Russell C. Reeves

Assessment of myocardial infarct size by means of T2-weighted 1H nuclear magnetic resonance imaging

Proton (1H) nuclear magnetic resonance (NMR) imaging is thought to depict zones of recent myocardial infarction in contrast to noninfarcted myocardium. This is related to T2 increases in infarct zones that have been verified previously by relaxometry measurements in excised myocardial samples. Accordingly the present study was undertaken to evaluate a 1H NMR imaging method to optimize T2 contrast and measure infarct size in a high-field imaging system (1.5 T). To accomplish this, NMR images were acquired every other R wave with echo times of 30 and 100 msec. The first echo image was used for myocardial border definition and the second echo image, which highlighted the myocardial infarction, for infarct border definition. This T2-weighted approach yielded a significant correlation between infarct size by NMR and pathologic methods. However, NMR imaging tended to overestimate infarct size, and the NMR image depicted abnormal signal well beyond the extent of the pathology-determined infarct. There was a significant relationship between NMR-imaged infarct size and myocardial mass with microsphere-determined reduction in blood flow of 25% or more. These data suggest that T2-weighted NMR imaging depicts not only infarct but also some reversibly injured myocardium.

Collateral flow in patients with acute myocardial infarction

To assess the change in angiographically visualized collaterals in evolving acute myocardial infarction (AMI), coronary arteriograms from 53 patients obtained 6.2 +/- 0.2 hours after onset of AMI symptoms were compared with follow-up angiograms obtained 14 +/- 1 days later. Collaterals were graded according to intensity score and percent of distal infarct-related artery visualized. Collateral intensity score and the percent of distal infarct vessel visualized by collaterals at baseline were low, and there was a significant increase in both values at follow-up angiography. The group of 20 patients with occluded infarct vessels at follow-up study accounted for these increases. In 33 patients with patent infarct vessels at repeat angiography, collateral intensity score and percent of segment visualized were unchanged. Among the patients with occluded infarct vessels at baseline and subsequent improvement in left ventricular (LV) ejection fraction (EF), baseline collateral score and percent of segment visualized were significantly greater than in patients in whom LVEF did not improve. Thus, in patients with evolving AMI, (1) angiographically visible collaterals are not extensive within the early hours of AMI, (2) the extent of collaterals on follow-up angiography may not be representative of that on the day of AMI, (3) collaterals are considerably more common 2 weeks after AMI, especially in patients with occluded infarct arteries during follow-up, and (4) collaterals present at the time of AMI are associated with improved LVEF at 2 weeks.

Single‐Pill Therapy in the Treatment of Concomitant Hypertension and Dyslipidemia (The Amlodipine/Atorvastatin Gemini Study)

The Gemini Study was a 14‐week, open‐label, noncomparative, office‐based, multicenter trial to evaluate single‐pill therapy in the treatment of concomitant hypertension and dyslipidemia. In addition to recommending lifestyle modifications, eight dosage strengths of amlodipine/atorvastatin single pill (5/10, 5/20, 5/40, 5/80,10/10,10/20,10/40, and 10/80 mg) were electively titrated to improve blood pressure and lipid control. A total of 1220 patients with uncontrolled hypertension at baseline received study medication. At baseline, mean blood pressure was 146.6/87.9 mm Hg and mean low‐density lipoprotein cholesterol concentration was 152.9 mg/dL. At study end, 57.7% of patients had achieved both their blood pressure and low‐density lipoprotein cholesterol goals (51.9% of patients with uncontrolled low‐density lipoprotein cholesterol at baseline). The mean dose of study medication at end point was amlodipine component 7.1 mg and atorvastatin component 26.2 mg. Fifty‐eight patients (4.8%) discontinued therapy due to adverse events. Single‐pill therapy is effective in reducing both blood pressure and lipid levels and in helping patients achieve goals for both hypertension and dyslipidemia.

Monitoring the bioenergetics of cardiac allograft rejection using in vivo P-31 nuclear magnetic resonance spectroscopy

Monitoring human cardiac allograft rejection is currently accomplished by endomyocardial biopsy. Available noninvasive methods for identifying rejection have lacked the necessary sensitivity or specificity, or both, for routine clinical application. In vivo phosphorus-31 (P-31) nuclear magnetic resonance (NMR) spectroscopy has been used for monitoring phosphorus metabolism in both animal models and humans. In the present study this technique was employed as a noninvasive means to assess the bioenergetic processes that occur during cardiac allograft rejection in a rat model. Brown Norway rat hearts were transplanted subcutaneously into the anterior region of the neck of Lewis rat recipients (allografts). Control isografts employed Lewis donors and recipients. Phosphocreatine to inorganic phosphate (PCr/Pi), phosphocreatine to beta-adenosine triphosphate (PCr/ATP beta), beta-adenosine triphosphate to inorganic phosphate (ATP beta/Pi) ratios and pH of the transplanted hearts were monitored using surface coil P-31 NMR spectroscopy (at 4.7 tesla) daily for 7 days. To allow recovery from the compromise induced by the surgical procedure, the measurements obtained on day 2 were taken as a baseline. PCr/Pi was unchanged or increased in the isografts but decreased continually in allografts, with the difference becoming significant by day 4 when compared with levels in day 2 allografts (p less than 0.005) and by day 3 when compared with levels in the isograft group (p less than 0.05). PCr/ATP beta in isografts did not change throughout the study; however, allografts demonstrated a significant decrease as early as day 3 (p less than 0.01), although a significant difference between isografts and allografts did not become manifest until day 4 (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Demonstration of increased myocardial lipid with postischemic dysfunction (“Myocardial Stunning”) by proton nuclear magnetic resonance spectroscopy☆☆☆

Histopathologic studies have demonstrated accumulation of lipid droplets in myocardium subjected to greater than or equal to 6 h of ischemic insult. Proton nuclear magnetic resonance (NMR) spectroscopy can provide a noninvasive means to evaluate changes in tissue lipid and, potentially, to characterize the ischemic insult. To determine whether lipids accumulate with a brief ischemic insult, myocardial lipid content was evaluated by 1H NMR spectroscopy of ex-vivo samples from seven dogs in a model of postischemic dysfunction created by 15 min of left anterior descending coronary artery occlusion followed by 3 h of reperfusion. Regional myocardial function was assessed by measuring segment length shortening with use of a pair of ultrasonic crystals placed in the ischemic zone and in the control zone. During the occlusion, all dogs had significant ischemia of the occlusion zone as measured by radiolabeled microspheres (0.08 +/- 0.08 versus 0.88 +/- 0.09 ml/g per min for the control zone), and all dogs developed systolic stretching of the ischemic zone segment. Myocardial lipid content was significantly elevated in the samples from the coronary occlusion zone (p less than 0.02). The increase in lipid signal may result from the ischemia-induced decrease in beta oxidation and resultant accumulation of fatty acyl esters (for example, fatty acids, triglycerides and acylcarnitines). In conclusion, this study shows that myocardium subjected to a brief (approximately 15 min) coronary occlusion followed by 3 h of reperfusion demonstrates a significant increase in NMR-detectable lipid content.

Proton nuclear magnetic resonance relaxation times in severe myocardial ischemia

Contrast produced by differences in regional proton relaxation times (T1 and T2) provides the potential to assess the extent of myocardial infarction using nuclear magnetic resonance (NMR) imaging. Previous laboratory studies have shown that longitudinal (T1) and transverse (T2) relaxation times are prolonged in acute myocardial infarction, and these prolongations have been attributed entirely to increases in tissue water content. The present study seeks to evaluate the relation between both T1 and T2 and regional myocardial perfusion and water content throughout a wide range of blood flow reduction. The left anterior descending coronary artery and collateral vessels supplying a region of the anterior wall of the left ventricle were ligated in 10 dogs for 4 hours until they were killed. Both water proton and bulk proton relaxation times of myocardial samples from ischemic and control zones were measured at 200 and 20 MHz, respectively. Regions of severe ischemia (flow less than 5% of control) demonstrated no significant alteration in T1 compared with nonischemic myocardium. Greatest T1 and T2 elevations were observed in moderately ischemic myocardium (flow = 5 to 50% of control). The water relaxation behavior differed with the severity of the flow reduction and was not totally dependent on changes in water content. These data suggest that relaxation time alterations are more complex than previously reported in myocardial ischemic insult. In the future, using T1 weighted imaging methods, myocardial ischemic insults associated with severe reductions in blood flow would be anticipated to demonstrate a doughnut pattern with an area of abnormal intensity in the peripheral zone surrounding a central ischemic zone with normal intensity.

Heparin and Infarct Coronary Artery Patency After Streptokinase in Acute Myocardial Infarction

Anticoagulant therapy is frequently used after thrombolytic agents in the treatment of acute myocardial infarction (AMI) although it is unclear that such therapy will prevent subsequent infarct vessel reocclusion. The role of duration of heparin therapy in maintaining infarct artery patency was studied retrospectively in 53 consecutive AMI patients who received streptokinase therapy and underwent coronary angiography acutely and at 14 +/- 1 days. Of the 39 patients with initial infarct vessel patency, patency at follow-up angiography was observed in 100% (22 of 22) of those who received greater than or equal to 4 days of intravenous heparin but in only 59% (10 of 17) of those patients who received less than 4 days of heparin (p less than 0.05). Of the 14 patients not initially recanalized after streptokinase, patent infarct-related arteries at follow-up angiography were found in 3 of 8 (38%) treated with greater than or equal to 4 days of heparin therapy but in none of the 6 patients treated for less than 4 days (difference not significant). No significant difference in hemorrhagic complications was noted between the short- and long-term heparin treatment groups. Thus, greater than or equal to 4 days of intravenous heparin therapy after successful streptokinase therapy in AMI is more effective in maintaining short-term infarct vessel patency than a shorter duration of therapy and it may maintain the short-term patency of the infarct vessel in those patients who later spontaneously recanalize.

Effects of ryanodine on contractile performance of intact length-clamped papillary muscle.

Extent, time course, and underlying mechanisms of the negative inotropic effect of ryanodine were examined in 22 length-clamped ferret right ventricular papillary muscles paced 12/min at 25° C. After 60 minutes of exposure to 5 μM ryanodine a new steady state was attained with developed forces averaging 10-15% of maximum twitch force. Ryanodine does not pharmacologically excise the sarcoplasmlc reticulum (SR) in this preparation. Ryanodine does not appreciably inhibit the ability of the SR to take up Ca2+ as evidenced by the potentiated beats obtained after a short pause that are nearly as large after ryanodine as before. On comparing equipotent beats before and after ryanodine, we found that ryanodine actually increases the rate at which Ca2+ is released during the twitch if the SR Ca2+ stores are equal or similar. The evidence for this conclusion is a larger maximum rate of tension rise and briefer time to peak tension after ryanodine. Since ryanodine increases the time that SR Ca2+ release channels are open and decreases their conductivity, it must follow that the former effect predominates over the latter in our experiments. Ryanodine increases the leakiness of the SR during diastole probably by inhibiting closure of SR Ca2+ release channels. The evidence for this conclusion is as follows: the early peak of the restitution curves after ryanodine, the brevity of the time required for a rested state contraction after ryanodine, and the small amplitude of the steady-state contraction at a rate of 12/min. The SR leaks even in the absence of ryanodine, but if external Ca2+ is so high that Ca1+ loss from the cell is slowed or a Ca2+ leak into the cell through the sarcolcmma cancels the SR leak, then the effects of the SR leak are minimized. The evidence for this conclusion is the time required for rested-state contraction to occur or the slope of the descending limb of restitution curve; however, in presence of ryanodine even high external Ca2+ cannot prevent rapid depletion of SR Ca2+ stores. Even though we have presented evidence for a mechanism whereby ryanodine increases the number of open SR Ca release channels in both systole and diastole, we do not mean to imply that most of them stay open in diastole; the SR would leak too fast to accumulate any Ca for the potentiated beat. Thus, probably most channels close after being open a certain length of time, even in the presence of ryanodine.

Mechanism of additive effects of digoxin and quinidine on contractility in isolated cardiac muscle

To evaluate the mechanism of the effect of the interaction of digoxin and quinidine on myocardial contractility, ferret right ventricular papillary muscles were isolated and the effects of digoxin, 4 x 10(-7) M, quinidine, 1 x 10(5) M and atropine, 1.5 x 10(-6) M, on peak developed force, peak rate of development of force (dF/dt) and time to peak tension were determined. The addition of quinidine to muscles treated with digoxin increased developed force 18 percent (p = 0.006) and dF/dt 35 percent (p = 0.001) without significantly changing time to peak tension. This effect was abolished by pretreatment with atropine. Quinidine alone increased developed force 35 percent (p less than 0.001) and dF/dt 70 percent (p less than 0.001) and decreased time to peak tension 22 percent (p less than 0.001) from pretreatment control values. Atropine alone increased developed force 17 percent (p = 0.02) and dF/dt 32 percent (p = 0.001) and decreased time to peak tension 13 percent (p = 0.003) from pretreatment control values. The addition of quinidine to muscles treated with atropine or of atropine to muscles treated with quinidine did not significantly change developed force, dF/dt or time to peak tension from values with either drug alone. It is concluded that digoxin and quinidine in these doses have additive effects of myocardial contractility, and that this interaction is at least partially mediated through antagonism of cholinergic influences by quinidine.

Potential approaches to evaluating the cardiovascular system using NMR

The current status and some of the future possibilities for nuclear magnetic resonance imaging of the cardiovascular system have been described. With many of these possibilities there is overlap with existing techniques. For example, functional analysis of the left ventricle can be obtained using either echocardiography or radionuclide techniques. With current instrumentation and current costs, these conventional techniques could frequently provide a more cost-effective approach for morphologic and functional assessment of the cardiovascular system. Nevertheless, because of the excellent resolution, the inherent contrast, the sensitivity to blood motion, the three-dimensional nature, and the lack of ionizing radiation, the cardiovascular morphologic imaging capabilities of NMR may provide justification for such applications. However, for NMR to achieve its most important status as a cardiovascular imaging technique, some of its unique possibilities will need to be developed. These include the ability to reproducibly depict the proximal coronary arteries, to define regional myocardial blood flow distribution, to evaluate regional high energy phosphate or other metabolic activity; and to characterize myocardial disease using proton T1 and T2 alterations.