Mario J. Garcia

Diabetic Cardiomyopathy: Insights into Pathogenesis, Diagnostic Challenges, and Therapeutic Options

Diabetic cardiomyopathy is the presence of myocardial dysfunction in the absence of coronary artery disease and hypertension. Hyperglycemia seems to be central to the pathogenesis of diabetic cardiomyopathy and to trigger a series of maladaptive stimuli that result in myocardial fibrosis and collagen deposition. These processes are thought to be responsible for altered myocardial relaxation characteristics and manifest as diastolic dysfunction on imaging. Sophisticated imaging technologies also have permitted the detection of subtle systolic dysfunction in the diabetic myocardium. In the early stages, these changes appear reversible with tight metabolic control, but as the pathologic processes become organized, the changes are irreversible and contribute to an excess risk of heart failure among diabetic patients independently of common comorbidities, such as coronary artery disease and hypertension. Therapeutic agents specifically targeting processes that lead to these pathophysiologic changes are in the early stages of development. Although glycemic control and early administration of neurohormonal antagonists remain the cornerstones of therapeutic approaches, newer treatment targets are currently being explored.

Evaluation of pulmonary artery stiffness in pulmonary hypertension with cardiac magnetic resonance.

OBJECTIVESnThis study sought to evaluate indexes of pulmonary artery (PA) stiffness in patients with pulmonary hypertension (PH) using same-day cardiac magnetic resonance (CMR) and right heart catheterization (RHC).nnnBACKGROUNDnPulmonary artery stiffness is increased in the presence of PH, although the relationship to PH severity has not been fully characterized.nnnMETHODSnBoth CMR and RHC were performed on the same day in 94 patients with known or suspected PH. According to the RHC, patients were classified as having no PH (n = 13), exercise-induced PH (EIPH) only (n = 6), or PH at rest (n = 75). On CMR, phase-contrast images were obtained perpendicular to the pulmonary trunk. From CMR and RHC data, PA areas and indexes of stiffness (pulsatility, compliance, capacitance, distensibility, elastic modulus, and the pressure-independent stiffness index beta) were measured at rest.nnnRESULTSnAll quantified indexes showed increased PA stiffness in patients with PH at rest in comparison with those with EIPH or no PH. Despite the absence of significant differences in baseline pressures, patients with EIPH had lower median compliance and capacitance than patients with no PH: 15 (interquartile range: 9 to 19.8) mm2/mm Hg versus 8.4 (interquartile range: 6 to 10.3) mm2/mm Hg, and 5.2 (interquartile range: 4.4 to 6.3) mm3/mm Hg versus 3.7 (interquartile range: 3.1 to 4.1) mm3/mm Hg, respectively (p < 0.05). The different measurements of PA stiffness, including stiffness index beta, showed significant correlations with PA pressures (r2 = 0.27 to 0.73). Reduced PA pulsatility (<40%) detected the presence of PH at rest with a sensitivity of 93% and a specificity of 63%.nnnCONCLUSIONSnPulmonary artery stiffness increases early in the course of PH (even when PH is detectable only with exercise and before overt pressure elevations occur at rest). These observations suggest a potential contributory role of PA stiffness in the development and progression of PH.

Early Metoprolol Administration Before Coronary Reperfusion Results in Increased Myocardial Salvage Analysis of Ischemic Myocardium at Risk Using Cardiac Magnetic Resonance

Background— &bgr;-Blockers improve clinical outcome when administered early after acute myocardial infarction. However, whether &bgr;-blockers actually reduce the myocardial infarction size is still in dispute. Cardiac magnetic resonance imaging can accurately depict the left ventricular (LV) ischemic myocardium at risk (T2-weighted hyperintense region) early after myocardial infarction, as well as the extent of necrosis (delayed gadolinium enhancement). The aim of this study was to determine whether early administration of metoprolol could increase myocardial salvage, measured as the difference between the extent of myocardium at risk and myocardial necrosis. Methods and Results— Twelve Yorkshire pigs underwent a 90-minute left anterior descending coronary occlusion, followed by reperfusion. They were randomized to metoprolol (7.5 mg during myocardial infarction) or placebo. Global and regional LV function, extent of myocardium at risk, and myocardial necrosis were quantified by cardiac magnetic resonance imaging studies performed 4 and 22 days after reperfusion in 10 survivors. Despite similar extent of myocardium at risk in metoprolol- and placebo-treated pigs (30.9% of LV versus 30.6%; P=NS), metoprolol resulted in 5-fold-larger salvaged myocardium (32.4% versus 6.2% of myocardium at risk; P=0.015). The LV ejection fraction significantly improved in metoprolol-treated pigs between days 4 and 22 (37.2% versus 43.0%; P=0.037), whereas it remained unchanged in pigs treated with placebo (35.1% versus 35.0%; P=NS). The extent of myocardial salvage was related directly to LV ejection fraction improvement (P=0.031) and regional LV wall motion recovery (P=0.039) at day 22. Conclusions— Early metoprolol administration during acute coronary occlusion increases myocardial salvage. The extent of myocardial salvage, measured as the difference between myocardium at risk and myocardial necrosis, was associated with regional and global LV motion improvement.

Influence of Concentric Left Ventricular Remodeling on Early Mortality After Aortic Valve Replacement

BACKGROUNDnSevere left ventricular (LV) hypertrophy increases risk for adverse outcome after aortic valve replacement. Whether LV geometry influences mortality risk after aortic valve replacement is unclear. And, whether LV mass or relative wall thickness (RWT) better predicts risk for adverse postoperative outcomes is unknown. The purpose of this investigation was to examine the influence of LV geometry and LV hypertrophy on morbidity and in-hospital mortality after aortic valve replacement, and to determine whether LV mass or RWT had better prognostic ability.nnnMETHODSnBetween January 1996 and June 2004, 5,083 patients underwent aortic valve replacement. Preoperative echocardiographic data was used to calculate LV mass and RWT. Left ventricular geometry was classified into one of four categories on the basis of LV mass indexed to body height and RWT: (1) concentric hypertrophy, (2) eccentric hypertrophy, (3) concentric remodeling, and (4) normal. Postoperative mortality and multisystem morbidities of patients with concentric geometries were compared to patients with nonconcentric geometries by propensity and logistic regression modeling. Also, prognostic ability of RWT and LV mass was compared.nnnRESULTSnNine hundred sixty-four patients with concentric geometry were propensity-matched to 964 patients with nonconcentric geometry. In-hospital mortality (38 [3.9%] versus 18 [1.9%]; p = 0.007), cardiac morbidity (33 [3.4%] versus 17 [1.8%]; p = 0.022), and prolonged intubation (85 [8.8%] versus 58 [6.0%]; p = 0.019) were higher in patients with concentric versus nonconcentric geometry. Increasing RWT, not LV mass, was associated with adverse outcomes.nnnCONCLUSIONSnConcentric geometries are associated with increased risk for in-hospital mortality after aortic valve replacement. Increased RWT is associated with adverse outcomes. Preoperative risk stratification should include assessments of LV hypertrophy and LV geometry.

Outcomes of patients with stable heart failure undergoing elective noncardiac surgery.

OBJECTIVEnTo evaluate modern surgical outcomes in patients with stable heart failure undergoing elective major noncardiac surgery and to compare the experience of patients with heart failure who have reduced vs preserved left ventricular ejection fraction (EF).nnnPATIENTS AND METHODSnWe retrospectively studied 557 consecutive patients with heart failure (192 EF less than or equal to 40% and 365 EF greater than 40%) and 10,583 controls who underwent systematic evaluation by hospitalists in a preoperative clinic before having major elective noncardiac surgery between January 1, 2003, and March 31, 2006. We examined outcomes in the entire cohort and in propensity-matched case-control groups.nnnRESULTSnUnadjusted 1-month postoperative mortality in patients with both types of heart failure vs controls was 1.3% vs 0.4% (P equals .009), but this difference was not significant in propensity-matched groups (P equals .09). Unadjusted differences in mean hospital length of stay among heart failure patients vs controls (5.7 vs 4.3 days; P less than .001) and 1-month readmission (17.8% vs 8.5%; P less than .001) were also markedly attenuated in propensity-matched groups. Crude 1-year hazard ratios for mortality were 1.71 (95% confidence interval [CI], 1.5-2.0) for both types of heart failure, 2.1 (95% CI, 1.7-2.6) in patients with heart failure who had EF less than or equal to 40%, and 1.4 (95% CI, 1.2-1.8) in those who had EF greater than 40% (P less than .01 for all 3 comparisons); however, the differences were not significant in propensity-matched groups (P equals .43).nnnCONCLUSIONnPatients with clinically stable heart failure did not have high perioperative mortality rates in association with elective major noncardiac surgery, but they were more likely than patients without heart failure to have longer hospital stays, were more likely to require hospital readmission, and had a substantial long-term mortality rate.

Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model

AIMSnAortic stenosis (AS) is associated with significant morbidity and mortality. Recombinant apolipoprotein A-I Milano (rApoA-I(M)) induces atherosclerotic plaque regression. The aims of this study were to determine the effects of rApoA-I(M) on experimental aortic valve degeneration and its mechanisms of action.nnnMETHODS AND RESULTSnNew Zealand White rabbits (n = 20) were fed an atherogenic diet for 9 months and then randomized to either placebo or rApoA-I(M). Echocardiography was used to assess the effect of the treatments on AS. Porcine aortic valve myofibroblasts (PAVMF) treated with oxidized low-density lipoprotein served to define the effects of rApoA-I(M) on the expression of monocyte chemoattractant protein-1 (MCP-1), nuclear factor (NF)-kappaB, and alkaline phosphatase (AP). Recombinant apolipoprotein A-I Milano increased aortic valve area (AVA) by 32% (0.25 +/- 0.05 to 0.34 +/- 0.07 cm(2), P < 0.01); whereas AVA remained unchanged in the placebo group (0.24 +/- 0.05 to 0.26 +/- 0.04 cm(2), P = 0.58). Histopathological examination of aortic valves in the rApoA-I(M) animals showed significantly less leaflet thickening, inflammation, and calcification vs. the placebo group. In vitro, rApoA-I(M) significantly inhibited MCP-1, AP, and NF-kappaB and decreased intracellular cholesterol content in PAVMF.nnnCONCLUSIONnRecombinant apolipoprotein A-I Milano treatment reverses AS in this experimental rabbit model. The beneficial effects seem to be mediated by enhanced cholesterol removal and by reduced inflammation and calcification.

Diagnosis of Atherosclerosis by Imaging

New and experimental imaging techniques are being developed that will permit better visualization and compositional characterization of atheromatous plaques. This review provides discussion of techniques that are currently used in clinical practice, as well as techniques that are investigational only, including coronary angiography, intravascular ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography, and single-photon emission computed tomography. Types of atheromatous plaque are reviewed, and the value of examining vascular calcification in risk assessment is discussed. Experimental use of these imaging techniques in animal models and in clinical studies will enhance our understanding of the development of plaque and will determine whether these techniques would be useful and practical for predicting disease course. Early detection and identification of the type of plaque that is present may generate novel opportunities for primary prevention through changes in lifestyle or even through drug therapy, especially in patients at high cardiovascular risk.

The cardioprotection granted by metoprolol is restricted to its administration prior to coronary reperfusion

BACKGROUNDnMyocardial infarct size is a strong predictor of cardiovascular events. Intravenous metoprolol before coronary reperfusion has been shown to reduce infarct size; however, it is unknown whether oral metoprolol initiated early after reperfusion, as clinical guidelines recommend, is similarly cardioprotective. We compared the extent of myocardial salvage associated with intravenous pre-reperfusion-metoprolol administration in comparison with oral post-reperfusion-metoprolol or placebo. We also studied the effect on suspected markers of reperfusion injury.nnnMETHODSnThirty Yorkshire-pigs underwent a reperfused myocardial infarction, being randomized to pre-reperfusion-metoprolol, post-reperfusion-metoprolol or placebo. Cardiac magnetic resonance imaging was performed in eighteen pigs at day 3 for the quantification of salvaged myocardium. The amounts of at-risk and infarcted myocardium were quantified using T2-weighted and post-contrast delayed enhancement imaging, respectively. Twelve animals were sacrificed after 24h for reperfusion injury analysis.nnnRESULTSnThe pre-reperfusion-metoprolol group had significantly larger salvaged myocardium than the post-reperfusion-metoprolol or the placebo groups (31 ± 4%, 13 ± 6%, and 7 ± 3% of myocardium at-risk respectively). Post-mortem analyses suggest lesser myocardial reperfusion injury in the pre-reperfusion-metoprolol in comparison with the other 2 groups (lower neutrophil infiltration, decreased myocardial apoptosis, and higher activation of the salvage-kinase phospho-Akt). Salvaged myocardium and reperfusion injury pair wise comparisons proved there were significant differences between the pre-reperfusion-metoprolol and the other 2 groups, but not among the latter two.nnnCONCLUSIONSnThe intravenous administration of metoprolol before coronary reperfusion results in larger myocardial salvage than its oral administration initiated early after reperfusion. If confirmed in the clinical setting, the timing and route of β-blocker initiation could be revisited.

Stimulating Myocardial Regeneration with Periostin Peptide in Large Mammals Improves Function Post-Myocardial Infarction but Increases Myocardial Fibrosis

Aims Mammalian myocardium has a finite but limited capacity to regenerate. Experimentally stimulating proliferation of cardiomyocytes with extracellular regeneration factors like periostin enhances cardiac repair in rodents. The aim of this study was to develop a safe method for delivering regeneration factors to the heart and to test the functional and structural effects of periostin peptide treatment in a large animal model of myocardial infarction (MI). Methods and Results We developed a controlled release system to deliver recombinant periostin peptide into the pericardial space. A single application of this method was performed two days after experimental MI in swine. Animals were randomly assigned to receive either saline or periostin peptide. Experimental groups were compared at baseline, day 2, 1 month and 3 months. Treatment with periostin peptide increased the EF from 31% to 41% and decreased by 22% the infarct size within 12 weeks. Periostin peptide-treated animals had newly formed myocardium strips within the infarct scar, leading to locally improved myocardial function. In addition the capillary density was increased in animals receiving periostin. However, periostin peptide treatment increased myocardial fibrosis in the remote region at one week and 12 weeks post-treatment. Conclusion Our study shows that myocardial regeneration through targeted peptides is possible. However, in the case of periostin the effects on cardiac fibrosis may limit its clinical application as a viable therapeutic strategy.

Accuracy of low-dose prospectively gated axial coronary CT angiography for the assessment of coronary artery stenosis in patients with stable heart rate

BACKGROUNDnDesirable methods for cardiac CT angiography would both reduce radiation exposure from cardiac CT angiography and preserve accuracy.nnnOBJECTIVESnWe assessed image quality, radiation dose, and diagnostic accuracy of a low-dose, prospectively gated axial cardiac CT angiography protocol for the evaluation of patients with suspected coronary artery disease (CAD).nnnMETHODSnFifty consecutive patients referred for diagnostic invasive coronary angiography (ICA) and with a stable heart rate < 60 beats/min after beta-blocker administration were prospectively enrolled in a single center study. Subjects underwent CT angiography with a 64-row multidetector CT scanner with a prospectively gated axial imaging protocol. If the examination was determined to be nondiagnostic, then a retrospectively gated helical scan was performed. Two reviewers independently assessed image quality and the presence of significant coronary artery stenosis (>50%).nnnRESULTSnProspectively gated CT angiography was successfully performed in 46 of 50 patients. Of 794 coronary segments, 777 were determined to be of diagnostic image quality. The overall patient-based sensitivity (95% CI), specificity, positive predictive value, negative predictive value, and accuracy for the diagnosis of significant coronary stenosis were 100% (87%-100%), 75% (53%-90%), 81% (64%-93%), 100% (81%-100%), and 88% (81%-95%), respectively. The mean effective radiation dose for CT angiography and ICA were 3.4 +/- 0.4 mSv and 6.9 +/- 0.8 mSv, respectively.nnnCONCLUSIONSnCardiac CT angiography performed in a prospectively gated axial mode with 64-row multidetector CT provides an accurate, low-dose alternative for the detection of CAD.