Kesavan Shan

Basic mechanisms in heart failure: The cytokine hypothesis*

Although the development and progression of heart failure have traditionally been viewed as hemodynamic disorders, there is now an increasing awareness that the syndrome of heart failure cannot be simply and/or precisely defined solely in hemodynamic terms. The inability of the so-called hemodynamic hypothesis to explain the progression of heart failure has given rise to the notion that heart failure may progress as a result of the overexpression of an ensemble of biologically active molecules referred to generically as neurohormones. More recently, it has become apparent that in addition to neurohormones, another portfolio of biologically active molecules, termed cytokines, are also expressed in the setting of heart failure. This article reviews recent clinical and experimental material that suggests that the cytokines, much like the neurohormones, may represent another class of biologically active molecules that are responsible for the development and progression of heart failure.

Relation of tissue Doppler derived myocardial velocities to myocardial structure and beta-adrenergic receptor density in humans.

OBJECTIVES We sought to evaluate the relation of segmental tissue Doppler (TD) velocities to both the regional amount of interstitial fibrosis and the myocyte beta-adrenergic receptor density in humans. BACKGROUND The systolic myocardial velocity (Sm) and early diastolic myocardial velocity (Em) acquired by TD are promising new indexes of left ventricular function. However, their structural and functional correlates in humans are still unknown. METHODS Ten patients with coronary artery disease underwent echocardiographic examination including TD imaging, along with transmural endomyocardial biopsy at the time of coronary bypass surgery (two biopsies per patient for a total of 20 specimens). The specimens were analyzed for percent interstitial fibrosis and beta-adrenergic receptor density. RESULTS Normal segments (n = 8) had a higher beta-adrenoceptor density (2,280 +/- 738 vs. 1,373 +/- 460, p = 0.03) and a lower amount of interstitial fibrosis (13 +/- 3.3% vs. 28 +/- 11.5%, p = 0.002) than dysfunctional segments (n = 12). Myocardial systolic velocity and Em were also significantly higher (9.5 +/- 2.7 vs. 5.9 +/- 1.8 cm/s, p = 0.025 and 11.3 +/- 2.8 vs. 6.4 +/- 2.1 cm/s, p = 0.002, respectively) in normal segments. A significant relationship was present between Em and the beta-adrenergic receptor density (r = 0.78, p < 0.001) and percent interstitial fibrosis (r = -0.7, p = 0.0026), which together accounted for 81% of the variance observed in Em. Likewise, a significant relationship was present between Sm and the beta-adrenergic receptor density (r = 0.68, p < 0.001) and the percent interstitial fibrosis (r = -0.66, p = 0.004) and together accounted for 62% of the variance observed in Sm. CONCLUSIONS Systolic myocardial velocity and Em are strongly dependent on both the number of myocytes and the myocardial beta-adrenergic receptor density.

Role of MRI in clinical cardiology

Rapid progress has been made in cardiac MRI (CMRI) over the past decade, which has firmly established it as a reliable and clinically important technique for assessment of cardiac structure, function, perfusion, and myocardial viability. Its versatility and accuracy is unmatched by any other individual imaging modality. CMRI is non-invasive and has high spatial resolution and avoids use of potentially nephrotoxic contrast agent or radiation. It has been extensively studied against other established non-invasive imaging modalities and has been shown to be superior in many scenarios, particularly with respect to assessment of cardiac and great vessel morphology and left ventricular function. Furthermore, its clinical use continues to expand with increasing experience and proliferation of CMRI centres. As worldwide prevalence of cardiovascular disease continues to rise, CMRI provides opportunity for improved and cost-effective non-invasive assessment. Continued progress in CMRI technology promises to further widen its clinical application in coronary imaging, myocardial perfusion, comprehensive assessment of valves, and plaque characterisation.

Role of Cardiac Magnetic Resonance Imaging in the Assessment of Myocardial Viability

Dysfunctional myocardium that remains viable has the potential for contractile recovery after reperfusion.1 Dysfunctional but viable myocardium has been broadly divided into 2 closely linked pathophysiological states, myocardial hibernation and stunning. Stunned myocardium is the result of an ischemic insult leading to contractile dysfunction despite adequate reperfusion. Hibernating myocardium describes downregulation of myocyte metabolism as a result of prolonged reduction in perfusion, or, in some cases, repetitive episodes of myocardial stunning.2 The exact nature of structural changes in hibernating myocardium remains controversial.3 However, a spectrum of histological alterations has been noted, ranging from cellular dedifferentiation (fetal phenotype) to cellular degeneration (with more extensive fibrosis) with loss of contractile and cytoskeletal proteins. Worsening histological perturbations correlate with increasing duration of chronically low perfusion. Thus, accurate and early detection of viable myocardium has become an increasingly important guide to prognosis and therapy. Until recently, scintigraphic techniques and stress echocardiography were the mainstay of diagnosis.4,5 The focus of the present article is on the rapidly emerging clinical role of cardiovascular MRI (CMR) in the detection of viable myocardium. In patients with chronic ischemic left ventricular dysfunction, improvements in ejection fraction and exercise capacity after revascularization have been well documented.6–10 The prognostic importance of detecting myocardial viability hinges on 2 major considerations. First, medically treated viable myocardium is a harbinger of further nonfatal ischemic events and higher overall mortality. In patients with significant viable myocardium, the annual mortality rate is more than 4-fold greater in those treated medically compared with those patients who have had successful revascularization.11 Second, discrimination between viable and nonviable dysfunctional myocardium allows patients to avoid the risks associated with revascularization when they are unlikely to benefit. Although limited by the lack of large randomized studies, a recent meta-analysis indicated that the annual mortality rate …

Identification of Hibernating Myocardium With Quantitative Intravenous Myocardial Contrast Echocardiography Comparison With Dobutamine Echocardiography and Thallium-201 Scintigraphy

Background—There are currently no data on the accuracy of intravenous myocardial contrast echocardiography (MCE) in detecting myocardial hibernation in man and its comparative accuracy to dobutamine echocardiography (DE) or thallium 201 (Tl201) scintigraphy. Methods and Results—Twenty patients with coronary artery disease and ventricular dysfunction underwent MCE 1 to 5 days before bypass surgery and repeat echocardiography at 3 to 4 months. Patients also underwent DE (n=18) and rest-redistribution Tl201 tomography (n=16) before revascularization. MCE was performed using continuous Optison infusion (12 to 16 cc/h) with intermittent pulse inversion harmonics and incremental triggering (1:1 to 1:8). Myocardial contrast intensity (MCI) replenishment curves were constructed to derive quantitative MCE indices of blood velocity and flow. Recovery of function occurred in 38% of dysfunctional segments. MCE parameters of perfusion in hibernating myocardium were similar to segments with normal function and higher than dysfunctional myocardium without recovery of function (P <0.001). The best MCE parameter for predicting functional recovery was Peak MCI×&bgr;, an index of myocardial blood flow (area under the curve, 0.83). MCE parameters were higher in segments with contractile reserve and Tl201 uptake ≥60% (P <0.05) and identified viable segments without contractile reserve by DE. The sensitivity of Peak MCI×&bgr; >1.5 dB/s for recovery of function was 90% and was similar to Tl201 scintigraphy (92%) and any contractile reserve (80%); specificity was higher than for Tl201 and DE (63%, 45%, and 54%, respectively;P <0.05). Conclusions—MCE with intravenous contrast identifies myocardial hibernation in humans. Prediction of viable myocardium with MCE is best using quantification of myocardial blood flow and provides improved accuracy compared with DE and Tl201 scintigraphy.

The role of cytokines in disease progression in heart failure.

Recent studies have identified the importance of biologically active molecules such as neurohormones as mediators of disease progression in heart failure. More recently it has become apparent that in addition to neurohormones, another portfolio of biologically active molecules, termed cytokines, are also expressed in the setting of heart failure. This article reviews recent clinical and experimental material that suggests that the cytokines, much like the neurohormones, may represent another class of biologically active molecules that are responsible for the development and progression of heart failure.

Microvascular Structural Correlates of Myocardial Contrast Echocardiography in Patients With Coronary Artery Disease and Left Ventricular Dysfunction Implications for the Assessment of Myocardial Hibernation

Background—Myocardial contrast echocardiography (MCE) has been used to evaluate myocardial viability. There are no data, however, on the pathological determinants of myocardial perfusion by MCE in humans and the implications of such determinants. Methods and Results—MCE was performed in 20 patients with coronary artery disease and ventricular dysfunction within 24 hours before myocardial biopsy at surgery using a continuous Optison infusion (12 to 16 cc/h), with intermittent pulse inversion harmonics and incremental triggering. Peak myocardial contrast intensity (MCI) and the rate of increase in MCI (&bgr;) were quantitated. Thirty-six transmural myocardial biopsies (2 per patient) were obtained by transesophageal echocardiography. Total microvascular (<100 &mgr;m) density, capillary density and area, arteriolar and venular density, and percent collagen content were quantitated with immunohistochemistry. Peak MCI correlated with microvascular density (r =0.59, P <0.001) and capillary area (r =0.64, P <0.001) and inversely correlated with percent collagen content (r =−0.45, P =<0.01). The best relation was observed when the ratio of peak MCI in the 2 biopsied segments in each patient was compared with the ratio of microvascular density and capillary area (r =0.84 and 0.87, respectively;P <0.001). A significant overlap in microvascular density was seen between segments with and without recovery of function. The new MCE indices of blood velocity (&bgr;) and flow (peak MCI×&bgr;) better identified recovery of function compared with microvascular density and the sole use of peak MCI. Conclusions—Microvascular integrity is a significant determinant of maximal MCI in humans. MCE indices of blood velocity and flow are important parameters that predict recovery of function after revascularization.

Active interstitial remodeling: an important process in the hibernating human myocardium

OBJECTIVES The purpose of this study is to investigate the morphologic characteristics of the cardiac interstitium in the hibernating human myocardium and evaluate whether active remodeling is present and is an important determinant of functional recovery. BACKGROUND Myocardial hibernation is associated with structural myocardial changes, which involve both the cardiomyocytes and the cardiac interstitium. METHODS We evaluated 15 patients with coronary disease with two-dimensional echocardiography and thallium-201 ((201)Tl) tomography before coronary bypass surgery. During surgery, transmural myocardial biopsies were performed guided by transesophageal echocardiography. Myocardial biopsies were stained immunohistochemically to investigate fibroblast phenotype and examine evidence of active remodeling in the heart. RESULTS Among the 29 biopsied segments included in the study, 24 showed evidence of systolic dysfunction. The majority of dysfunctional segments (86.4%) were viable ((201)Tl uptake > or = 60%). After revascularization, 12 dysfunctional segments recovered function as assessed with an echocardiogram three months after bypass surgery. Interstitial fibroblasts expressing the embryonal isoform of smooth muscle myosin heavy chain (SMemb) were noted in dysfunctional segments, predominantly located in border areas adjacent to viable myocardial tissue. Segments with recovery had higher SMemb expression (0.46 +/- 0.16% [n = 12] vs. 0.10 +/- 0.02% [n = 12]; p < 0.05) and a higher ratio of alpha-smooth muscle actin to collagen (0.14 +/- 0.026 [n = 12] vs. 0.07 +/- 0.01 [n = 12]; p < 0.05) compared with segments without recovery, indicating fibroblast activation and higher cellularity of the fibrotic areas. In addition, interstitial deposition of the matricellular protein tenascin, a marker of active remodeling, was higher in hibernating segments than in segments with persistent dysfunction (p < 0.05), suggesting an active continuous fibrotic process. Multiple logistic regression demonstrated a significant independent association between SMemb expression and functional recovery (p < 0.01). CONCLUSIONS Fibroblast activation and expression of SMemb and tenascin provide evidence of continuous remodeling in the cardiac interstitium of the hibernating myocardium, an important predictor of recovery of function after revascularization.

Evidence for an Active Inflammatory Process in the Hibernating Human Myocardium

Myocardial hibernation refers to a state of prolonged impairment of left ventricular function in the presence of coronary artery disease, which may be reversed by revascularization. In this study we present evidence for a local inflammatory reaction in hibernating myocardial segments from patients undergoing coronary revascularization. We obtained transmural myocardial biopsies guided by transesophageal echocardiography from patients with ischemic ventricular dysfunction undergoing bypass surgery. Among the 28 biopsied segments included in the study, 23 showed evidence of systolic dysfunction. The majority of dysfunctional segments (85.7%) were viable ((201)Tl uptake >/= 60%). The samples were stained with markers for mast cells, mature resident macrophages, and the monoclonal antibody Mac387 that labels newly recruited myeloid cells. Dysfunctional segments showed more extensive fibrosis and higher macrophage density than normal segments. Among the 23 dysfunctional segments, 12 recovered function as assessed with echocardiograms 3 months after revascularization. Segments with postoperative functional recovery had comparable macrophage and mast cell density with those showing persistent dysfunction. However, biopsied segments that subsequently recovered function contained significantly higher numbers of newly recruited Mac387-positive leukocytes (18.7 +/- 3.1 cells/mm(2), n = 12 versus 8.6 +/- 0.9 cells/mm(2), n = 11; P = 0.009). In addition, monocyte chemotactic protein-1, a potent mononuclear cell chemoattractant, was predominantly expressed in segments with recovery of function. Myocardial hibernation is associated with an inflammatory response leading to active leukocyte recruitment. Dysfunctional myocardial segments that show an active inflammatory reaction have a greater potential for recovery of function after revascularization. We postulate that revascularization may promote resolution of the ongoing inflammation, preventing further tissue injury and fibrosis.

Altered Adrenergic Receptor Density in Myocardial Hibernation in Humans A Possible Mechanism of Depressed Myocardial Function

Background—Alterations in adrenergic receptor densities can potentially contribute to myocardial dysfunction. Their relevance to myocardial hibernation in humans is unknown. Methods and Results—Accordingly, 22 transmural myocardial biopsies were obtained in 11 patients with ischemic ventricular dysfunction during bypass surgery, guided by transesophageal echocardiography. Patients underwent dobutamine echocardiography (DE) and rest scintigraphic studies before revascularization and DE at 3 to 4 months. &agr;- and &bgr;-receptor density (ARD and BRD) and extent of fibrosis were quantified from the myocardial biopsies. Of the 22 segments, 16 had abnormal rest function and 6 were normal. Severely hypokinetic or akinetic segments showed a 2.4-fold increase in ARD with a concomitant 50% decrease in BRD compared with normal segments. An increase in ARD, a decrease in BRD to a lesser extent, and thus an increase in ARD/BRD ratio were seen in dysfunctional segments with contractile reserve compared with normal segments and were most pronounced in those without contractile reserve (P <0.001). Similar findings were observed if recovery of function or scintigraphic uptake was analyzed as a marker for viability. No significant relation between either ARD or BRD and percent myocardial fibrosis was noted (r =0.37 and −0.39, respectively). Conclusions—Thus, graded and reciprocal changes in &agr;- and &bgr;-adrenergic receptor densities occur in viable, hibernating myocardium and may account in part for the observed depression in resting myocardial function and preserved contractile reserve in this entity.