Steven C. Smart

Randomized Comparison of Percutaneous Repair and Surgery for Mitral Regurgitation: 5-Year Results of EVEREST II.

BACKGROUND In EVEREST II (Endovascular Valve Edge-to-Edge Repair Study), treatment of mitral regurgitation (MR) with a novel percutaneous device showed superior safety compared with surgery, but less effective reduction in MR at 1 year. OBJECTIVES This study sought to evaluate the final 5-year clinical outcomes and durability of percutaneous mitral valve (MV) repair with the MitraClip device compared with conventional MV surgery. METHODS Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the device or conventional MV surgery in a 2:1 ratio (178:80). Patients prospectively consented to 5 years of follow-up. RESULTS At 5 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the as-treated population was 44.2% versus 64.3% in the percutaneous repair and surgical groups, respectively (p = 0.01). The difference was driven by increased rates of 3+ to 4+ MR (12.3% vs. 1.8%; p = 0.02) and surgery (27.9% vs. 8.9%; p = 0.003) with percutaneous repair. After percutaneous repair, 78% of surgeries occurred within the first 6 months. Beyond 6 months, rates of surgery and moderate-to-severe MR were comparable between groups. Five-year mortality rates were 20.8% and 26.8% (p = 0.4) for percutaneous repair and surgery, respectively. In multivariable analysis, treatment strategy was not associated with survival. CONCLUSIONS Patients treated with percutaneous repair more commonly required surgery for residual MR during the first year after treatment, but between 1- and 5-year follow-up, comparably low rates of surgery for MV dysfunction with either percutaneous or surgical therapy endorse the durability of MR reduction with both repair techniques. (EVEREST II Pivotal Study High Risk Registry; NCT00209274).

Dobutamine Stress Echocardiography for Risk Stratification After Myocardial Infarction

BACKGROUND Because dobutamine stress echocardiography (DSE) provides assessment of left ventricular function and ischemia at a distance, the major determinants of adverse outcome after acute myocardial infarction (AMI), we undertook this study to determine the role of DSE in risk stratification after AMI. METHODS AND RESULTS A graded DSE in 5-minute stages was performed in 214 patients (age, 57 +/- 13 years [mean +/- SD]) at 2 to 7 days after AMI. Coronary angiography was performed in 193 patients. Follow-up data regarding major cardiac events were obtained through telephone interviews and chart reviews. All patients were followed for > or = 500 days or until a hard cardiac event occurred. The mean follow-up interval was 494 +/- 182 days after AMI. Peak heart rate and systolic blood pressure were 115 +/- 21 bpm and 135 +/- 29 mm Hg, respectively. An adverse outcome occurred in 80 of 214 patients; cardiac death occurred in 15, nonfatal AMI occurred in 15, sustained or symptomatic ventricular arrhythmia occurred in 5, congestive heart failure occurred in 14, and unstable angina occurred in 31. Significant predictors of adverse outcome by univariate analysis were prior myocardial infarction (P = .005), anterior infarction (P = .006), multivessel coronary artery disease (P < .0001), global resting left ventricular wall motion score index (P < .0001), infarction zone nonviability based on akinesis unresponsive to low-dose dobutamine (P < .0001), and ischemia/infarction at a distance (P < .0001). Furthermore, the extent of infarct zone and nonviability correlated with the severity of the cardiac event. Multivariate analysis of clinical, angiographic, and DSE variables revealed that the only independent predictors of adverse outcome were ischemia/infarction at a distance (P < .0001) and infarction zone nonviability (P < .0001). Multivessel disease identified through DSE was more predictive of adverse outcome than was angiographically determined multivessel disease. CONCLUSIONS DSE can be used to predict adverse outcomes after AMI.

Safety and Accuracy of Dobutamine-Atropine Stress Echocardiography for the Detection of Residual Stenosis of the Infarct-Related Artery and Multivessel Disease During the First Week After Acute Myocardial Infarction

BACKGROUND The safety of dobutamine-atropine echocardiography early after acute myocardial infarction is unknown. Its accuracy for the early detection of infarct artery stenosis and multivessel coronary artery disease is also unclear. The objective of the present study was to document its safety and accuracy during the first week after acute myocardial infarction. METHODS AND RESULTS Multistage dobutamine-atropine stress echocardiography was performed in 232 patients (age, 58 +/- 13 years; 58 women) at 5 +/- 2 days after acute myocardial infarction. The peak heart rate was 116 +/- 20 bpm. There were no episodes of sustained ventricular tachycardia, myocardial infarction, or death. Atropine with dobutamine was tolerated well. Coronary angiography was performed in 206 patients (89%). There were 171 patients (83%) with infarct artery stenosis of > or = 50% and 114 patients (55%) with multivessel disease. Ischemic or biphasic responses in the infarction zone were 82% (140 of 171) sensitive and 80% (28 of 35) specific for residual stenosis. Sensitivity was similar for occluded arteries (77%, 36 of 47) and patent but stenotic arteries (84%, 104 of 124). Wall motion abnormalities outside the infarction zone were specific (97%, 89 of 92) and moderately sensitive (68%, 77 of 114) for multivessel disease. The only determinant of sensitivity for residual infarct artery stenosis was improved wall motion at low dose (P < .01). The determinants of sensitivity for multivessel disease were peak heart rate and infarct size (P < .01). CONCLUSIONS Dobutamine-atropine stress echocardiography was safely used to detect residual infarct artery stenosis and multivessel disease during the first week after acute myocardial infarction. The test may be very effective for evaluating patients with acute myocardial infarction because sensitivity for residual stenosis and multivessel disease was maximal in the high-risk subsets of patients with viable, jeopardized myocardium and large infarct size.

Dobutamine-Atropine Stress Echocardiography for the Detection of Coronary Artery Disease in Patients With Left Ventricular Hypertrophy Importance of Chamber Size and Systolic Wall Stress

BACKGROUND Left ventricular hypertrophy is a heterogeneous disorder with distinct morphologies. Changes in wall thickness, left ventricular chamber diameter, and mass alter systolic wall stress of the left ventricle and may influence ischemic threshold. Thus, the goal of this study was to investigate the effect of the different patterns of left ventricular hypertrophy on the accuracy of dobutamine-atropine stress echocardiography. METHODS AND RESULTS Three-hundred eighty-six patients underwent multistage dobutamine-atropine stress echocardiography and diagnostic angiography. Echocardiograms were measured for mean and relative wall thicknesses, chamber size, left ventricular mass, and end-systolic wall stress. The patterns of ventricular hypertrophy were concentric hypertrophy (increased wall thickness and mass), eccentric hypertrophy (normal wall thickness and increased mass), and concentric remodeling (increased wall thickness and normal mass). The overall sensitivity, specificity, and accuracy of dobutamine-atropine stress echocardiography for the detection of coronary artery disease were 85%, 87%, and 86%, respectively. Increased left ventricular mass index alone did not affect accuracy. Sensitivity was markedly reduced (36%) only in those with concentric remodeling. The univariate predictors of false-negative studies were single-vessel left circumflex disease, increased wall thickness, small chamber size, hyperdynamic ejection fraction, and left ventricular concentric remodeling. Multivariate predictors were concentric remodeling (P<0.0001; odds ratio, 13.5), left ventricular ejection fraction >2 SD above normal (P<0.0001), and single-vessel left circumflex disease (P<0.0007; odds ratio, 7.6). Sensitivity was excellent in patients with small ventricles and normal wall thickness and in those with normal or large chambers regardless of wall thickness. CONCLUSIONS Dobutamine-atropine stress echocardiography is an accurate test in most patients with left ventricular hypertrophy, but it is insensitive in the small subset with concentric remodeling.

Modulation of myocardial function and [Ca2+] sensitivity by moderate hypothermia in guinea pig isolated hearts

Cardiac hypothermia alters contractility and intracellular Ca2+ concentration ([Ca2+]i) homeostasis. We examined how left ventricular pressure (LVP) is altered as a function of cytosolic [Ca2+]iover a range of extracellular CaCl2 concentration ([CaCl2]e) during perfusion of isolated, paced guinea pig hearts at 37°C, 27°C, and 17°C. Transmural LV phasic [Ca2+] was measured using the Ca2+ indicator indo 1 and calibrated (in nM) after correction was made for autofluorescence, temperature, and noncytosolic Ca2+. Noncytosolic [Ca2+]i, cytosolic diastolic and systolic [Ca2+]i, phasic [Ca2+]i, and systolic Ca2+ released per beat (area Ca2+) were plotted as a function of 0.3-4.5 mM [CaCl2]e, and indexes of contractility [LVP, maximal rates of LVP development (+dLVP/d t) and relaxation (-dLVP/d t), and the integral of the LVP curve per beat (LVParea)] were plotted as a function of [Ca2+]i. Hypothermia increased systolic [Ca2+]iand slightly changed systolic LVP but increased diastolic LVP and [Ca2+]i. The relationship of diastolic and noncytosolic [Ca2+] to [CaCl2]ewas shifted upward at 17°C and 27°C, whereas that of phasic [Ca2+]ito [CaCl2]ewas shifted upward at 17°C but not at 27°C. The relationships of phasic [Ca2+]ito developed LVP, +dLVP/d t, and LVParea were progressively reduced by hypothermia so that maximal Ca2+-activated LVP decreased and hearts were desensitized to Ca2+. Thus mild hypothermia modestly increases diastolic and noncytosolic Ca2+ with little effect on systolic Ca2+ or released (area) Ca2+, whereas moderate hypothermia markedly increases diastolic, noncytosolic, peak systolic, and released Ca2+ and results in reduced maximal Ca2+-activated LVP and myocardial sensitivity to systolic Ca2+.Cardiac hypothermia alters contractility and intracellular Ca2+ concentration ([Ca2+]i) homeostasis. We examined how left ventricular pressure (LVP) is altered as a function of cytosolic [Ca2+]i over a range of extracellular CaCl2 concentration ([CaCl2]e) during perfusion of isolated, paced guinea pig hearts at 37 degrees C, 27 degrees C, and 17 degrees C. Transmural LV phasic [Ca2+] was measured using the Ca2+ indicator indo 1 and calibrated (in nM) after correction was made for autofluorescence, temperature, and noncytosolic Ca2+. Noncytosolic [Ca2+]i, cytosolic diastolic and systolic [Ca2+]i, phasic [Ca2+]i, and systolic Ca2+ released per beat (area Ca2+) were plotted as a function of 0.3-4.5 mM [CaCl2]e, and indexes of contractility [LVP, maximal rates of LVP development (+dLVP/dt) and relaxation (-dLVP/dt), and the integral of the LVP curve per beat (LVParea)] were plotted as a function of [Ca2+]i. Hypothermia increased systolic [Ca2+]i and slightly changed systolic LVP but increased diastolic LVP and [Ca2+]i. The relationship of diastolic and noncytosolic [Ca2+] to [CaCl2]e was shifted upward at 17 degrees C and 27 degrees C, whereas that of phasic [Ca2+]) to [CaCl2]e was shifted upward at 17 degrees C but not at 27 degrees C. The relationships of phasic [Ca2+]i to developed LVP, +dLVP/dt, and LVP(area) were progressively reduced by hypothermia so that maximal Ca2+-activated LVP decreased and hearts were desensitized to Ca2+. Thus mild hypothermia modestly increases diastolic and noncytosolic Ca2+ with little effect on systolic Ca2+ or released (area) Ca2+, whereas moderate hypothermia markedly increases diastolic, noncytosolic, peak systolic, and released Ca2+ and results in reduced maximal Ca2+-activated LVP and myocardial sensitivity to systolic Ca2+.

Dobutamine-Atropine Stress Echocardiography for Risk Stratification in Patients with Chronic Left Ventricular Dysfunction

OBJECTIVE To assess the prognostic value of sustained improvement, scar and inducible ischemia with or without viability in patients with chronic left ventricular dysfunction (LVD). BACKGROUND Dobutamine-atropine stress echocardiography (DASE) accurately detects scar, reversible dysfunction and the extent of coronary artery disease in LVD. METHODS Three hundred fifty consecutive patients (age 62+/-13 years, mean+/-SD, 215 men/135 women) with moderate to severe LVD (LVEF < 40%, mean 30+/-8%) underwent DASE and were followed for > or =18 months. Dobutamine-atropine stress echocardiographic findings were classified according to sustained improvement in all vascular territories, scar, inducible ischemia (worsening wall motion at peak dose only or biphasic responses) and their extent. RESULTS Sustained improvement occurred in 83 patients (24%), scar alone in 99 (28%) and inducible ischemia in 168 (48%, with biphasic responses in 104). Ischemia was induced in all vascular territories in 26 patients. Patients with sustained improvement or scar alone were treated medically, whereas 46% (78/168) with inducible ischemia were revascularized (coronary bypass surgery, n = 67 or angioplasty, n = 11). There were 76 hard events including cardiac death in 59, nonfatal myocardial infarction in 11, and resuscitated sudden death in 6. Hard events were rare in sustained improvement (5%, 4/83), uncommon in scar (13%, 13/99) and common (p < 0.01) in medically treated patients with inducible ischemia (59%, 53/90). Cardiac deaths were especially common (p < 0.01) in patients with biphasic responses (55%, 28/51). Inducible ischemia independently predicted hard events (chi2 = 75.35, p < 0.001) along with reduced LVEF at peak dose (chi2 = 8.38, p = 0.004). Hard cardiac events were uncommon (8%, 6/78, p < 0.001) in patients with inducible ischemia who underwent early revascularization. CONCLUSIONS Inducible ischemia during DASE was the major determinant of outcome in LVD and independent of clinical data and left ventricular function. Improved wall thickening alone and scar alone predicted good outcome. Survival of patients with inducible ischemia was better after revascularization.

Reduced Cytosolic Ca2+ Loading and Improved Cardiac Function After Cardioplegic Cold Storage of Guinea Pig Isolated Hearts

BackgroundHypothermia is cardioprotective, but it causes Ca2+ loading and reduced function on rewarming. The aim was to associate changes in cytosolic Ca2+ with function in intact hearts before, during, and after cold storage with or without cardioplegia (CP). Methods and ResultsGuinea pig hearts were initially perfused at 37°C with Krebs-Ringer’s (KR) solution (in mmol/L: Ca2+ 2.5, K+ 5, Mg2+ 2.4). One group was perfused with CP solution (Ca2+ 2.5, K+ 18, Mg2+ 7.2) during cooling and storage at 3°C for 4 hours; another was perfused with KR. LV pressure (LVP), dP/dt, O2 consumption, and cardiac efficiency were monitored. Cytosolic phasic [Ca2+] was calculated from indo 1 fluorescence signals obtained at the LV free wall. Cooling with KR increased diastolic and phasic [Ca2+], whereas cooling with CP suppressed phasic [Ca2+] and reduced the rise in diastolic [Ca2+]. Reperfusion with warm KR increased phasic [Ca2+] 86% more after CP at 20 minutes and did not increase diastolic [Ca2+] at 60 minutes, compared with a 20% increase in phasic [Ca2+] after KR. During early and later reperfusion after CP, there was a 126% and 50% better return of LVP than after KR; during later reperfusion, O2 consumption was 23% higher and cardiac efficiency was 38% higher after CP than after KR. ConclusionsCP decreases the rise in cardiac diastolic [Ca2+] observed during cold storage in KR. Decreased diastolic [Ca2+] and increased systolic [Ca2+] after CP improves function on reperfusion because of reduced Ca2+ loading during and immediately after cold CP storage.

Dobutamine-Atropine Stress Echocardiography for Reversible Dysfunction During the First Week After Acute Myocardial Infarction: Limitations and Determinants of Accuracy

OBJECTIVES We sought to compare the accuracy of biphasic and ischemic responses and sustained improvement for reversible dysfunction and to identify causes of false negative and false positive findings. BACKGROUND Previous studies have shown that low dose dobutamine echocardiography was accurate for detecting reversible dysfunction after acute myocardial infarction (MI) but did not determine whether accuracy was improved by peak dose findings or influenced by the test interval or clinical or angiographic factors. METHODS Dobutamine-atropine stress echocardiography (DASE) (baseline, low dose [5 and 10 microg/kg body weight per min] and peak dose) and coronary angiography were performed in 115 patients 2 to 7 days after MI (test interval). Segmental wall thickening was analyzed according to the 16-segment model. Sustained improvement and biphasic and ischemic responses included improved wall thickening at low and peak doses, improved wall thickening at the low dose with worsening at peak dose and no change in wall thickening at the low dose with worsening at peak dose, respectively. Follow-up echocardiography was performed at 4 to 8 weeks, and reversible dysfunction was defined as improved wall thickening. RESULTS Wall thickening improved at follow-up in 305 (44%) of 688 dysfunctional segments. The test interval was 2 days in 16 patients, 3 days in 24, 4 days in 24, 5 days in 12, 6 days in 16 and 7 days in 23. No change at low and peak doses accurately predicted fixed dysfunction (318 [88%] of 360 segments), especially in akinetic and dyskinetic segments (276 [91%] of 303), irrespective of the test interval or clinical and angiographic factors. Ischemic segmental responses also predicted fixed dysfunction (63% [12 of 19 patients]), especially in medically treated compared with revascularized patients (100% [8 of 8] vs. 36% [4 of 11], p = 0.013). Both biphasic responses and sustained improvement (77% [179 of 231 segments] vs. 87% [84 of 97], p = 0.082) were highly predictive of reversible dysfunction, especially in akinetic segments, irrespective of the test interval or clinical and angiographic factors. The only limitation was reduced accuracy (77% [177 of 222 segments], p < 0.001) due to false positive results (16%) in hypokinetic segments. CONCLUSIONS No change and ischemic responses during DASE were specific for fixed dysfunction. Improved wall thickening at the low dose, irrespective of changes at peak dose, was highly predictive of reversible dysfunction. Accuracy was only limited by false positive results in hypokinetic segments and not by the test interval or clinical or angiographic factors.

Differential roles of myocardial Ca2+ channels and Na+/Ca2+ exchange in myocardial reperfusion injury in open chest dogs: relative roles during ischemia and reperfusion.

OBJECTIVE Compare the roles of Ca2+ channels and Na+/Ca2+ exchange in reperfusion injury (reperfusion ventricular fibrillation and myocardial stunning). METHODS Open chest dogs undergoing 15 minutes of left anterior descending coronary artery occlusion and 3 hours of reperfusion were randomized to controls or intracoronary infusions of the respective antagonists, nifedipine (50 micrograms/min) or amiloride (5 mg/min), according to five protocols: (A) 40 minutes before occlusion to 30 minutes after reperfusion; (B) 2 minutes before to 5 minutes after reperfusion; (C) 10 minutes before to 10 minutes after reperfusion (two step infusion for nifedipine only 5 micrograms/min during occlusion and 50 micrograms/min after reperfusion); and (D) 0 to 30 minutes after reperfusion. The role of Ca2+ channels was further investigated by infusing the agonist, Bay K 8644 (50 micrograms/min), alone or simultaneously with any protocol B, C, or D infusions altering both reperfusion ventricular fibrillation and myocardial stunning. RESULTS Effects of the agents on injury did not result from hemodynamic effects or alterations in blood flow. Amiloride had no effect on ventricular fibrillation. Only protocol A infusion of amiloride prevented myocardial stunning. In contrast, protocol A and B infusions of nifedipine prevented both myocardial stunning (p = ns vs. baseline, p < 0.01 vs. control) and ventricular fibrillation (0%, p < 0.01). Protocol C prevented reperfusion ventricular fibrillation, but not stunning (p = ns vs. control). Protocol D did not alter injury. Bay K 8644 co-treatment reversed the effects of Protocol B infusion of nifedipine. Ventricular fibrillation was common and postischemic function worst in dogs treated with Bay K 8644 alone (protocol B). CONCLUSION Myocardial Ca2+ channels contribute to both reperfusion ventricular fibrillation and stunning, whereas Na+/Ca2+ exchange contributes only to stunning. Inhibitors of myocardial Ca2+ channels are protective when infused in high doses just before reperfusion, whereas the efficacy of Na+/Ca2+ exchange inhibitors is dependent on pretreatment.

Injury to the Ca2+ ATPase of the sarcoplasmic reticulum in anesthetized dogs contributes to myocardial reperfusion injury

OBJECTIVE Sarcoplasmic reticulum dysfunction may contribute to calcium (Ca2+) overload during myocardial reperfusion. The aim of this study was to investigate its role in reperfusion injury. METHODS Open chest dogs undergoing 15 min of left anterior descending coronary artery occlusion and 3 h of reperfusion were randomized to intracoronary infusions of 0.9% saline, vehicle, or the Ca2+ channel antagonist, nifedipine (50 micrograms/min from 2 minutes before to 5 minutes after reperfusion). After each experiment, transmural myocardial biopsies were removed from ischemic/reperfused and nonischemic myocardium in the beating state and analyzed for (i) sarcoplasmic reticulum protein content (Ca2+ ATPase, phospholamban, and calsequestrin) by immunoblotting and (ii) Ca2+ uptake by sarcoplasmic reticulum vesicles with and without 300 micromolar ryanodine or the Ca2+ ATPase activator, antiphospholamban (2D12) antibody. RESULTS Contractile function did not recover in controls and vehicle-treated dogs after ischemia and reperfusion (mean systolic shortening, -2 +/- 2%), but completely recovered in nifedipine-treated dogs (17 +/- 2%, p = NS vs. baseline, p < 0.01 vs. control). Ventricular fibrillation occurred in 50% of controls and vehicle dogs and 0% of nifedipine-treated dogs (p < 0.01). Ca2+ uptake by the sarcoplasmic reticulum vesicles was severely reduced in ischemic/reperfused myocardium of controls and vehicle dogs (p < 0.01 vs. nonischemic). Ryanodine and the 2D12 antibody improved, but did not reverse the low Ca2+ uptake. Protein content was similar in ischemic/reperfused and nonischemic myocardium. In contrast, Ca2+ uptake and the responses to ryanodine and 2D12 antibody were normal in ischemic/reperfused myocardium from nifedipine-treated dogs. CONCLUSION Dysfunction of the sarcoplasmic reticulum Ca2+ ATPase pump correlates with reperfusion injury. Reactivation of Ca2+ channels at reperfusion contributed to Ca2+ pump dysfunction. Ca2+ pump injury may be a critical event in myocardial reperfusion injury.