kg i.v.) or papaverine (12,5 mg i.c.) were acquired in a 512 x 512 matrix at 8 bit resolution (ADAC 4100) and stored on a digital disk at 25 frames/sec. or 2 frames/cardiac cycle (PPR-mode). Angiograms were processed by cyclic R-wave-gated mask mode subtraction and coronary flow in the LAD area was assessed by three different approaches: 1. A traditional densitometric principle. 2. The 'CMAP' principle. 3. A modification of the Stewart-Hamilton principle comparing the total amount of contrast medium that enters the coronary circulation to the area of the contrast dilution curve in a fixed portion of the LAD. Flow was measured simultaneously during angiography using the thermodilution technique for coronary sinus/great cardiac vein flow. Drug stimulation resulted in an increased coronary blood flow up to five times of resting flow. Regression analysis revealed the following results for the assessment of the coronary flow reserved by digital angiography (y) when compared to thermodilution (x): [table: see text] Method 2 could be improved by replacing the density factor by morphometrically measured proximal LAD volume (y = 0.77x + 0.55; r = 0.78; SEE = +/- 0.43). In conclusion, our data suggest that the Stewart-Hamilton principle may be advantageous over time parameter-dependent approaches in the assessment of coronary flow reserve by digital angiography.

[X-ray cinematographic studies of local ventricular dynamics after aortocoronary bypass]. / Röntgenkinematografische Studien der lokalen Ventrikeldynamik nach aorto-coronarem Bypass.

In 12 patients with high-grade coronary stenosis local motility before and after aortocoronary vein bypass was estimated by cineradiography of coronary bifurcations and surgically implanted myocardial metal markers. A group of patients with relief of angina showed significant increase of local segment shortening within the first postoperative days. During the following months no further alteration occurred. In three patients with persisting angina no improvement of local motility could be found.

Ventricular function and calcium handling during ischemia.

Ischemia-induced ventricular dysfunction has been shown to be associated with increased diastolic and systolic intracellular concentrations of free, ionized calcium ([CA2+]i). The present study was designed to determine the effects of the calcium antagonist nisoldipine on the relationship between [Ca2+]i and left ventricular contraction and relaxation during ischemia and reperfusion on a beat-to-beat basis. Nine isovolumic coronary-perfused ferret hearts were made globally ischemic for 3 min and reperfused for 10 min. Ischemia and reperfusion were repeated during perfusion with buffer containing 10(-8) M nisoldipine. From the left ventricular developed pressure, the time to peak pressure and time to 50% pressure decline were obtained. [Ca2+]i was determined with the bioluminescent protein aequorin. Global ischemia caused a rapid decline in contractile function and a significant increase in diastolic [Ca2+]i from 0.35 to 0.81 microM and in systolic [Ca2+]i, from 0.61 to 0.96 microM. During reperfusion, [Ca2+]i returned to baseline while ventricular function was still impaired. Relaxation was more affected than systolic contractile function (Fig. 1). Nisoldipine significantly reduced the ischemia-induced rise in diastolic [Ca2+]i to 0.62 microM and in systolic [Ca2+]i to 0.77 microM and lessened the decrease in contractile function. Nisoldipine significantly accelerated the decline in [Ca2+]i during reperfusion and improved recovery of contractility and relaxation. These effects were associated with a significant diminution in ischemic lactate production. Taken together, our results provide direct quantitative evidence on a beat-to-beat basis that the calcium antagonist nisoldipine can ameliorate ischemia-induced abnormalities in [Ca2+]i handling, an effect that was associated with improved myocardial function during early reperfusion.

[Hemodynamics in ischemia: diastolic phase]. / Hämodynamik unter Ischämie: Diastolische Phase.

The diastolic portion of the cardiac cycle can be divided into sequential phases: isovolumic ventricular relaxation; rapid ventricular filling; slow, or passive, ventricular filling; and atrial contraction. Contraction and relaxation are to some extent interrelated; however, relaxation is not simply a passive reversal of events during systole. Rather, relaxation is an energy-consuming process which involves dissociation of calcium from the actin-myosin-complex and reuptake of calcium by the sarcoplasmic reticulum. Left ventricular diastolic function is determined by the interrelationship of several/factors, including some intrinsic to the left ventricular chamber (completeness of left ventricular relaxation, time course of left ventricular contraction, and elastic and viscous properties of the myocardium) and others extrinsic to the left ventricle (pericardial and pleural pressure, right ventricular contraction, and coronary perfusion pressure). Acute ischemia alters diastolic left ventricular function by: slowing isovolumic relaxation, delaying left ventricular filling and altering passive elastic properties of the myocardium. Slowing of isovolumic relaxation is measured as a fall in the maximal rate of left ventricular pressure decline (peak negative dP/dt) and as an increase in the time constant (T) of left ventricular pressure fall. Delayed left ventricular filling is manifested regionally as a reduced rate of septal and posterior wall thinning (by echocardiography) and globally as a reduced rate of chamber filling (by gated radionuclide angiography).(ABSTRACT TRUNCATED AT 250 WORDS)

Intracoronary nisoldipine: effects on acute myocardial ischemia during coronary angioplasty.

The effects on ischemic myocardium of 0.05 mg nisoldipine given by intracoronary injection were studied in 22 patients subjected to percutaneous transluminal coronary angioplasty. The angioplasty balloon was inflated for periods of 60 seconds. During the occlusion period, pulmonary wedge pressure was measured, an intracoronary epicardial ECG recorded, and ventricular volumes and ejection fraction were determined by means of digital subtraction angiography. After the intracoronary administration of nisoldipine, the onset of the rise in diastolic filling pressure was slightly delayed from 29 to 36 seconds. While affecting neither the rise in filling pressure nor the increase in end-diastolic and end-systolic volumes after 60 seconds of ischemia, nisoldipine delayed the occurrence (from 13 to 33 seconds; p less than 0.005) and reduced the extent (from 1.5 to 0.6 mV; p less than 0.001) of ischemic ST elevation in the intracoronary ECG. After nisoldipine, anginal symptoms were clearly reduced during the ischemic phase in the majority of patients. These findings suggest that intracoronary pretreatment with nisoldipine leads to a regional protection of ischemic myocardium without any appreciable effect on ischemia-induced myocardial dysfunction.

Effects of intravenous verapamil on left ventricular systolic function and diastolic filling dynamics in patients with coronary artery disease: analysis of intramyocardial markers.

Left ventricular (LV) intramyocardial markers (MM) were used to study the effects of intravenous verapamil on LV pump function and diastolic filling dynamics. Verapamil (0.1 mg/kg bolus followed by 0.005 mg/kg/min) was administered to 10 patients with severe coronary artery disease 4 years after coronary bypass grafting and implantation of 7 tantalum markers into the LV. MM were filmed at 100 frames/sec (biplane 30 degrees RAO/60 degrees LAO). The digitized biplane MM coordinates were transformed into 3-dimensional coordinates and maximal projection area was defined. LV volumes were calculated frame-by-frame and ejection fraction and peak filling rate derived. Pressure-volume relations were calculated in early-, mid-, and end-diastole. Verapamil caused a slight rise in end-diastolic pressure (12 to 14 mmHg, p less than 0.001) and end-diastolic volume (142 to 152 ml; p less than 0.005) and a fall in max dP/dt (1732 to 1570 mmHg/s; p less than 0.01) reflecting the drug's negative inotropic action. Verapamil reduced LV systolic pressure (136 to 126 mmHg; p less than 0.01), diastolic aortic pressure (74 to 68 mmHg; p less than 0.001) and peripheral resistance (1496 to 1348 dynes.s.cm-5; p less than 0.025); cardiac index was increased (2.7 to 2.9 l/min/m2; p less than 0.05), as were ejection fraction (47 to 49%; p less than 0.02) and stroke volume (67 to 75 ml; p less than 0.001). Great cardiac vein flow increased as well (88 to 102 ml/min; p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)