Ignazio Simonetti

Sequence of events in angina at rest: primary reduction in coronary flow.

To investigate the events that lead to acute myocardial ischemia we monitored continuously the ECG, the left ventricular (four patients) or aortic (two patients) pressure and the great cardiac vein oxygen saturation (CSO2S) by a fiberoptic catheter in six patients with frequent anginal attacks at rest. We recorded 137 transient ischemic episodes (10 with chest pain) characterized by ST-segment elevation in 28 episodes, depression in three episodes and by pseudonormalization of previously inverted or flat T waves in 106 episodes. The onset of electrocardiographic and hemodynamic changes was preceded by a large drop in CSO2S in all 135 episodes with ST-T changes in the anterior leads but not in two episodes with ST elevation on inferior leads. The fall in CSOS2, consistently followed by signs of left ventricular function impairment and never preceded by any detectable increase in the hemodynamic determinants of myocardial oxygen consumption, probably reflects a reduction in regional perfusion. Thus, a reduction in coronary flow may cause transient ischemia in patients with angina at rest. These episodes may be associated with variable, often minor electrocardiographic changes and occasionally with anginal pain.

Cardiac Growth Factors in Human Hypertrophy Relations With Myocardial Contractility and Wall Stress

The aim of the present study was to investigate whether and which cardiac growth factors are involved in human hypertrophy, whether growth factor synthesis is influenced by overload type and/or by the adequacy of the hypertrophy, and the relationships between cardiac growth factor formation and ventricular function. Cardiac growth factor formation was assessed by measuring aorta-coronary sinus concentration gradient in patients with isolated aortic stenosis (n=26) or regurgitation (n=15) and controls (n=12). Gene expression and cellular localization was investigated in ventricular biopsies using reverse transcriptase-polymerase chain reaction and in situ hybridization. Cardiac hypertrophy with end-systolic wall stress <90 kdyne/cm2 was associated with a selective increased formation of insulin-like growth factor (IGF)-I in aortic regurgitation and of IGF-I and endothelin (ET)-1 in aortic stenosis. mRNA levels for IGF-I and preproET-1 were elevated and mainly expressed in cardiomyocytes. At stepwise analysis, IGF-I formation was correlated to the mean velocity of circumferential fiber shortening (r=0.86, P<0.001) and ET-1 formation to relative wall thickness (r=0.82, P<0. 001). When end-systolic wall stress was >90 kdyne/cm2, IGF-I and ET-1 synthesis by cardiomyocytes was no longer detectable, and only angiotensin (Ang) II was generated, regardless of the type of overload. The mRNA level for angiotensinogen was high, and the mRNA was exclusively expressed in the interstitial cells. Ang II formation was positively correlated to end-systolic stress (r=0.89, P<0.001) and end-diastolic stress (r=0.84, P<0.001). Multivariate stepwise analysis selected end-systolic stress as the most predictive variable and left ventricular end-diastolic pressure as the independent variable for Ang II formation (r=0.93, P<0.001). In conclusion, the present results indicate that the course of human left ventricular hypertrophy is characterized by the participation of different cardiac growth factors that are selectively related both to the type of hemodynamic overload and to ventricular function.

Comparative Effects of Enalapril and Verapamil on Myocardial Blood Flow in Systemic Hypertension

BACKGROUNDnThe comparative effects of calcium channel blockers and ACE inhibitors on myocardial blood flow (MBF) in hypertensive patients after long-term treatment are still unknown.nnnMETHODS AND RESULTSnTwenty hypertensive subjects with normal coronary arteries were randomly assigned to verapamil 240 to 480 mg/d or enalapril 10 to 40 mg/d. MBF was quantified at rest, during pacing tachycardia, and after dipyridamole by positron emission tomography and 13N-ammonia before and 6 months after treatment after 1 week of pharmacological washout. In both groups, blood pressure and heart rate during flow measurements were not different before and after therapy. Before treatment, mean MBF at rest, during pacing tachycardia, and after dipyridamole infusion was similar in the two groups; however, pacing and dipyridamole flows were significantly lower than those obtained in a control group of normotensive subjects. After treatment, in the enalapril-treated patients, MBF did not change in the three study conditions. In the verapamil-treated patients, MBF did not change at rest and significantly increased during pacing and after dipyridamole. The inhomogeneity of regional MBF distribution, evaluated from the coefficient of variation, decreased at rest after both treatments and, in the enalapril group, also during pacing. No relation was found between changes in MBF and changes in left ventricular mass.nnnCONCLUSIONSnIn arterial hypertension, MBF during pacing tachycardia and after dipyridamole is impaired. Successful therapy with verapamil increases MBF response to these stimuli, independent of changes in perfusion pressure and left ventricular mass. These results suggest that verapamil directly improves coronary microcirculatory function in hypertension. Enalapril does not significantly change MBF but reduces the inhomogeneity of regional flow distribution.

Evidence for the Existence of a Functional Cardiac Renin-Angiotensin System in Humans

BACKGROUNDnThe presence of mRNA for the essential components of the renin-angiotensin system (RAS) has been found in animal and human hearts. The present study was designed to provide evidence for the existence of a (functional) cardiac RAS.nnnMETHODS AND RESULTSnTwenty-four patients with atypical chest pain undergoing coronary angiography for diagnostic purposes were investigated. The cardiac production rate of angiotensins was estimated by measurement of the cardiac extraction of 125I-angiotensin I and 125I-angiotensin II associated with the determination of endogenous angiotensins in aortic and coronary sinus blood in normal, low, or high sodium diets. In a normal sodium diet, angiotensin I and II aorta-coronary sinus gradients were tendentially negative (-1.8 +/- 2.5 and -0.9 +/- 1.7 pg/mL, respectively), and the amounts of angiotensin I and II added by cardiac tissues were 6.5 +/- 3.1 and 2.7 +/- 1.3 pg/mL, respectively. The low sodium diet caused a significant increase in both plasma renin activity (PRA) and angiotensin I concentration in aortic but not in coronary sinus blood, resulting in a more negative aorta-coronary sinus gradient (-9.7 +/- 3.1 pg/mL, P < .01). Angiotensin formation by PRA in blood during transcardiac passage increased (P < .001), whereas angiotensin I formed by cardiac tissues decreased dramatically. Accordingly, in the low sodium diet, 125I-angiotensin II extraction did not change, the cardiac fractional conversion rate of 125I-angiotensin I to 125I-angiotensin II notably decreased (P < .01), and angiotensin II formation by cardiac tissues was undetectable. The high sodium diet caused a decrease in PRA and no changes in cardiac extraction of radiolabeled angiotensins; conversely, angiotensin I formed by cardiac tissues, cardiac Ang I fractional conversion rate, and angiotensin II formed during transcardiac passage significantly (P < .01 for all) increased.nnnCONCLUSIONSnThese results provide evidence for the existence of a functional cardiac RAS independent of but related to the circulating RAS.

Transient myocardial dysfunction during pharmacologic vasodilation as an index of reduced coronary reserve: A coronary hemodynamic and echocardiographic study

Regional coronary flow reserve and regional myocardial contractility were evaluated in 29 patients after maximal pharmacologic coronary vasodilation (intravenous dipyridamole, 0.56 mg/kg body weight, administered over 4 minutes). Nineteen patients had a severe (80 to 99%) proximal and isolated stenosis of the left anterior descending coronary artery and 10 patients had normal coronary arteries; all had normal ventricular function under rest conditions. Myocardial contractility was assessed by means of continuous two-dimensional echocardiographic monitoring; coronary reserve was evaluated by coronary sinus thermodilution. After dipyridamole infusion, 9 of the 19 patients with left anterior descending artery stenosis had transient myocardial asynergy involving the septum or apex, or both (Group IA), whereas 10 patients showed no asynergy (Group IB). No impairment of contractility was observed in the 10 patients with normal coronary arteries (Group II). Coronary blood flow was measured under basal conditions and up to 10 minutes after the end of dipyridamole infusion. In patients in Group II, dipyridamole induced an increase in great cardiac vein flow of 167 +/- 68% (mean +/- SD). The 10 patients in Group IB showed a response comparable with that of the control group (Group II) (136 +/- 45% increase in great cardiac vein flow; NS versus Group II), whereas the 9 patients in Group IA had an increase of 46 +/- 30% (p less than 0.01 versus both Group IB and Group II). No significant difference was found in the angiographic severity of the stenosis expressed in terms of minimal cross-sectional area (Group IA = 0.30 +/- 0.13 mm2, Group IB = 0.34 +/- 0.18 mm2; p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Verapamil versus propranolol for angina at rest

We previously showed that verapamil is highly effective in the treatment of patients with angina at rest, in whom coronary vasospasm likely represents the primary underlying pathophysiologic mechanism. Beta-adrenergic blocking drugs, on the other hand, do not exert any vasodilating effect on large coronary arteries, and hence do not represent a rational therapeutic approach to the treatment of patients with this syndrome. n nThe present report reviews the results of three clinical trials comparing the effectiveness of verapamil and propranolol in patients with angina at rest. In 17 patients enrolled in a randomized triplecrossover study, verapamil was superior to propranolol in preventing ergonovine-induced coronary artery spasm (p < 0.001). In 18 patients with rest angina evaluated in a double-blind crossover study, both verapamil and propranolol reduced the number of episodes of angina at rest (from 3.0/day to 1.7/day with propranolol, p < 0.05, and to 0.2/day with verapamil, p < 0.001); the degree of improvement with verapamil was superior to that seen with propranolol (p < 0.005). In 10 patients with rest angina evaluated in a single-blind multiple crossover trial which assessed symptomatic and asymptomatic ischemia, the number of ischemic events was reduced significantly only by verapamil (5 ± 1 episodes/48 hours) but not by placebo or propranolol (25 ± 3 and 23 ± 3 episodes/48 hours, respectively). n nThese studies confirm the effectiveness of verapamil in the management of patients with angina at rest; in contrast, the effectiveness of propranolol in this syndrome appears comparable to that of placebo.

Long-term efficacy and safety of propafenone and sotalol for the maintenance of sinus rhythm after conversion of recurrent symptomatic atrial fibrillation

This study was performed to evaluate, using a randomized double-blind, placebo-controlled protocol, the long-term efficacy and safety of propafenone and sotalol in maintaining sinus rhythm after conversion of recurrent symptomatic atrial fibrillation (AF). The maintenance of sinus rhythm in patients with recurrent AF has several potential benefits, the most important being a reduced risk of thromboembolic events. Three hundred patients with recurrent AF (> or = 4 episodes in the last year) and AF at enrollment lasting < 48 hours were randomized to receive either propafenone (mean daily dose 13 +/- 1.5 mg/kg; 102 patients), sotalol (mean daily dose 3 +/- 0.4 mg/kg; 106 patients), or placebo (92 patients). After 1-year follow-up, Kaplan-Meier estimates of the proportion of patients remaining in sinus rhythm were comparable between propafenone (63%) and sotalol (73%) and superior to placebo (35%; p = 0.001 vs both drugs). Symptomatic recurrences occurred later with propafenone and sotalol than with placebo. Nine patients (9%) in the propafenone group, 11 (10%) in the sotalol group, and 3 (3%) in the placebo group discontinued therapy due to adverse effects. Malignant nonfatal arrhythmias due to proarrhythmic effects were documented with sotalol only, and occurred < 72 hours from the beginning of therapy in 4 patients (4%). During recurrences, the ventricular rate was significantly reduced in patients taking propafenone and sotalol (p = 0.001 for both drugs vs placebo). The likelihood of remaining in sinus rhythm during follow-up was higher in younger patients with smaller left atrial size and without concomitant heart disease. In patients with recurrent symptomatic AF, propafenone and sotalol are not significantly different from each other and are superior to placebo in maintaining sinus rhythm at 1 year. Recurrences occur later and tend to be less symptomatic with propafenone and sotalol compared with placebo.

EFFECTS OF ISCHEMIA AND REPERFUSION ON QT DISPERSION DURING CORONARY ANGIOPLASTY

The effects of ischemia and reperfusion on QT interval dispersion (QTD: QTmax‐QTmin in the 12‐lead ECG) were analyzed in 15 patients (12 males, 57 ± 13 years) undergoing coronary angiopiasty (PTCA). AH patients had single‐vessel coronary artery disease (only one ≥ 85% stenosis in a major coronary artery) and normal left ventricular function. AH were in sinus rhythm with normal atrioventricular and intraventricular conduction on the surface ECG. No patient was on therapy that could affect the QT interval. The ECG was recorded (all 12 leads simultaneously) at 50 mm/s speed before the first balloon inflation, at the end of the first inflation during PTCA, and at 30″ and 60″ during reperfusion following the first inflation. In order to avoid ischemic preconditioning, only recordings of the first inflation were used. In each tracing QTmax and QTmin were evaluated. All values were rate corrected using a simple linear equation (QT linear corrected = QT + 0.154 [1‐RR]). QTD increased significantly during both ischemia and reperfusion. QTmax was not changed by ischemia and was increased by reperfusion. QTmin was reduced by ischemia and increased by reperfusion. These results indicate that both ischemia and reperfusion alter ventricular repolarization, inducing a less homogeneous ventricular recovery pattern.

Tako-Tsubo-like syndrome during anaphylactic reaction

Tako‐Tsubos syndrome (apical ballooning or broken heart syndrome) is a reversible left ventricular dysfunction due to apical asynergy that occurs typically after sudden emotional stress in a subject without coronary disease. It is characterized by acute onset of chest pain or dyspnoea or both and is associated with electrocardiographic changes such as ST segment elevation and/or T wave inversion. Myocardial biomarkers may be normal or slightly elevated.

Prediction of functional recovery in patients with chronic coronary artery disease and left ventricular dysfunction combining the evaluation of myocardial perfusion and of contractile reserve using nitrate-enhanced technetium-99m sestamibi gated single-photon emission computed tomography and Dobutamine stress

This study aimed to assess whether contractile reserve evaluation using dobutamine gated single-photon emission computed tomography (SPECT) improves the capability of quantitative perfusion analysis to predict functional recovery of viable hibernating myocardium. Resting and dobutamine nitrate-enhanced technetium-99m sestamibi (sestamibi) gated SPECT studies were performed in patients with coronary artery disease who had left ventricular dysfunction. Tracer activity was quantified, and wall motion and thickening visually scored. Reversible dysfunction was identified with gated SPECT repeated after coronary revascularization. Using the best activity threshold, perfusion quantification achieved 85% sensitivity and 55% specificity. Contractile reserve detection was significantly less sensitive (64%, p <0.0005), but more specific (88%, p <0.00001) than perfusion quantification. However, in the subgroup of hypokinetic segments, the sensitivity of contractile reserve assessment was just slightly lower than perfusion quantification (72% vs 91%, p = NS), whereas specificity was significantly higher (94% vs 23%, p <0.00001). Conversely, in the adyskinetic segments, perfusion quantification was significantly more sensitive than contractile reserve (82% vs 59%, p <0.005), but similarly specific (76% vs 85%, p = NS). Therefore, the identification of reversible dysfunction based on perfusion quantification in adyskinetic segments and on contractile reserve detection in hypokinetic segments was significantly more specific (83% vs 55%, p <0.00001) than standard quantitative perfusion SPECT, without major loss in sensitivity (78% vs 85%, p = NS). In conclusion, contractile reserve evaluation using dobutamine gated SPECT enhances the reliability of nitrate-enhanced sestamibi SPECT when used to predict reversible dysfunction in hypokinetic segments, whereas perfusion quantification remains superior in adyskinetic segments.