Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure (HF) in older adults, particularly women, and is increasing in prevalence as the population ages. With morbidity and mortality on par with HF with reduced ejection fraction, it remains a most challenging clinical syndrome for the practicing clinician and basic research scientist. Originally considered to be predominantly caused by diastolic dysfunction, more recent insights indicate that HFpEF in older persons is typified by a broad range of cardiac and non-cardiac abnormalities and reduced reserve capacity in multiple organ systems. The globally reduced reserve capacity is driven by: 1) inherent age-related changes; 2) multiple, concomitant co-morbidities; 3) HFpEF itself, which is likely a systemic disorder. These insights help explain why: 1) comorbidities are among the strongest predictors of outcomes; 2) approximately 50% of clinical events in HFpEF patients are non-cardiovascular; 3) clinical drug trials in HFpEF have been negative on their primary outcomes. Embracing HFpEF as a true geriatric syndrome, with complex, multi-factorial pathophysiology and clinical heterogeneity could provide new mechanistic insights and opportunities for progress in management.

Although it is well-known that excess renin angiotensin system (RAS) activity contributes to the pathophysiology of cardiac and vascular disease, tissue-based expression of RAS genes has given rise to the possibility that intracellularly produced angiotensin II (Ang II) may be a critical contributor to disease processes. An extended form of angiotensin I (Ang I), the dodecapeptide angiotensin-(1-12) [Ang-(1-12)], that generates Ang II directly from chymase, particularly in the human heart, reinforces the possibility that an alternative noncanonical renin independent pathway for Ang II formation may be important in explaining the mechanisms by which the hormone contributes to adverse cardiac and vascular remodeling. This review summarizes the work that has been done in evaluating the functional significance of Ang-(1-12) and how this substrate generated from angiotensinogen by a yet to be identified enzyme enhances knowledge about Ang II pathological actions.

The left ventricle (LV) and arterial system are nearly optimally coupled to produce stroke work (SW) at rest. However, the effect of exercise on the coupling between the LV and arterial system has not been directly determined. We evaluated 11 dogs who were instrumented to determine LV volume from three diameters. The LV end-systolic pressure (Pes)-volume (Ves) relation was determined by transient caval occlusion at rest and while the animals ran at 5-7 mph on a treadmill. During exercise, the Pes-Ves relation was shifted toward the left and the slope [end-systolic elastance (Ees)] increased from 7.7 +/- 2.8 to 12.7 +/- 4.2 (SD) mmHg/ml (P < 0.05). The arterial end-systolic elastance (Ea), calculated as Pes divided by stroke volume, increased during exercise (8.8 +/- 3.0 to 10.9 +/- 4.7 mmHg/ml, P < 0.05). The ratio of Ees to Ea increased during exercise from 0.89 +/- 0.31 to 1.27 +/- 0.12 (P < 0.05). The portion of the pressure-volume area expressed as SW increased during exercise from 0.63 +/- 0.07 to 0.69 +/- 0.10 (P < 0.05). After adrenergic blockade, the Ees-to-Ea ratio was not significantly altered during exercise (0.90 +/- 0.24 vs. 0.83 +/- 0.15, P = NS). At rest and during exercise, both with intact reflexes and after beta-adrenergic blockade, the ratio of Ees to Ea remained within the range in which SW is > 95% of maximum. We conclude that during exercise, beta-adrenergic stimulation shifts the LV Pes-Ves relation to the left with an increased slope. This more than offsets the increase in Ea.(ABSTRACT TRUNCATED AT 250 WORDS)

We compared left ventricle (LV) volume (V) simultaneously measured using the conductance catheter (VM) with volume calculated from three LV dimensions (VD) determined ultrasonically from endocardial crystals. Seven adult mongrel dogs (20-30 kg) were anesthetized and instrumented to measure micromanometer LV pressure and V. Three pairs of crystals were placed orthogonally in subendocardial positions and a conductance catheter was placed in the LV retrograde across the aortic valve. Under steady-state conditions, over the range of a single cardiac cycle, the relation between VM and VD was well described by a straight line. There was an excellent correlation of conductance and dimension volumes with r equal to 0.97+±0.04 and SEE 0.8 +0.5 ml. The gain (1/ce) and parallel conductance volume (cYVc) were constant. At lower volumes obtained during bicaval occlusion, however, the relation between VM and VD was curvilinear. 1/a and aVc both decreased as LVV fell. Thus, determination of absolute volume using the conductance catheter depended on the conditions under which the data were obtained. Under steady-state conditions, aYVc calculated by both the saline method (mean+ SD, 50±t15 ml) and by regression of VM and VD, (45+±21 ml) were similar. Consequently, absolute LV end-diastolic volumes and end-systolic volumes by the conductance and dimension methods were similar (53±14 ml and 38±14 ml vs. 56±17 ml and 44+16 ml, respectively,p=NS). When volume decreased during bicaval occlusion, there was a progressively greater decrease in VM as compared with VD. The absolute slope (EES) of the end-systolic pressure-volume relation (ESPVR) was consistently higher by the dimension method, group average, 16.3+±7.6, than by the catheter, 8.5 ±5.9, p <0.05. The direction and magnitude of the change in EEs at different inotropic states (autonomic blockade; dobutamine), however, was similarly measured by both the conductance catheter and dimension method. We conclude that the gain and offset of the conductance catheter are relatively constant at steady state but vary when volume is reduced by caval occlusion. Thus, the conductance catheter accurately measures absolute volumes at steady state but can underestimate the slope and position of the ESPVR when it is determined by caval occlusion. The conductance catheter does, however, accurately measure the directions and magnitude of change in contractile state. (Circulation 1990;81:638-648) A nalysis of the left ventricle (LV) in the pressure-volume plane has provided insights into LV performance.1-5 Clinical application of pressure-volume analysis, however, has been limited because of the difficulty in measur-