INTRODUCTION
The number of seniors in the United States and throughout the developed world is rising. As of 2003, roughly 36 million, or 12%, of the U.S. population were older than 65 years of age. Improvements in nutrition, disease prevention, and treatment have all contributed to this rise, with life expectancy at birth increasing from 47.3 years in 1900 to 76.9 years in 2000. Despite declining death rates from cardiovascular disease, more seniors now are living with chronic heart conditions, including hypertension (HTN), coronary artery disease (CAD), and congestive heart failure (CHF). In fact, the primary index diagnosis for the majority of hospitalizations of seniors in the United States is now CHF. The morbidity, mortality, and financial costs of this disease are substantial in this population, with approximately 43,600 deaths (94% of total deaths from CHF) and 700,000-plus hospitalizations costing more than $20 billion per year in the United States. This epidemic is likely to worsen in the near future, as the “baby boom” generation enters its seventh decade ( Fig. 30-1 ). By 2050, the senior population is expected to top 86 million individuals, highlighting the importance of this issue.
To effectively manage this rising burden of CHF in the senior population, a better understanding of the specific cardiovascular changes that occur with senescence is necessary. Unlike younger CHF patients, who often present with depressed ventricular function and chamber dilatation due to ischemic heart disease, as many as half of the senior CHF population has no evidence of depressed ventricular function and actually has a normal ejection fraction (EF), or so-called diastolic heart failure (DHF). This chapter will address the effect of DHF in the senior population, explore the specific age-associated pathophysiological changes of the heart that may provide the substrate for the development of DHF, and finally examine the challenges involved in devising new therapies for this disorder.
PATHOPHYSIOLOGY
Clinical Presentation of Diastolic Heart Failure in the Senior Population
The clinical profile of senior heart failure patients is markedly different than that of younger patients. In 1995, Vasan et al. concluded, based on a cumulative analysis of available studies of CHF and normal left ventricular (LV) systolic function, that the prevalence of normal function in CHF patients under 65 years of age was significantly lower than that in those older than 65. More recent data support this claim. Based on population and hospitalization registry data, such as the Olmsted County experience, the Enhanced Feedback for Effective Cardiac Treatment (EFFECT) dataset from Ontario, Canada, and the Acute Decompensated Heart Failure National Registry (ADHERE), DHF is predominantly a disease of the elderly, and its prevalence is on the rise ( Fig. 30-2 ). Data from these and several other studies have demonstrated that the prototypical patient presenting with this disorder is in the seventh or eighth decade of life, female, obese, hypertensive, more often diabetic, and often afflicted with atrial fibrillation. These comorbid conditions are not simply innocent bystanders but, as will be described in this chapter, may actively contribute to the pathophysiology of DHF.
Diagnosis of Diastolic Heart Failure in the Senior Population
The diagnostic criteria for DHF have been reviewed elsewhere in this book and are no different in the senior population (see Chapter 6 ). It should be emphasized, however, that it is difficult, if not impossible, to make a diagnosis of DHF, as opposed to systolic heart failure (SHF), by history or clinical presentation alone. Patients with DHF may have higher blood pressure and more often have atrial fibrillation at the time of presentation, but these are by no means universal findings. The most recent Heart Failure Society 2006 guidelines recommend that a diagnosis of DHF “can be made by the combination of clinical signs and symptoms of CHF coupled with a preserved or relatively preserved EF.” In contrast, the 2005 guidelines from the American Heart Association/American College of Cardiology for the diagnosis and management of chronic heart failure suggest that the addition of measures of LV relaxation and LV volume are needed for a definitive diagnosis. Unfortunately, the inclusion criteria for a diagnosis of DHF and the terms “preserved” and “normal” are open to interpretation, and this uncertainty has led to significant debate and inconsistency among studies.
The vague definition of DHF is a source of much controversy in its trials. The EF used in the clinical studies, registry analyses, and population surveys has varied ( Table 30-1 ). For example, in the dataset from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) trial, of the 3023 patients with “preserved” systolic function randomized, 35% (1072 patients) had EFs of 41%-49%. These EF determinations are not absolute numbers and carry with them a margin of error. The EF measurement has a high degree of variability, depending on the specific technique used, and is subject to both intra- and interobserver variability. Using noncontrast echocardiography, for example, the variation for individual patients can be as high as 10% (EF units) compared with measurements on magnetic resonance imaging (MRI), and the intra- and interobserver variabilities can reach as high as 10%-15% (EF units). Therefore, an EF at the lower limits of what is considered normal in a clinical trial, such as 41% in the CHARM trial, could actually be significantly lower and introduce error into the dataset.
| STUDY | EF % USED AS “NORMAL” OR “PRESERVED” |
|---|---|
| Olmsted County study | ≥50 |
| ADHERE | ≥40 |
| Ancillary DIG study | ≥45 |
| CHARM-Preserved study | ≥40 |
| MISCHF registry | ≥50 |
| PEP-CHF | ≥45 |
| Yale–New Haven Experience | ≥40 |
This issue may be of particular importance in women. The Dallas Heart Study examination of MRI-derived EF in a probability-based sample of Dallas County residents aged 30 to 65 years (1435 women and 1183 men) found that women tended to have higher EFs than men ( Fig. 30-3 ). These findings persisted even when body size was taken into consideration. The authors concluded that a low EF (below the 2.5th percentile of the population sampled) was defined as below 61% in women and below 55% in men. These data suggest that an EF of 50% in women may not be normal, and an EF of 40% is certainly abnormal.
While the designation of a particular EF as “normal” is somewhat arbitrary, the use of a higher EF as the cutoff for differentiating systole versus diastole may be more helpful in limiting inclusion of patients with SHF into clinical trials. This ambiguity surrounding EF also raises the point that the actual incidence of DHF in the community may not be as high as the rates that have been previously reported. Since the prototypical patient with DHF is more often female, the growing epidemic of DHF in women may reflect inclusion of patients with occult or misclassified systolic dysfunction. The use of more rigid EF criteria in population studies may also help clarify this issue as well.
In addition to controversies regarding EF, there has been discussion in the literature as to whether Doppler velocity patterns are sufficient to diagnose DHF, or for that matter whether such measurements are even needed at all. DHF, like all forms of CHF, is a clinical diagnosis that should be supported by an objective assessment of LV systolic function. The use of Doppler echocardiography in the senior population, in particular, raises some important considerations. It is true that most, if not all, senior patients with DHF will have alterations in Doppler measures of diastolic function (diastolic dysfunction); however, these measurements should not be assumed to be specific or pathognomonic for DHF. Both completely healthy sedentary seniors and highly trained senior master athletes manifest profound changes in their Doppler patterns compared with young controls, suggesting that these alterations are a specific manifestation of normal aging ( Figs. 30-4 and 30-5 ). The master athletes, who from a symptomatic and functional standpoint are at the extreme opposite spectrum from DHF patients, have marked Doppler abnormalities despite also having peak oxygen uptakes comparable to individuals 30 years younger. Given these data, one could make the argument that the terms diastolic dysfunction and abnormal filling pattern are inexact when used in this context and should perhaps be revised. The diastolic Doppler patterns seen in the senior population are best described as normal for age, much like gray hair or wrinkling of the skin (see Appendix ).
Prognosis of Diastolic Heart Failure in the Senior Population
While slightly better than that of SHF, the short-term prognosis of patients with DHF is not benign. The mortality rate during acute hospitalization was 2.8% in ADHERE (vs. 3.9% in the SHF group). Similar to patients with SHF, patients with DHF and concomitant hypotension, hyponatremia, advanced age (>73 years), and elevated blood urea nitrogen (BUN) were at increased odds for mortality based on multivariate analysis. Notably, elevation of resting heart rate (HR) (>78 bpm) was particularly detrimental to patients with preserved function, perhaps suggesting the importance of maintaining an adequate diastolic filling period in this population.
The longer-term prognosis of patients with DHF versus SHF has been debated. These results have been conflicting, primarily because of differences in study design and inclusion of community versus clinicaltrial patient populations. Two recent studies may help shed light on this issue. The long-term survival data from the Olmsted County study are detailed in Figure 30-6A . In this study, data from 4596 consecutive patients admitted with a diagnosis of CHF were examined and segregated by EF. The mortality rate in DHF patients admitted with CHF was only slightly lower than in patients with SHF (29% vs. 32% at one year and 65% vs. 68% at 5 years). Interrogation of the EFFECT dataset from Canada, which examined similar variables in 2802 patients with a discharge diagnosis of CHF, found no statistically significant difference in adjusted mortality rates at one year (see Fig. 30-6B ). These studies suggest that the late survival in the two forms of CHF is not radically different from each other, despite very different pathophysiological mechanisms.
Etiology of Diastolic Dysfunction and Diastolic Heart Failure in the Senior Population
The cause or causes of DHF in seniors remain controversial. As the name “diastolic heart failure” implies, the long-accepted but poorly understood explanation for the etiology of this disorder has centered on impairments of lusitropic function in these patients. Recent studies have now confirmed the presence of abnormalities in active ventricular relaxation and static chamber stiffness, mostly in male patients with heart failure and a normal EF. However, our laboratory has demonstrated that even healthy sedentary aging results in marked abnormalities of these very same diastolic properties, suggesting that additional factors influence the development of DHF in seniors. What then separates a patient with DHF from an otherwise healthy sedentary adult? To answer this question, we will first examine the changes in diastolic function that occur with normal aging and then discuss the comorbid conditions that might be additive and result in heart failure.
Sedentary aging, even in the absence of comorbid conditions, results in marked changes of cardiovascular structure and function, including slowing of active myocardial relaxation and decreased static LV chamber compliance. While a detailed examination of the hemodynamic determinants of diastolic function has been reviewed in Chapters 2 , 5 , and 7 , we will examine the effects of aging on these processes in some detail.
Slowing of Myocardial Relaxation and Impairment of Ventricular Suction
There have been few invasive studies directly examining LV relaxation of the aged human heart because of the obvious ethical concerns about cardiac catheterization in normal healthy subjects. Furthermore, the few available studies have included only small numbers of seniors, making it difficult to draw definite conclusions. One of the first invasive studies to suggest a relationship between age and slowing of active myocardial relaxation was done by Hirota in 1980. He examined the time constant of LV pressure decline using micromanometer-tipped high-fidelity catheters in several groups of subjects with sufficient symptoms to warrant referral for diagnostic cardiac catheterization. His subjects included a group of 18 individuals (4 of whom were older than 60 years) whom he deemed “normal” because of an absence of LV dysfunction or CAD. In these subjects, he noted a weak but significant correlation between age and prolongation of the time constant of LV relaxation ( Fig. 30-7A ). In contrast, Yamakado et al. examined LV relaxation using similar methods and found no correlation with age and the time constants of relaxation (see Fig. 30-7B ). Unfortunately, of the 55 patients who met inclusion criteria for this study, only 9 were older than 65 years of age.
The most robust information examining the issue of aging and LV relaxation in humans comes from noninvasive data. Alterations in LV diastolic function with senescence were first hinted at by Harrison et al., who in 1964 used carotid pulse contour analysis and precordial “kinetocardiograms” (measuring chest wall motion) to suggest a prolongation of isovolumetric relaxation time in older compared with younger individuals. Subsequently, M-mode echocardiograms were examined from the Baltimore Longitudinal Study on Aging and demonstrated a reduction in the rate of mitral valve closure (E-F slope) with increasing age, also consistent with slowed relaxation. Since then, similar observations have been made by many investigators, by assessing either peak filling rates by nuclear imaging or mitral inflow patterns by Doppler echocardiography, involving many thousands of patients from diverse ethnic, geographic, and age distributions. One of the largest studies published to date, from the Cardiovascular Health Study examining more than 5000 men and women in a community-based population, confirmed that regardless of gender or the presence of specific cardiovascular diseases such as HTN or CAD, there is a progressive reduction in early filling velocity (E wave) and increase in late flow velocity (A wave) with increasing age, consistent with the pattern of impaired relaxation.
With the introduction of newer Doppler techniques as discussed in Chapters 11 and 12 , there have been additional insights into the alterations of specific components of myocardial relaxation processes with aging. Early diastolic tissue Doppler velocities, which represent longitudinal myocardial motion during active relaxation, are slower with aging. In addition, color M-mode-derived indices such as the propagation velocity of early mitral inflow (Vp) and the magnitude of early diastolic intraventricular pressure gradients (IVPGs) appear to be diminished by aging. The changes in these newer Doppler variables highlight an important characteristic of the senescent heart, namely the loss of vigorous diastolic suction. As discussed in a previous chapter of this book, diastolic suction is the result of restoring forces created during contraction to below the equilibrium volume during the prior ventricular systole (see Chapter 5 ). This stored potential energy is released during the subsequent diastolic period, actively drawing blood from the base of the heart to the apex. The magnitude of this force can be estimated by examining the pressure differences within the LV chamber itself. These IVPGs are markedly reduced during sedentary but healthy aging compared with healthy young adults ( Fig. 30-8 ). In theory, decreased suction could impair filling of a stiff noncompliant heart during conditions of rapid heart rate, orthostatic stress (as left atrial [LA] pressure is acutely lowered), or a volume challenge when the left ventricle must accommodate a large amount of blood in a relatively short time. The potential clinical effect of this loss of suction and its hemodynamic consequences in the aged population has not yet been fully examined.
Most of our knowledge of the mechanisms underlying the age-associated changes in LV relaxation comes from animal- and cell-based experimental data. Concordant with human Doppler data, invasive studies in rodents have demonstrated a reduction in the rate of LV pressure decline during early diastole (−dP/dT) and therefore prolongation of the time constant of early relaxation (Tau, τ) with normal aging. There are a variety of well-described changes that occur within the aging cardiac myocyte, resulting in alterations of both the electrical and mechanical processes underlying contraction and relaxation. Some of these changes include altered myocyte Ca 2+ handling, shifts in myosin heavy chain isoforms, and reductions of β-receptor activity. There is a large body of data, derived predominantly from rodent experiments, to support the role of changes in Ca 2+ handling as the central etiology of this process. Since sequestration of Ca 2+ occurs during the first third of diastole, it is not surprising that the Doppler measures we have described, which examine early diastolic processes, would be altered with aging.
Early diastole is very dependent on reuptake of Ca 2+ from the cytosol back into the sarcoplasmic reticulum ( Fig. 30-9 ) (see Chapter 1 ). This is an energy-dependent process requiring the activity of sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA2a) and the sarcolemmal Na + /Ca 2+ exchanger. Regulation of SERCA2a is modulated by the inhibitory subunit phospholamban. Phosphorylation of phospholamban removes inhibition of SERCA2a activity. Normal aging results in numerous changes of this Ca 2+ -regulating system, including reduced SERCA2a pumping rate, decreased SERCA2a-to-phospholamban ratio, and reduced protein levels of the sarcolemmal Na + /Ca 2+ exchanger, all of which contribute to the slowing of early relaxation. Further supporting the role of altered Ca 2+ reuptake in this regard is a series of experiments by Schmidt et al. that demonstrated restoration of Tau and −dP/dT to younger levels in senescent hearts by adenoviral gene transfer of SERCA2a, suggesting that these Ca 2+ -handling mechanisms could also be potential targets for therapeutic intervention in DHF ( Fig. 30-10 ).
Decreased Left Ventricular Compliance and Physical Deconditioning
When examining the diastolic process, not only LV relaxation but also LV compliance must be considered. Animal studies have generally suggested that the heart may stiffen with age. Sophisticated analysis of contractile performance and diastolic stiffness in older rats demonstrated prominent decreases in cardiac compliance as assessed from pressure-volume curves. Our laboratory has recently studied the effect of aging and lifelong fitness on the end diastolic pressure-volume relationship in normal healthy adults across five different levels of cardiac filling using invasive determination of pulmonary capillary wedge pressure (PCWP) and concomitant measurement of LV end diastolic volume by echocardiography ( Fig. 30-11 ). These measurements were obtained in three groups of healthy subjects that consisted of young individuals, sedentary seniors, and Masters athletes (competitive athletes over the age of 50 participating successfully in USA Masters sanctioned events, such as track and field, swimming, and cycling). Based on the data obtained from this study, normal sedentary aging results in a marked decrease of LV compliance.
When examining such data, it is important to consider the contribution of deconditioning. LV compliance is sensitive to even relatively short periods of deconditioning. For example, as little as 2 weeks of strict bed-rest deconditioning leads to a shift of the end diastolic pressure-volume relationship to the left ( Fig. 30-12 ). Normal aging alone generally leads to reductions in physical activity, in both humans and experimental animals. It is therefore crucial to ascertain whether the loss of LV compliance is specific to the aging process or is instead the result of lifelong deconditioning, which is known to increase LV stiffness. If the end diastolic pressure-volume curves for the Masters athletes in Figure 30-11 are examined, it can be seen that the loss of LV compliance in the sedentary senior group is not specific for senescence and is completely prevented by lifelong endurance exercise. It should be pointed out that these data are in marked contrast to the noninvasive data for these very same subjects, which demonstrate little if any effect of lifelong fitness on Doppler measures of relaxation (see Figs. 30-4 and 30-5 ). The discordance between the training effect on LV compliance and relaxation is best explained by the fundamental differences in cellular regulation of these two processes. LV relaxation, as controlled by Ca 2+ handling, appears to be resistant to aerobic training in many species, including humans. These particular protein alterations may be specific to the aging process and not influenced by physical activity. LV compliance is regulated by a separate set of proposed pathways, which warrant some detailed discussion.
The proposed pathophysiology of increased stiffness of the left ventricle with aging is multifactorial. Much of the focus in this field has centered on the extracellular matrix (ECM). The ECM is composed of a basement membrane and a fibrillar collagen network providing support and structural integrity to myocytes ( Fig. 30-13 ). The ECM is also highly metabolically active and serves as a source for anti-apoptotic signals and growth factors, a substrate for cell adhesion, and a determinant of myocyte mechanics. The ECM undergoes extensive turnover and remodeling. Altering the balance between collagen synthesis and degradation results in myocardial collagen accumulation, stiffening, and cardiac dysfunction. A common thread among diverse etiologies of CHF appears to be the dynamic remodeling of the ECM, which in turn results in myocardial fibrosis, impairing both ventricular relaxation and compliance.
Recently, it has been recognized that the regulation of the ECM depends on an interplay between matrix metalloproteinases (MMPs), a family of enzymes present in the myocardium and responsible for degrading the matrix components of the heart, and specific tissue inhibitors of matrix metalloproteinases (TIMPs) ( Table 30-2 ). Activity of MMPs is regulated at both pre- and posttranscriptional levels and may be modulated by inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, as well as mechanical physiological signals such as load and stretch. Increased MMP activity has been associated with LV enlargement and dilation, and inhibiting these enzymes limits the severity of pacing-induced CHF in pigs.
| ENZYME | MMP | ENZYME (KDA LATENT/ACTIVE) | SUBSTRATE | REMODELING * |
|---|---|---|---|---|
| Collagenases | MMP-1 | Interstitial collagenase (52/42) | Collagen type I, II, III, VII, and X; gelatins; proteoglycans; entactin | + |
| MMP-8 | Neutrophil collagenase (85/64) | Collagen type I, II, and III | + | |
| MMP-13 | Collagenase-3 (52/42) | Collagen type I, II, and III | + | |
| Gelatinases | MMP-2 | Gelatinase A (72/66), type IV collagenase | Gelatins (type I), collagen type I, II, III, IV, V, VII, and XI; fibronectin; laminin; elastin; proteoglycans | + |
| MMP-9 | Gelatinase B (92/84), type V collagenase | Gelatins (type I and V), collagen type I, II, III, IV, V, and VII; elastin; entactin; proteoglycans | + | |
| Stromelysins | MMP-3 | Stromelysin 1 (57/45) | Gelatins (type I, III, IV, and V), collagen type III, IV, IX, and X; collagen telopeptides; proteoglycans; fibronectin; laminin; MMP activation | + |
| MMP-10 | Stromelysin 2 (54/44) | Collagen type IV; proteoglycans; laminin; fibronectin | ? | |
| MMP-11 | Stromelysin 3 (64/46) | Furin deavage | − | |
| Membrane type | MMP-14 | MT1-MMP (66/54) | Collagen type I, II, III, and IV; gelatin; fibronectin; laminin; activation of proMMP-2 and proMMP-13 | + |
| … | (MT2-MT3-MT4-MMPs) | (Not known) | ? | |
| Others | MMP-7 | Matrilysin, PUMP-1 (28/19) | Proteoglycans, fibronectin, gelatins, collagen type IV, elastin, entactin | ? |
| MMP-12 | Matalloelastase (54/22) | Elastin (macrophage elastase) | ? |
* Role in cardiac remodeling was classified as documented ( + ), probable (?), or not known ( − ).
However, these changes (expected to augment proteolysis of collagen) do not readily explain the increased fibrosis and stiffness associated with end-stage CHF. In this regard, aged rats appear to have substantial decreases (40%-45%) in MMP activity. Transgenic mice that overexpress cardiac-specific TNF-alpha may help to reconcile this apparent contradiction with respect to aging. In this model, young mice initially demonstrated a significant increase in MMPs associated with LV structural remodeling. However, as the mice aged, there was a time-dependent increase in TIMP-1 levels, associated with an overall reduction in the MMP/TIMP ratio and progressive fibrotic stiffening without further enlargement. This time course and pattern of MMP/TIMP profiles has also been demonstrated in pressure overload hypertrophy due to aortic banding. Thus the activity of MMPs and their TIMPs may be time dependent, with differing effects dependent on the specific pathophysiology and phase of the life cycle.
Aging also has prominent effects on the balance between myocyte volume and the ECM. For example, the aged heart has substantially fewer myocytes than the young heart, accompanied by significant increases in the volume fraction of collagen. In rats, this reduced number of myocytes is associated with increases in the size of each individual myocyte that may be adaptive. Increased myocardial fibrosis has also been noted in senescent animal hearts. In otherwise “healthy” but aged human hearts, there appear to be focal areas of interstitial fibrosis, predominantly in the subendocardium of the left ventricle, that increase with age and may be related to the loss of myocyte volume as “replacement fibrosis.”
Metabolic Hypothesis of Cardiac Aging
The exact mechanism by which sedentary aging could lead to inhibition of MMPs with increases in TIMPs leading to fibrosis and cardiac stiffening is uncertain. Another, possibly interrelated mechanism could be that relative energy imbalance, specifically insufficient energy expenditure relative to caloric intake, may present a unifying hypothesis for why the heart stiffens with sedentary aging, yet is preserved with lifelong exercise training. For example, aged rats show clear evidence of progressive increases in collagen deposition in the left ventricle with age. However, this fibrosis was substantially reduced in rats maintained on a calorie-restricted diet. More recently, gene chip array analysis has identified prominent alterations in transcription with aging in a mouse model, including marked upregulation of the expression of ECM genes, such as procollagens. Similar to the aged rat, these mice demonstrated a 150% to 200% reduction in expression of these genes when fed a hypocaloric diet. Progressive weight gain/obesity is one of the hallmarks of the aging process. For most individuals, such weight gain with age is due predominantly to reduced levels of physical activity and caloric expenditure, with severe health consequences. Obesity is a particularly important risk factor for the syndrome of heart failure with a normal EF. For example, obese individuals display increased LV mass and wall thickness coupled with reduced LV filling dynamics—maladaptations that may predispose individuals to heart failure, particularly with advancing age. Interestingly, these adverse LV adaptations appear to develop independently of hemodynamic load, thus pointing to a metabolic cause for these cardiac consequences.
These data suggest the possibility of a “metabolic hypothesis” of cardiac stiffening with sedentary aging. This hypothesis proposes that the metabolic consequences of sedentary aging’ relative insulin resistance and excess caloric intake relative to expenditure, with or without obesity—lead to “lipotoxicity” and the accumulation of abnormal metabolites such as triglycerides (TGs) and advanced glycation end-products (AGEs) that separately and/or together contribute to the stiffening of the aged heart. Studies in animal models of human obesity have led to the development of this novel concept of “lipotoxicity,” which may explain the multiple pathological features associated with obesity. Specifically, in these animals the consequences of excess fat mass develop secondary to the toxic effects of an accumulation of intracellular lipid within non-adipocytes. While few human data are available, evidence is emerging that an excessive accumulation of lipid within the myocardium develops in obesity and is associated with sedentary aging ( Fig. 30-14 ). In animal models of human obesity, myocardial TG increases 2.5- and 4-fold by 7 and 14 weeks of age, respectively, while lean wild-type animals display no change in myocardial TG over the same time frame. This increase in myocardial TG content is associated with a 15-fold increase in markers of apoptosis and profoundly depressed LV systolic performance, implying that intramyocardial TG accumulation may explain the cardiac maladaptations that develop secondary to chronic obesity. When animals are treated with an agent that lowers tissue TG, intracellular lipid content is effectively diminished, markers of apoptosis are attenuated, and LV systolic performance is restored. In summary, substantial evidence from animal studies suggests that excessive myocardial lipid accumulation is a key feature in the pathogenesis of obesity-related disorders and contributes to cardiac dysfunction.
