Fadi G. Hage

Estrogen and Mechanisms of Vascular Protection

Estrogen has antiinflammatory and vasoprotective effects when administered to young women or experimental animals that appear to be converted to proinflammatory and vasotoxic effects in older subjects, particularly those that have been hormone free for long periods. Clinical studies have raised many important questions about the vascular effects of estrogen that cannot easily be answered in human subjects. Here we review cellular/molecular mechanisms by which estrogen modulates injury-induced inflammation, growth factor expression, and oxidative stress in arteries and isolated vascular smooth muscle cells, with emphasis on the role of estrogen receptors and the nuclear factor-kappaB (NFkappaB) signaling pathway, as well as evidence that these protective mechanisms are lost in aging subjects.

The scope of coronary heart disease in patients with chronic kidney disease.

Chronic kidney disease (CKD) affects approximately 13% of the U.S. population and is associated with increased risk of cardiovascular complications. Once renal replacement therapy became available, it became apparent that the mode of death of patients with advanced CKD was more likely than not related to cardiovascular compromise. Further observation revealed that such compromise was related to myocardial disease (related to hypertension, stiff vessels, coronary heart disease, or uremic toxins). Early on, the excess of cardiovascular events was attributed to accelerated atherosclerosis, inadequate control of blood pressure, lipids, or inflammatory cytokines, or perhaps poor glycemia control. In more recent times, outcome research has given us further information that relates even lesser degrees of renal compromise to an excess of cardiovascular events in the general population and in those with already present atherosclerotic disease. As renal function deteriorates, certain physiologic changes occur (perhaps due to hemodynamic, inflammatory, or metabolic changes) that decrease oxygen-carrying capacity of the blood by virtue of anemia, make blood vessels stiffer by altering collagen or through medial calcinosis, raise the blood pressure, increase shearing stresses, or alter the constituents of atherosclerotic plaque or the balance of thrombogenesis and thrombolysis. At further levels of renal dysfunction, tangible metabolic perturbations are recognized as requiring specific therapy to reduce complications (such as for anemia and hyperparathyroidism), although outcome research to support some of our current guidelines is sorely lacking. Understanding the process by which renal dysfunction alters the prognosis of cardiac disease might lead to further methods of treatment. This review will outline the relationship of CKD to coronary heart disease with respect to the current understanding of the traditional and nontraditional risk factors, the role of various imaging modalities, and the impact of coronary revascularization on outcome.

Prognosis in the era of comparative effectiveness research: Where is nuclear cardiology now and where should it be?

In our recently published review, we inadvertently omitted references to two studies. The results do not substantially change. By adding these references (128a and 128b), we now have 5 studies instead of 3 which makes up Figure 7. Below are the references as well as a corrected Figure 7. When pooling the event-free survival from five series including a total of 4,257 patients, the overall survival was 96.5% for a normal MFR as compared to 77.7% for an abnormal MFR (Figure 7) (126-128, 128a, 128b). References

Atrial Natriuretic Peptide Dose-Dependently Inhibits Pressure Overload-Induced Cardiac Remodeling

We hypothesized that a single copy of the proatrial natriuretic peptide gene (Nppa+/−) would not be adequate to protect heterozygous mice against exaggerated cardiac hypertrophy and remodeling after pressure-overload stress. Nppa+/+, Nppa+/−, and Nppa−/− mice were subjected to sham surgery or transverse aortic constriction and fed a basal salt diet. Heart weight varied inversely with Nppa gene load by 1 week after either surgery. Fractional shortening did not differ among genotypes at baseline and fell in Nppa−/− mice only after transverse aortic constriction. There was a graded response in collagen deposition related to atrial natriuretic peptide (ANP) expression after either surgery. A robust interstitial and perivascular fibrosis was noted in Nppa−/− and Nppa+/− but not in Nppa+/+ mice after transverse aortic constriction. Our findings are consistent with a growing body of evidence that ANP is an important modulator of cardiac hypertrophy and remodeling in response to hemodynamic stress. The observation that partial ANP deficiency results in exaggerated hypertrophy and remodeling after pressure overload suggests that genetic or environmental variation in ANP levels may play a role in the development of cardiac hypertrophy, remodeling, and failure in humans.

Inhibition of transforming growth factor-β signaling induces left ventricular dilation and dysfunction in the pressure-overloaded heart

This study utilized a transgenic mouse model that expresses an inducible dominant-negative mutation of the transforming growth factor (TGF)-beta type II receptor (DnTGFbetaRII) to define the structural and functional responses of the left ventricle (LV) to pressure-overload stress in the absence of an intact TGF-beta signaling cascade. DnTGFbetaRII and nontransgenic (NTG) control mice (male, 8-10 wk) were randomized to receive Zn(2+) (25 mM ZnSO(4) in drinking H(2)O to induce DnTGFbetaRII gene expression) or control tap H(2)O and then further randomized to undergo transverse aortic constriction (TAC) or sham surgery. At 7 days post-TAC, interstitial nonmyocyte proliferation (Ki67 staining) was greatly reduced in LV of DnTGFbetaRII+Zn(2+) mice compared with the other TAC groups. At 28 and 120 days post-TAC, collagen deposition (picrosirius-red staining) in LV was attenuated in DnTGFbetaRII+Zn(2+) mice compared with the other TAC groups. LV end systolic diameter and end systolic and end diastolic volumes were markedly increased, while ejection fraction and fractional shortening were significantly decreased in TAC-DnTGFbetaRII+Zn(2+) mice compared with the other groups at 120 days post-TAC. These data indicate that interruption of TGF-beta signaling attenuates pressure-overload-induced interstitial nonmyocyte proliferation and collagen deposition and promotes LV dilation and dysfunction in the pressure-overloaded heart, thus creating a novel model of dilated cardiomyopathy.

The Value of Live/Real Time Three-Dimensional Transesophageal Echocardiography in the Assessment of Valvular Vegetations

We studied 13 patients with valvular vegetations who underwent intraoperative live/real time three‐dimensional transesophageal echocardiography (3DTEE) and real time two‐dimensional transesophageal echocardiography (2DTEE). The 3DTEE provided incremental value on top of 2DTEE in its ability to accurately identify and localize vegetations and in identifying complications of infective endocarditis such as abscesses, perforations, and ruptured chordae. By using 3DTEE, we were able to measure vegetation volumes, perforation areas, and estimate the area of the valve that is involved in the infective process. These preliminary results suggest the superiority of 3DTEE over 2DTEE in the evaluation of valvular vegetations and provide incremental knowledge that is useful to the cardiac surgeons. (ECHOCARDIOGRAPHY, Volume 26, November 2009)

Safety of Regadenoson in Patients with End-Stage Renal Disease

Regadenoson is a selective A(2A) receptor agonist that was recently approved by the Food and Drug Administration for vasodilator stress myocardial perfusion imaging. Because the drug is cleared by renal excretion, its safety in patients with end-stage renal disease (ESRD) needs to be determined. We studied 277 consecutive patients with ESRD who had undergone regadenoson stress gated single photon emission computed tomography myocardial perfusion imaging and compared their side effect profile and safety outcome to those of 134 patients with normal kidney function. The ESRD group included 164 men (59%) and the control group included 73 men (54%; p = NS). The patients with ESRD were younger than the controls (52 +/- 11 years vs 61 +/- 12 years; p <0.001). The myocardial perfusion imaging findings were abnormal in 53 patients (19%) with ESRD and in 24 patients in the control group (18%; p = NS). The left ventricular ejection fraction was 57 +/- 12% in the ESRD group and 64 +/- 12% in the control group (p <0.001). The changes in heart rate and systolic blood pressure (from baseline to peak stress) were 20 +/- 12 beats/min versus 22 +/- 13 beats/min and -11 +/- 24 mm Hg versus -12 +/- 23 mm Hg in the ESRD and control groups, respectively (p = NS for both). Very few patients in either group reported symptoms during the stress test. No medication-related hospitalizations, serious events, or death occurred in either group within 30 days of the study. In conclusion, this is the first study to document the safety of regadenoson in a large number of patients with ESRD. The drug was well tolerated, and the hemodynamic and side effect profiles were similar to those of patients with normal renal function.

Serial Myocardial Perfusion Imaging: Defining a Significant Change and Targeting Management Decisions

Myocardial perfusion imaging (MPI) with gated single-photon emission tomography provides important information on the extent and severity of myocardial perfusion abnormalities, including myocardial ischemia. The availability of software for automated quantitative assessment of myocardial perfusion in an objective and more reproducible manner than visual assessment has allowed MPI to be particularly effective in serial evaluation. Serial testing using MPI is widely used in guiding patient care despite the lack of well-defined appropriateness use criteria. This should not be surprising because ischemic heart disease is a life-long malady subject to dynamic changes throughout its natural course and particularly following man-made interventions that may improve or worsen the disease process, such as medical therapy and coronary revascularization. Serial MPI has filled an important clinical gap by providing crucial information for managing patients with changes in clinical presentations or in anticipation of such changes in patients with stable symptoms. In the research arena, serial MPI has been widely applied in randomized controlled trials to study the impact of various medical and interventional therapies on myocardial perfusion, as well as the relative merits of new imaging procedures (hardware and/or software), radiotracers, and stressor agents. Serial testing, however, unlike initial or 1-time testing, has more stringent requirements and is subject to variability because of technical, procedural, interpretational, and biological factors. The intrinsic variability of MPI becomes important in interpreting serial tests in order to define a true change in a given patient and to guide clinical decision making. The purpose of this first comprehensive review on this subject is to illustrate where serial MPI may be useful clinically and in research studies, and to highlight strategies for addressing the various issues that are unique to serial testing in order to derive more valid and robust data from the serial scans.

QT Prolongation Is an Independent Predictor of Mortality in End-Stage Renal Disease

Coronary artery disease (CAD) is the predominant cause of sudden cardiac death in the general population, and sudden cardiac death is the leading cause of mortality in end‐stage renal disease (ESRD).

Comparison of the Prognostic Value of Normal Regadenoson With Normal Adenosine Myocardial Perfusion Imaging With Propensity Score Matching

OBJECTIVES The aim of this study was to test the hypothesis that patients with normal regadenoson myocardial perfusion imaging (MPI) have a low rate of cardiac events, similar to patients with normal adenosine MPI. BACKGROUND Regadenoson, a new selective adenosine A(2A) receptor agonist, is now a widely used stress agent for MPI. The low rate of cardiac events in patients with normal adenosine MPI is well-documented, but the prognostic implications of a normal regadenoson MPI have not been examined and compared with those with adenosine. METHODS Data on primary composite endpoint (cardiac death, myocardial infarction, and coronary revascularization) were collected for 2,000 patients (1,000 regadenoson, and 1,000 adenosine stress) with normal myocardial perfusion and left ventricular ejection fraction referred for vasodilator MPI. In addition, propensity scores were used to assemble a balanced cohort of 505 pairs of patients who were balanced on 36 baseline characteristics. RESULTS The primary endpoint occurred in 21 (2.1%; 1.1%/year) patients in the regadenoson group and 33 (3.3%; 1.7%/year) patients in the adenosine group (hazard ratio [HR] for regadenoson vs. adenosine: 0.62; 95% confidence interval [CI]: 0.36 to 1.08; p = 0.090). In the propensity-matched pairs, the primary endpoint occurred in 7 (1.4%; 0.7%/year) patients in the regadenoson group and 13 (2.6%; 1.3%/year) patients in the adenosine group (matched HR: 0.58; 95% CI: 0.23 to 1.48; p = 0.257). Cardiac deaths were infrequent in the entire sample and in the propensity-matched groups; the cardiac death rate was 0.9%/year and 1.15%/year in the regadenoson and adenosine groups (HR: 0.77; 95% CI: 0.42 to 1.43; p = 0.404) in the pre-match sample and 0.5%/year and 0.7%/year in the matched groups, respectively (HR: 0.83; 95% CI: 0.25 to 2.73; p = 0.763). CONCLUSIONS Major cardiac events are infrequent in patients with normal regadenoson MPI. These findings provide assurance that normal MPI using a simpler stress protocol with regadenoson provides prognostic data similar to normal adenosine MPI.