Sandro Betocchi

EFFICACY OF IMPLANTABLE CARDIOVERTER-DEFIBRILLATORS FOR THE PREVENTION OF SUDDEN DEATH IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY

BACKGROUND Hypertrophic cardiomyopathy is a genetic disease associated with a risk of ventricular tachyarrhythmias and sudden death, especially in young patients. METHODS We conducted a retrospective multicenter study of the efficacy of implantable cardioverter-defibrillators in preventing sudden death in 128 patients with hypertrophic cardiomyopathy who were judged to be at high risk for sudden death. RESULTS At the time of the implantation of the defibrillator, the patients were 8 to 82 years old (mean [+/-SD], 40+/-16), and 69 patients (54 percent) were less than 41 years old. The average follow-up period was 3.1 years. Defibrillators were activated appropriately in 29 patients (23 percent), by providing defibrillation shocks or antitachycardia pacing, with the restoration of sinus rhythm; the average age at the time of the intervention was 41 years. The rate of appropriate defibrillator discharge was 7 percent per year. A total of 32 patients (25 percent) had episodes of inappropriate discharges. In the group of 43 patients who received defibrillators for secondary prevention (after cardiac arrest or sustained ventricular tachycardia), the devices were activated appropriately in 19 patients (11 percent per year). Of 85 patients who had prophylactic implants because of risk factors (i.e., for primary prevention), 10 had appropriate interventions (5 percent per year). The interval between implantation and the first appropriate discharge was highly variable but was substantially prolonged (four to nine years) in six patients. In all 21 patients with stored electrographic data and appropriate interventions, the interventions were triggered by ventricular tachycardia or fibrillation. CONCLUSIONS Ventricular tachycardia or fibrillation appears to be the principal mechanism of sudden death in patients with hypertrophic cardiomyopathy. In high-risk patients with hypertrophic cardiomyopathy, implantable defibrillators are highly effective in terminating such arrhythmias, indicating that these devices have a role in the primary and secondary prevention of sudden death.

Dobutamine Echocardiography Predicts Improvement of Hypoperfused Dysfunctional Myocardium After Revascularization in Patients With Coronary Artery Disease

BACKGROUND In patients with coronary artery disease, dysfunctional hypoperfused myocardium at rest may represent either necrotic or viable hibernating myocardium. The accuracy of inotropic stimulation in identifying hypoperfused, reversibly dysfunctional myocardium has not been extensively investigated. METHODS AND RESULTS Eighteen patients with stable chronic coronary artery disease underwent, while off drugs, quantitative 201Tl single-photon emission computed tomography after rest injection (2 to 3 mCi), two-dimensional echocardiography at rest and during dobutamine (5 to 10 micrograms/kg per minute i.v.), and radionuclide angiography. Single-photon emission computed tomography and echocardiography at rest were repeated 34 +/- 10 days after coronary revascularization, and radionuclide angiography was repeated 45 +/- 13 days after revascularization. Resting hypoperfusion was defined as 201Tl uptake < 80% of maximal activity. Systolic function was scored from 1 (normal) to 4 (dyskinesia), and functional improvement was defined as a score change > 1 grade. Of 79 dysfunctional hypoperfused segments, 48 (61%) improved function after revascularization. In 42 (88%) of these latter segments, function had improved during dobutamine. Conversely, systolic function after revascularization did not improve in 31 segments, and in 27 (87%), it had not improved during dobutamine. Functional improvement after revascularization was observed in 42 (91%) of 46 segments manifesting an improvement during dobutamine as opposed to 6 (18%) of 33 segments that did not improve during dobutamine. Resting 201Tl uptake (% of maximal activity) before revascularization (65 +/- 9%) significantly increased at follow-up in segments where function improved (70 +/- 12%, P < .005), whereas it did not change significantly in segments with unchanged systolic function after revascularization (from 57 +/- 13% to 60 +/- 17%, P = NS). In 10 patients with prerevascularization ejection fraction < 45%, left ventricular ejection fraction significantly increased from 36 +/- 7% before revascularization to 42 +/- 7% at follow-up (P < .05). CONCLUSIONS Inotropic stimulation using dobutamine echocardiography identifies hypoperfused reversibly dysfunctional myocardium. Functional improvement during dobutamine is highly predictive of improvement after revascularization.

Assessment of Myocardial Viability in Patients With Chronic Coronary Artery Disease Rest–4-Hour–24-Hour 201Tl Tomography Versus Dobutamine Echocardiography

BACKGROUND To date, late redistribution after resting 201Tl injection has not been evaluated. In addition, the concordance between resting 201Tl imaging and dobutamine echocardiography in identifying viable myocardium has not been assessed. METHODS AND RESULTS Forty patients with coronary artery disease underwent rest-4-hour-24-hour 201Tl tomography and dobutamine echocardiography (5 to 10 micrograms.kg-1.min-1). Late redistribution occurred in 46 (21%) of 219 persistent defects at 4 hours. Systolic function and contractile reserve were similar among persistent defects at 4 hours with and without late redistribution. Contractile reserve was more frequent in segments with normal 201Tl uptake (59%), completely reversible defects (53%), or mild to moderate defects at 4 hours (56%) compared with severe defects (14%; P < .02 versus all). Of 105 hypokinetic segments, 99 (94%) were viable by 201Tl, and 88 (84%) showed contractile reserve. In contrast, of 155 akinetic segments, 119 (77%) were viable by 201Tl, but only 34 (22%) had contractile reserve. Concordance between 201Tl and dobutamine was 82% in hypokinetic segments but 43% in akinetic segments. In 109 revascularized segments, positive accuracy for functional recovery was 72% for 201Tl and 92% for dobutamine, whereas negative accuracy was 100% and 65%, respectively. Sensitivity was 100% for 201Tl and 79% for dobutamine. CONCLUSIONS Late redistribution occurs in one fifth of persistent defects at 4 hours, and it does not correlate to systolic function or contractile reserve. Dobutamine and 201Tl yield concordant information in the majority of hypokinetic segments, whereas concordance is low in akinetic segments. Dobutamine demonstrates higher positive accuracy and sensitivity in predicting recovery of dysfunctional myocardium, whereas 201Tl shows higher negative predictive accuracy but reduced positive accuracy.

Myocardial Collagen Turnover in Hypertrophic Cardiomyopathy

Background—Myocardial interstitial fibrosis is a characteristic of hypertrophic cardiomyopathy (HCM). This study evaluates the collagen turnover in HCM and its impact on left ventricular (LV) diastolic function. Methods and Results—Thirty-six HCM patients and 14 sex- and age-matched controls were studied. Collagen turnover was assessed as follows. By radioimmunoassay, a byproduct of collagen III synthesis (PIIINP) and 3 peptides resulting from collagen I synthesis (PICP and PINP) and degradation (ICTP) were measured. By ELISA, matrix metalloproteinases (MMPs) were determined, as follows: active MMP-2; active MMP-9; and MMP-1 as active, free (as active MMP-1 plus its precursor), and total (as free MMP-1 plus MMP-1/tissue inhibitor complexes). Tissue inhibitor of metalloproteinases-1 (TIMP-1) was also assayed. All patients underwent echocardiography. The difference in duration between transmitral forward (A) and pulmonary venous retrograde (AR) waves (A−Ar) was considered an estimate of passive diastolic function. Furthermore, restrictive or pseudonormal LV filling patterns were considered to identify patients with passive diastolic dysfunction. Patients had higher levels of PIIINP, ICTP, MMP-2, MMP-9, and total TIMP-1 than did controls. PIIINP was inversely related to LV end-diastolic diameter. A−Ar was inversely related to PICP, PINP, and their differences with ICTP (estimates of collagen I buildup). Furthermore, A−Ar was directly related to MMP-1 and MMP-2. Conclusions—As compared with controls, collagen turnover is enhanced in HCM patients. As collagen I synthesis prevails over degradation and MMP-1 and MMP-2 are inhibited, passive diastolic dysfunction occurs in patients with HCM.

Circulating miR-29a, Among Other Up-Regulated MicroRNAs, Is the Only Biomarker for Both Hypertrophy and Fibrosis in Patients With Hypertrophic Cardiomyopathy

OBJECTIVES The purpose of this paper was to determine whether microRNAs (miRNAs) involved in myocardial remodeling were differentially expressed in the blood of hypertrophic cardiomyopathy (HCM) patients, and whether circulating miRNAs correlated with the degree of left ventricular hypertrophy and fibrosis. BACKGROUND miRNAs-small, noncoding ribonucleic acids (RNAs) that regulate gene expression by inhibiting RNA translation-modulate cellular function. Myocardial miRNAs modulate processes such as cardiomyocyte (CM) hypertrophy, excitation-contraction coupling, and apoptosis; non-CM-specific miRNAs regulate myocardial vascularization and fibrosis. Recently, the possibility that circulating miRNAs may be biomarkers of cardiovascular disease has been raised. METHODS Forty-one HCM patients were characterized with conventional transthoracic echocardiography and cardiac magnetic resonance. Peripheral plasma levels of 21 miRNAs were assessed by quantitative real-time polymerase chain reaction and were compared with levels in a control group of 41 age- and sex-matched blood donors. RESULTS Twelve miRNAs (miR-27a, -199a-5p, -26a, -145, -133a, -143, -199a-3p, -126-3p, -29a, -155, -30a, and -21) were significantly increased in HCM plasma. However, only 3 miRNAs (miR-199a-5p, -27a, and -29a) correlated with hypertrophy; more importantly, only miR-29a correlated also with fibrosis. CONCLUSIONS Our data suggest that cardiac remodeling associated with HCM determines a significant release of miRNAs into the bloodstream: the circulating levels of both cardiac- and non-cardiac-specific miRNAs are significantly increased in the plasma of HCM patients. However, correlation with left ventricular hypertrophy parameters holds true for only a few miRNAs (i.e., miR-199a-5p, -27a, and -29a), whereas only miR-29a is significantly associated with both hypertrophy and fibrosis, identifying it as a potential biomarker for myocardial remodeling assessment in HCM.

Infective Endocarditis in Hypertrophic Cardiomyopathy Prevalence, Incidence, and Indications for Antibiotic Prophylaxis

BACKGROUND The literature on infective endocarditis in hypertrophic cardiomyopathy (HCM) is virtually confined to case reports. Consequently, the risk of endocarditis in HCM remains undefined. METHODS AND RESULTS We assessed the occurrence of endocarditis in 810 HCM patients evaluated between 1970 and 1997. Endocarditis was diagnosed in 10 patients, 2 of whom were excluded from analysis of prevalence and incidence because they were referred for acute endocarditis. At first evaluation, echocardiographic features consistent with prior endocarditis were identified in 3 of 808 patients, a prevalence of 3.7 per 1000 patients (95% CI, 0.8 to 11). Of 681 patients who were followed, 5 developed endocarditis, an incidence of 1.4 per 1000 person-years (95% CI, 0.5 to 3.2); outflow obstruction was present in each of these 5 patients and was associated with the risk of endocarditis (P=0.006). In the 224 obstructive patients, incidence of endocarditis was 3.8 per 1000 person-years (95% CI, 1.6 to 8.9) and probability of endocarditis 4. 3% at 10 years. Left atrial size was also associated with the risk of endocarditis (P=0.007). In patients with both obstruction and atrial dilatation (>/=50 mm), incidence of endocarditis increased to 9.2 per 1000 person-years (95% CI, 2.5 to 23.5). Analysis of all 10 patients with endocarditis identified outflow obstruction in each and atrial dilatation in 7. CONCLUSIONS Endocarditis in HCM is virtually confined to patients with outflow obstruction and is more common in those with both obstruction and atrial dilatation. These results indicate that antibiotic prophylaxis is required only in patients with obstructive HCM.

Isovolumic relaxation period in hypertrophic cardiomyopathy: Assessment by radionuclide angiography

Left ventricular isovolumic relaxation and the relation between relaxation and filling were studied in 90 patients with hypertrophic cardiomyopathy and 29 control subjects using radionuclide angiography. The isovolumic relaxation period was determined automatically on left ventricular time-activity curves as the interval between minimal volume and onset of rapid filling. In 17 patients, M-mode echocardiography performed simultaneously with radionuclide angiography demonstrated that onset of mitral valve opening correlated well with onset of rapid filling (r = 0.84, p less than 0.001). The isovolumic relaxation period was longer in patients with hypertrophic cardiomyopathy than in control subjects (95 +/- 44 versus 50 +/- 23 ms, p less than 0.01) and was longer in patients without an outflow tract gradient at rest than in patients with a gradient (109 +/- 37 versus 86 +/- 35 ms, p less than 0.05). In these patients without obstruction, a weak linear relation between duration of the isovolumic period and peak filling rate was found (r = 0.48, p less than 0.02). Filling was impaired in patients with hypertrophic cardiomyopathy, as assessed by lower peak filling rate (3.2 +/- 1.2 versus 3.5 +/- 0.5 end-diastolic volume/s, p less than 0.05) and prolonged time to peak filling rate (185 +/- 44 versus 145 +/- 20 ms, p less than 0.01) compared with values in control subjects. The delay in time to peak filling rate was caused primarily by the prolonged isovolumic period, because the interval from onset of rapid filling to peak filling rate was similar in patients with hypertrophic cardiomyopathy and control subjects (87 +/- 31 versus 95 +/- 25 ms, NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of induced asynchrony on left ventricular diastolic function in patients with coronary artery disease

OBJECTIVES This study was designed to increase asynchrony with sequential atrioventricular (AV) pacing and to study its effects on left ventricular isovolumetric relaxation, rapid filling and stiffness. BACKGROUND Left ventricular nonuniformity is a major determinant of diastolic function. METHODS Thirteen patients with coronary artery disease were studied by simultaneous equilibrium radionuclide angiography and cardiac catheterization during atrial and AV pacing. Ejection fraction and peak filling rate were measured by radionuclide angiography. Regional analysis was obtained by analyzing time-activity curves of four left ventricular sectors; systolic and diastolic asynchrony were evaluated as the coefficient of variation of time to end-systole and, respectively, time to peak filling rate in the four sectors. Cardiac index and left ventricular pressure were measured with high fidelity catheters at cardiac catheterization. The time constant of isovolumetric relaxation was derived from left ventricular pressure. Pressure-volume loops were assembled and constants of chamber stiffness were computed. RESULTS Atrioventricular pacing led to a decrease in cardiac index (3.7 +/- 0.9 to 3.3 +/- 0.8 liters/min per m2, p = 0.01) and peak filling rate (352 +/- 125 to 287 +/- 141 ml/s, p = 0.03; 2.4 +/- 0.8 to 2.0 +/- 0.8 end-diastolic counts/s, p = 0.02; 4 +/- 1.3 to 3.2 +/- 1.0 stroke counts/s, p = 0.008). The time constant of isovolumetric relaxation increased (57 +/- 10 to 64 +/- 12 ms, p = 0.04) and the global diastolic pressure-volume relation shifted upward. CONCLUSIONS Atrioventricular pacing induces left ventricular asynchrony, which is associated with a slower rate of isovolumetric relaxation. The isovolumetric relaxation lasts after the filling phase has begun, thereby reducing the rate of rapid filling.

Resolution of Established Cardiac Hypertrophy and Fibrosis and Prevention of Systolic Dysfunction in a Transgenic Rabbit Model of Human Cardiomyopathy Through Thiol-Sensitive Mechanisms

Background— Cardiac hypertrophy, the clinical hallmark of hypertrophic cardiomyopathy (HCM), is a major determinant of morbidity and mortality not only in HCM but also in a number of cardiovascular diseases. There is no effective therapy for HCM and generally for cardiac hypertrophy. Myocardial oxidative stress and thiol-sensitive signaling molecules are implicated in pathogenesis of hypertrophy and fibrosis. We posit that treatment with N-acetylcysteine, a precursor of glutathione, the largest intracellular thiol pool against oxidative stress, could reverse cardiac hypertrophy and fibrosis in HCM. Methods and Results— We treated 2-year-old β-myosin heavy-chain Q403 transgenic rabbits with established cardiac hypertrophy and preserved systolic function with N-acetylcysteine or a placebo for 12 months (n=10 per group). Transgenic rabbits in the placebo group had cardiac hypertrophy, fibrosis, systolic dysfunction, increased oxidized to total glutathione ratio, higher levels of activated thiol-sensitive active protein kinase G, dephosphorylated nuclear factor of activated T cells (NFATc1) and phospho-p38, and reduced levels of glutathiolated cardiac α-actin. Treatment with N-acetylcysteine restored oxidized to total glutathione ratio, normalized levels of glutathiolated cardiac α-actin, reversed cardiac and myocyte hypertrophy and interstitial fibrosis, reduced the propensity for ventricular arrhythmias, prevented cardiac dysfunction, restored myocardial levels of active protein kinase G, and dephosphorylated NFATc1 and phospho-p38. Conclusions— Treatment with N-acetylcysteine, a safe prodrug against oxidation, reversed established cardiac phenotype in a transgenic rabbit model of human HCM. Because there is no effective pharmacological therapy for HCM and given that hypertrophy, fibrosis, and cardiac dysfunction are common and major predictors of clinical outcomes, the findings could have implications in various cardiovascular disorders.

Exercise capacity in hypertrophic cardiomyopathy depends on left ventricular diastolic function

Some studies have demonstrated that left ventricular (LV) diastolic function is the principal determinant of impaired exercise capacity in hypertrophic cardiomyopathy (HC). In this study we sought the capability of echocardiographic indexes of diastolic function in predicting exercise capacity in patients with HC. We studied 52 patients with HC while they were not on drugs;12 of them had LV tract obstruction at rest. Diastolic function was assessed by M-mode and Doppler echocardiography by measuring: (1) left atrial fractional shortening, and the slope of posterior aortic wall displacement during early atrial emptying on M-mode left atrial tracing; and (2) Doppler-derived transmitral and pulmonary venous flow velocity indexes. Exercise capacity was assessed by maximum oxygen consumption by cardiopulmonary test during cycloergometer upright exercise. Maximum oxygen consumption correlated with the left atrial fractional shortening (r = 0.63, p <0.001), the slope of posterior aortic wall displacement during early atrial emptying (r = 0.55, p <0.001), age (r = -0.50; p <0.001), pulmonary venous diastolic anterograde velocity (r = 0.41, p <0.01), and the systolic filling fraction (r = -0.43; p <0.01). By stepwise multiple linear regression analysis, left atrial fractional shortening and the pulmonary venous systolic filling fraction were the only determinants of the maximum oxygen consumption (multiple r = 0.70; p <0.001). Exercise capacity did not correlate with Doppler-derived transmitral indexes. Thus, in patients with HC, exercise capacity was determined by passive LV diastolic function, as assessed by the left atrial M-mode and Doppler-derived pulmonary venous flow velocities.