The relationship between markers of extracellular cardiac matrix turnover: infarct healing and left ventricular remodelling following primary PCI in patients with first-time STEMI.

AIMS: We investigated the temporal changes in circulating levels of markers of extracellular cardiac matrix (ECCM) turnover and their relationship with infarct size (IS), ejection fraction (EF), and left ventricular (LV) volumes, determined by serial cardiac magnetic resonance (CMR) imaging in patients with first-time ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Forty-two patients with a first-time STEMI, successfully revascularized by primary percutaneous coronary intervention (pPCI) had serum samples taken prior to pPCI, 2, 7 days, 2 months, and 1 year following STEMI for the analysis of the markers of collagen synthesis, and collagen degradation. Late enhancement and cine CMR was performed on Days 2, 7, 2 months, and 1-year post-STEMI. There was a significant increase in type I collagen degradation following STEMI that was not accompanied by an increase in collagen type I synthesis until 2 months and 1 year. In contrast to the delay in type I collagen synthesis, there was an immediate increase in type III collagen synthesis that was sustained for 1 year. N-terminal procollagen type I levels assessed prior to pPCI were predictive of adverse LV remodelling at all CMR time-points. CONCLUSIONS: Our findings indicate a net type I collagen breakdown in the first week following STEMI compensated by an early increase in collagen type III synthesis. There is an increase in both type I and III collagen synthesis markers at 2 months and 1 year, indicating a persistent increase in collagen turnover even in these apparently successfully treated patients.

Attenuation of increased secretory leukocyte protease inhibitor, matricellular proteins and angiotensin II and left ventricular remodeling by candesartan and omapatrilat during healing after reperfused myocardial infarction.

While secretory-leukocyte-protease-inhibitor (SLPI) may promote skin wound healing, its role in infarct healing after reperfused myocardial infarction (RMI) remains unclear. Short-term intravenous angiotensin II (AngII) receptor blocker therapy with candesartan (CN) attenuates increased SLPI and markers of early matrix/left ventricular (LV) in acute RMI. To determine whether reducing effects of AngII with CN or the vasopeptidase inhibitor omapatrilat (OMA) during the healing phase after RMI attenuates SLPI and other mediators of healing and matrix/LV remodeling, we measured these in Sprague-Dawley rats randomized to oral placebo, CN (30 mg/kg/day) or OMA (10 mg/kg/day) therapy during healing between days 2 and 23 after RMI and sham. On day-25, RMI-placebo showed significant LV remodeling, systolic/diastolic dysfunction and impaired passive compliance, and ischemic zone increases in SLPI, secreted-protein-acidic-and-rich-in-cysteine (SPARC) and osteopontin (OPN) mRNA and protein. In addition, metalloproteinase (MMP)-9 and -2, a-disintegrin-and-metalloproteinase (ADAM)-10 and -17, inducible-nitric-oxide-synthase (iNOS), pro-inflammatory cytokines interleukin (IL)-6, and tumor necrosis factor-α, transforming growth factor (TGF)-ß(1) and its signaling molecule p-Smad-2, myeloperoxidase (MPO), AngII, MPO-positive granulocytes, MAC387-positive macrophages and monocytes, scar collagens, cardiomyocyte and fibroblast apoptosis, and microvascular no-reflow also increased whereas anti-inflammatory cytokine IL-10 decreased. Both CN and OMA attenuated all the changes except IL-10, which normalized. Thus, CN or OMA treatment during healing after RMI results in attenuation of SLPI as well as tissue AngII and mediators of inflammation and matrix/LV remodeling including SPARC, OPN, and ADAMs. Whether increasing SLPI on top of background AngII inhibition or therapy such as CN or OMA might produce added remodeling benefit needs study.

The paradox of left ventricular assist device unloading and myocardial recovery in end-stage dilated cardiomyopathy: implications for heart failure in the elderly.

Dilated cardiomyopathy (DCM) is a common debilitating condition with limited therapeutic options besides heart transplantation or palliation. It is characterized by maladaptive remodeling of cardiomyocytes, extracellular collagen matrix (ECCM) and left ventricular (LV) geometry which contributes to further dysfunction. LV assist devices (LVADs) can reverse adverse remodeling in end-stage DCM. However, there is a disconnect between the benefits of prolonged unloading with LVAD at molecular and cellular levels and the low rate of bridge to recovery (BTR). Potential explanations for this paradox include insufficient reverse ECCM remodeling and/or excessive reverse cardiomyocyte remodeling with atrophy. LVAD therapy is associated with decreased collagen turnover and cross-linking and increased tissue angiotensin II (AngII), whereas LVAD combined with angiotensin-converting enzyme inhibition results in decreased tissue AngII and collagen cross-linking, normalizes LV end-diastolic pressure volume relationships and is associated with modestly higher rates of BTR. Much remains to be learned about ventricular reverse remodeling after LVAD. This can be facilitated through systematic collection and comparison of recovered and unrecovered myocardium. Importantly, vigilant monitoring for ventricular recovery among LVAD patients is needed, particularly in older patients receiving LVAD for destination therapy. In addition, prospective multicenter trials are needed to clarify the potential benefit of concomitant heart failure therapy with selective ß2 agonism on ventricular recovery.

Nuclear-mitochondrial cross-talk in global myocardial ischemia. A time-course analysis.

Myocardial ischemia results in early and progressive damage to mitochondrial structure and function, but the molecular events leading to these changes have not been clearly established. We hypothesized that mitochondrial dysfunction and a coordinated expression of nuclear and mitochondrial genes occur in a time-dependent manner by relating the time courses of changes in parameters of mitochondrial bioenergetics after ischemia-reperfusion. Using a Langendorff rat heart model, mitochondrial bioenergetics and protein levels were assessed at different times of ischemia and ischemia/reperfusion. Mitochondrial and nuclear gene expression (super array analysis) and mitochondrial DNA levels were evaluated after late ischemia. Ischemia induced progressive and marked decreases in complex I, III, and V activities. Reperfusion (15, 30, and 60 min) after 45 min of ischemia had little further effect on enzyme activities or respiration. Super array analysis after 45 min ischemia revealed increased levels of the proteins with more pronounced increases in the corresponding mRNAs. Expression of mitochondrial and nuclear genes involved in oxidative phosphorylation increased after 45 min of ischemia but not after reperfusion. Myocardial ischemia induces mitochondrial dysfunction and differential but coordinated expression of nuclear and mitochondrial genes in a time-dependent manner. Our observations are pertinent to the search for molecular stimuli that generate mitochondrial defects and alter mitochondrial and nuclear transcriptional responses that may impact ischemic preconditioning and cardioprotection.

Mechanical circulatory support for elderly heart failure patients.

End-stage systolic heart failure is an increasingly common problem in elderly patients and is associated with high cost, poor quality of life, and poor outcomes. Mechanical circulatory support is a promising therapy as both a bridge to transplantation and destination therapy. Elderly patients are frequently ineligible for heart transplantation because of their age and comorbidities, and the application of mechanical circulatory support for destination therapy in this population is not well defined. A review of the literature was undertaken to better characterize our experience to date with mechanical circulatory support in older heart failure populations. Mechanical circulatory support is being employed increasingly for destination therapy indications in older patients. The newer continuous flow devices appear to have disproportionate advantage in elderly patients, which has translated into marked improvement in 1- and 2-year survival. The rational implementation of MCS devices in elderly heart failure patients needs to focus on (1) continuous flow devices that appear to have particular benefit in this population, (2) extensive pre-MCS assessment including variables relating to frailty, and (3) intervening before these patients develop cardiogenic shock. More data are needed on the cost-benefit analysis of routine use of CF devices as destination therapy in elderly patients with heart failure.

Prevention of heart failure in the elderly: when, where and how to begin?

Significant growth in the elderly population (age ≥ 65 years) with heart failure (HF) has taken place in developed countries and is occurring in most developing countries. Projections from population studies in the United States, Europe and other developed countries suggest that this trend will very likely continue and tax healthcare systems worldwide. Prevention of HF in the elderly should be a healthcare priority. Preventive strategies are urgently needed to combat the rising burden of HF and related complications in elderly men and women of tomorrow. The strategies should address the aging continuum and the cumulative impact of lifelong exposure to cardiovascular (CV) risk factors and consider the associated pathobiology and pathophysiology of aging for optimal impact. Besides implementation of conventional primary and secondary prevention measures in young and older adults, more emphasis should be placed on education about the role of exposure to adverse CV risk factors from early childhood in the march to HF. More research is also needed to identify optimal HF therapies for different aging subgroups ranging from young adults to the elderly and very old based on understanding of pathobiology and pathophysiology.

Systolic heart failure in the elderly: optimizing medical management.

The aging population with hypertension and coronary artery disease is rapidly increasing worldwide and develops heart failure (HF). A wide range of pharmacotherapeutic drugs are recommended in the HF management guidelines. For the most part, these recommendations are based on the results of studies in the younger population, and most drugs were not adequately tested in the elderly. However, many changes that occur during the aging process affect the response to several of the recommended therapeutic drugs. Physicians will be increasingly involved in managing the expanding elderly population with HF. It is therefore imperative that they recognize ways to use current pharmacotherapeutic agents and the increasing need for novel agents for optimizing the management of the elderly patient with HF.

Ischemia/Infarction.

Myocardial infarction (MI) accounts for most incidences of heart failure (HF) and low ejection fraction. Evidence suggests that acute MI leads to early cardiac remodeling, with changes in ventricular geometry and structure that in turn lead to a vicious cycle of ventricular dilation, increased wall stress, hypertrophy and more ventricular dilation and dysfunction, and worsening of HF. The early geometric and structural changes contribute to early mechanical complications and subsequent progressive ventricular remodeling and the development of chronic HF. A clear understanding of the underlying mechanisms is helpful in developing optimal preventive and therapeutic strategies for HF.

Atrial fibrillation and heart failure in the elderly.

Atrial fibrillation (AF) is a common clinical problem in elderly patients and especially in those with heart failure (HF). It is a major risk factor for serious cardiovascular events, such as stroke, HF and premature death. Both the prevalence and incidence of AF increase with age and its prevalence in the United States are estimated at more than 2.2 million, with nearly 75% of patients aged >65 years. Aging-related atrial remodeling with fibrosis, dilation and mitochondrial DNA mutations predispose elderly patients to AF. Current management options for AF, including rate control and anticoagulation therapy, can be successfully applied to the elderly population. New antiarrhythmic and anticoagulation medications such as dronedarone and dabigatran, respectively, can impact the approach to therapy in the elderly. Non-pharmacological options such as catheter-based ablation have also gained prominence and have been incorporated into the guidelines for management of AF. However, more trials in the elderly and very elderly segments are needed to clarify the safety and long-term efficacy of the new treatment options.

Clinical effectiveness of telmisartan alone or in combination therapy for controlling blood pressure and vascular risk in the elderly.

Elderly patients (age ≥ 65 years) with hypertension are at high risk for vascular complications, especially when diabetes is present. Antihypertensive drugs that inhibit the renin-angiotensin system have been shown to be effective for controlling blood pressure in adult and elderly patients. Importantly, renin-angiotensin system inhibitors were shown to have benefits beyond their classic cardioprotective and vasculoprotective effects, including reducing the risk of new-onset diabetes and associated cardiovascular effects. The discovery that the renin-angiotensin system inhibitor and angiotensin II type 1 (AT(1)) receptor blocker (ARB), telmisartan, can selectively activate the peroxisome proliferator-activated receptor-γ (PPARγ, an established antidiabetic drug target) provides the unique opportunity to prevent and treat cardiovascular complications in high-risk elderly patients with hypertension and new-onset diabetes. Two large clinical trials, ONTARGET (Ongoing Telmisartan Alone in combination with Ramipril Global Endpoint Trial) and TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE-I iNtolerant subjects with cardiovascular disease) have assessed the cardioprotective and antidiabetic effects of telmisartan. The collective data suggest that telmisartan is a promising drug for controlling hypertension and reducing vascular risk in high-risk elderly patients with new-onset diabetes.

Aging-related early changes in markers of ventricular and matrix remodeling after reperfused ST-segment elevation myocardial infarction in the canine model: effect of early therapy with an angiotensin II type 1 receptor blocker.

BACKGROUND: Elderly patients with reperfused ST-segment-elevation myocardial infarction are at increased risk for left ventricular remodeling. Extracellular matrix damage has been implicated in early remodeling. We hypothesized that aging results in enhanced early reperfusion injury and left ventricular remodeling after reperfused ST-segment-elevation myocardial infarction and that early therapy initiated at the time of reperfusion with an angiotensin II type 1 receptor blocker such as candesartan attenuates age-related increases in reperfusion injury and remodeling. METHODS AND RESULTS: We randomized 3 groups of dogs (age, 1 to 2, 2.1 to 5, and 5.1 to 10 years) with reperfused ST-segment-elevation myocardial infarction (90 minutes of ischemia, 2 hours of reperfusion) to therapy with placebo or candesartan (1 mg/kg CV-11974) over 30 minutes from the onset of reperfusion. Reperfusion in placebo groups was associated with aging-related changes in the ischemic zones in markers of damage (increased ischemic injury, infarct size [as percent risk], cardiomyocyte apoptosis, blood flow impairment, no reflow), structural remodeling (increased left ventricular dilation and dysfunction), extracellular matrix remodeling (increased expression of secretory leucocyte protease inhibitor, secreted protein acidic and rich in cysteine, osteopontin, a disintegrin and metalloproteinase-10 and -17, and matrix metalloproteinase-9 and -2), and inflammation (increased inducible nitric oxide synthase, proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha, and transforming growth factor-beta(1); decreased antiinflammatory cytokine interleukin-10). Compared with placebo, candesartan attenuated these age-dependent changes. CONCLUSIONS: Aging results in age-dependent early increases in markers of damage and adverse structural and matrix remodeling after ST-segment-elevation myocardial infarction reperfused after 90 minutes of ischemia, and early therapy initiated at the time of reperfusion with the angiotensin II type 1 receptor blocker candesartan attenuates these changes. This strategy needs clinical confirmation.

STEMI and heart failure in the elderly: role of adverse remodeling.

The elderly population (age > or = 65 years) has been increasing worldwide. In North America and Europe, both heart failure (HF) and ST-segment elevation MI (STEMI) are more prevalent in the elderly. Morbidity, hospitalizations and costs associated with HF are higher in the elderly. Despite improved therapies, the bulk of cardiovascular deaths occur in the elderly. Survivors of acute STEMI develop progressive ventricular remodeling that leads to HF. There are several reasons for the increased HF burden in the elderly. First, there is a lack of clinical trial data exclusively in elderly patients for specific therapy of adverse remodeling post-STEMI and HF with low ejection fraction (HF/low-EF) or HF with preserved ejection fraction (HF/PEF). Second, there is the lack of data on the impact of aging on remodeling during healing post-STEMI and HF. Third, HF therapy in the elderly is more challenging because of aging-specific biological changes and associated comorbidities and polypharmacy. More research on aging and post-STEMI remodeling and clinical trials on post-STEMI remodeling and HF in the elderly are needed, especially in the "older-elderly" population segment aged > or =75 years.