Arterial–Ventricular Coupling with Aging and Disease

Age is the dominant risk factor for cardiovascular diseases. Understanding the coupling between the left ventricle (LV) and arterial system, termed arterial–ventricular coupling (EA/ELV), provides important mechanistic insights into the complex cardiovascular system and its changes with aging in the absence and presence of disease. EA/ELV can be indexed by the ratio of effective arterial elastance (EA; a measure of the net arterial load exerted on the LV) to left ventricular end-systolic elastance (ELV; a load-independent measure of left ventricular chamber performance). Age-associated alterations in arterial structure and function, including diameter, wall thickness, wall stiffness, and endothelial dysfunction, contribute to a gradual increase in resting EA with age. Remarkably there is a corresponding increase in resting ELV with age, due to alterations to LV remodeling (loss in myocyte number, increased collagen) and function. These age-adaptations at rest likely occur, at least, in response to the age-associated increase in EA and ensure that EA/ELV is closely maintained within a narrow range, allowing for optimal energetic efficiency at the expense of mechanical efficacy. This optimal coupling at rest is also maintained when aging is accompanied by the presence of hypertension, and obesity, despite further increases in EA and ELV in these conditions. In contrast, in heart failure patients with either reduced or preserved ejection fraction, EA/ELV at rest is impaired. During dynamic exercise, EA/ELV decreases, due to an acute mismatch between the arterial and ventricular systems as ELV increases disproportionate compared to EA (≈200 vs. 40%), to ensure that sufficient cardiac performance is achieved to meet the increased energetic requirements of the body. However, with advancing age the reduction in EA/ELV during acute maximal exercise is blunted, due to a blunted increase ELV. This impaired EA/ELV is further amplified in the presence of disease, and may explain, in part, the reduced cardiovascular functional capacity with age and disease. Thus, although increased stiffness of the arteries itself has important physiological and clinical relevance, such changes also have major implications on the heart, and vice versa, and the manner in the way they interact has important ramifications on cardiovascular function both at rest and during exercise. Examination of the alterations in arterial–ventricular coupling with aging and disease can yield mechanistic insights into the pathophysiology of these conditions and increase the effectiveness of current therapeutic interventions

Dual Activation of Phosphodiesterases 3 and 4 Regulates Basal Spontaneous Beating Rate of Cardiac Pacemaker Cells: Role of Compartmentalization?

Spontaneous firing of sinoatrial (SA) node cells (SANCs) is regulated by cyclic adenosine monophosphate (cAMP)-mediated, protein kinase A (PKA)-dependent (cAMP/PKA) local subsarcolemmal Ca2+ releases (LCRs) from ryanodine receptors (RyR). The LCRs occur during diastolic depolarization (DD) and activate an inward Na+/Ca2+ exchange current that accelerates the DD rate prompting the next action potential (AP). Basal phosphodiesterases (PDEs) activation degrades cAMP, reduces basal cAMP/PKA-dependent phosphorylation, and suppresses normal spontaneous firing of SANCs. The cAMP-degrading PDE1, PDE3, and PDE4 represent major PDE activities in rabbit SANC, and PDE inhibition by 3-isobutyl-1-methylxanthine (IBMX) increases spontaneous firing of SANC by ∼50%. Though inhibition of single PDE1–PDE4 only moderately increases spontaneous SANC firing, dual PDE3 + PDE4 inhibition produces a synergistic effect hastening the spontaneous SANC beating rate by ∼50%. Here, we describe the expression and distribution of different PDE subtypes within rabbit SANCs, several specific targets (L-type Ca2+ channels and phospholamban) regulated by basal concurrent PDE3 + PDE4 activation, and critical importance of RyR Ca2+ releases for PDE-dependent regulation of spontaneous SANC firing. Colocalization of PDE3 and PDE4 beneath sarcolemma or in striated patterns inside SANCs strongly suggests that PDE-dependent regulation of cAMP/PKA signaling might be executed at the local level; this idea, however, requires further verification

A general theory to explain heart rate and cardiac contractility changes with advancing age

Sinus node dysfunction and chronic heart failure have been, and will continue to be , major health issue issues in humans for the foreseeable future future. The heartbeat originateoriginates from spontaneously firing sinoatrial nodal (SAN) pacemaker cells. A coupledcoupled-clock system underlies the robust and flexible automaticity in these cells cells. The basal action potential (AP) firing rate of SAN cells is largely determined by the degree of phosphorylation o of critical proteins in th the coupledcoupled-clock system. Autonomic neuronal signaling from the brain effects changes in AP firing rate via modulatmodulation of cAMP and cAMP cAMP-mediated PKAPKA-dependent phosphorylationphosphorylation. Age -associated alterationalterations in intrinsic SAN cell behavior and associated changes in brainbrain-heart communication play cent ral role roles in the development of SAN cell pacemaker failure. This minimini-review provides integrated insights into the molecular mechanisms underlying the effects of aging on deterioration in beating rate and contractility of the heart in animal models and in apparently healthy humans.Sociedad Argentina de Fisiologí

Increased Aortic Calpain-1 Activity Mediates Age-Associated Angiotensin II Signaling of Vascular Smooth Muscle Cells

Angiotensin II (Ang II) signaling, including matrix metalloproteinase type II (MMP2) activation, has been linked to an age-associated increase in migration capacity of vascular smooth muscle cells (VSMC), and to other proinflammatory features of arterial aging. Calpain-1 activation is required for MMP2 expression in fibroblasts and is induced in cardiomyocytes by Ang II. The consequences of engagement of calpain-1 with its substrates, however, in governing the age-associated proinflammatory status within the arterial wall, remains unknown.The present findings demonstrate that transcription, translation, and activity of calpain-1 are significantly up-regulated in rat aortae or early-passage aortic VSMC from old (30-mo) rats compared to young (8-mo). Dual immunolabeling of the arterial wall indicates that colocalization of calpain-1 and Ang II increases within the aged arterial wall. To further explore the relationship of calpain-1 to Ang II, we chronically infused Ang II into young rats, and treated cultured aortic rings or VSMC with Ang II. We also constructed adenoviruses harboring calpain-1 (CANP1) or its endogenous inhibitor calpastatin (CAST) and infected these into VSMC. Ang II induces calpain-1 expression in the aortic walls in vivo and ex vivo and VSMC in vitro. The Ang II mediated, age-associated increased MMP2 activity and migration in VSMC are both blocked by calpain inhibitor 1 or CAST. Over-expression of calpain-1 in young VSMC results in cleavage of intact vimentin, and an increased migratory capacity mimicking that of old VSMC, which is blocked by the MMP inhibitor, GM6001.Calpain-1 activation is a pivotal molecular event in the age-associated arterial Ang II/MMP2 signaling cascade that is linked to cytoskeleton protein restructuring, and VSMC migration. Therefore, targeting calpain-1 has the potential to delay or reverse the arterial remodeling that underlies age-associated diseases i.e. atherosclerosis

A novel conceptual model of heart rate autonomic modulation based on a small-world modular structure of the sinoatrial node

The present view on heartbeat initiation is that a primary pacemaker cell or a group of cells in the sinoatrial node (SAN) center paces the rest of the SAN and the atria. However, recent high-resolution imaging studies show a more complex paradigm of SAN function that emerges from heterogeneous signaling, mimicking brain cytoarchitecture and function. Here, we developed and tested a new conceptual numerical model of SAN organized similarly to brain networks featuring a modular structure with small-world topology. In our model, a lower rate module leads action potential (AP) firing in the basal state and during parasympathetic stimulation, whereas a higher rate module leads during β-adrenergic stimulation. Such a system reproduces the respective shift of the leading pacemaker site observed experimentally and a wide range of rate modulation and robust function while conserving energy. Since experimental studies found functional modules at different scales, from a few cells up to the highest scale of the superior and inferior SAN, the SAN appears to feature hierarchical modularity, i.e., within each module, there is a set of sub-modules, like in the brain, exhibiting greater robustness, adaptivity, and evolvability of network function. In this perspective, our model offers a new mainframe for interpreting new data on heterogeneous signaling in the SAN at different scales, providing new insights into cardiac pacemaker function and SAN-related cardiac arrhythmias in aging and disease

TGF beta 1 reinforces arterial aging in the vascular smooth muscle cell through a long-range regulation of the cytoskeletal stiffness

Here we report exquisitely distinct material properties of primary vascular smooth muscle (VSM) cells isolated from the thoracic aorta of adult (8 months) vs. aged (30 months) F344XBN rats. Individual VSM cells derived from the aged animals showed a tense internal network of the actin cytoskeleton (CSK), exhibiting increased stiffness (elastic) and frictional (loss) moduli than those derived from the adult animals over a wide frequency range of the imposed oscillatory deformation. This discrete mechanical response was long-lived in culture and persistent across a physiological range of matrix rigidity. Strikingly, the pro-fibrotic transforming growth factor beta 1 (TGF beta 1) emerged as a specific modifier of age-associated VSM stiffening in vitro. TGF beta 1 reinforced the mechanical phenotype of arterial aging in VSM cells on multiple time and length scales through clustering of mechanosensitive alpha(5)beta(1) and alpha(v)beta(3) integrins. Taken together, these studies identify a novel nodal point for the long-range regulation of VSM stiffness and serve as a proof-of-concept that the broad-based inhibition of TGF beta 1 expression, or TGF beta 1 signal transduction in VSM, may be a useful therapeutic approach to mitigate the pathologic progression of central arterial wall stiffening associated with aging

Lower mitochondrial energy production of the thigh muscles in patients with low-normal ankle-brachial index

Background--Lower muscle mitochondrial energy production may contribute to impaired walking endurance in patients with peripheral arterial disease. A borderline ankle-brachial index (ABI) of 0.91 to 1.10 is associated with poorer walking endurance compared with higher ABI. We hypothesized that in the absence of peripheral arterial disease, lower ABI is associated with lower mitochondrial energy production. Methods and Results--We examined 363 men and women participating in the Baltimore Longitudinal Study of Aging with an ABI between 0.90 and 1.40. Muscle mitochondrial energy production was assessed by post-exercise phosphocreatine recovery rate constant (kPCr) measured by phosphorus magnetic resonance spectroscopy of the left thigh. A lower post-exercise phosphocreatine recovery rate constant reflects decreased mitochondria energy production.The mean age of the participants was 71\uc2\ub112 years. A total of 18.4% had diabetes mellitus and 4% were current and 40% were former smokers. Compared with participants with an ABI of 1.11 to 1.40, those with an ABI of 0.90 to 1.10 had significantly lower post-exercise phosphocreatine recovery rate constant (19.3 versus 20.8 ms-1, P=0.015). This difference remained significant after adjusting for age, sex, race, smoking status, diabetes mellitus, body mass index, and cholesterol levels (P=0.028). Similarly, post-exercise phosphocreatine recovery rate constant was linearly associated with ABI as a continuous variable, both in the ABI ranges of 0.90 to 1.40 (standardized coefficient=0.15, P=0.003) and 1.1 to 1.4 (standardized coefficient=0.12, P=0.0405). Conclusions--An ABI of 0.90 to 1.10 is associated with lower mitochondrial energy production compared with an ABI of 1.11 to 1.40. These data demonstrate adverse associations of lower ABI values with impaired mitochondrial activity even within the range of a clinically accepted definition of a normal ABI. Further study is needed to determine whether interventions in persons with ABIs of 0.90 to 1.10 can prevent subsequent functional decline