Heart Failure with Preserved Ejection Fraction: Persistent Diagnosis, Therapeutic Enigma.

Heart failure with preserved ejection fraction (HFPEF) is increasing in prevalence with the aging of the population, and morbidity and mortality rates are comparable to that of heart failure with reduced ejection fraction (HFREF). The diagnosis can be difficult to make, especially in older adults, stemming from the presence of multiple comorbid illnesses with confounding symptoms. New diagnostic tools have resulted in guidelines proposed to define and diagnose HFPEF. Recent literature focusing on the pathophysiology underlying this disease suggests multiple mechanisms are involved in the generation of the phenotype, such as abnormal relaxation and ventricular-vascular coupling, chronotropic incompetence, volume overload, and redistribution and /or endothelial dysfunction. Currently, no clinically proven treatments are shown to decrease morbidity and mortality in this population; however, there may be a novel multidisciplinary and multistage treatment strategy that can be studied to address this complex disease which incorporates pharmacologic and non-pharmacologic therapeutics.

Pressure-volume relationships in patients with transthyretin (ATTR) cardiac amyloidosis secondary to V122I mutations and wild-type transthyretin: Transthyretin Cardiac Amyloid Study (TRACS).

BACKGROUND: ATTR cardiac amyloidosis can result from a mutated variant of transthyretin (eg, V122I) or wild-type variant (ATTRwt). We evaluated pressure-volume (PV) indices at baseline and over time to further characterize abnormal pump function in these subjects. METHODS AND RESULTS: Twenty-nine subjects (18 with ATTRwt and 11 with ATTRm (V122I) had 2-dimensional echocardiograms with complete Doppler measures at baseline and every 6 months for up to 2 years. PV indices were derived from echocardiographic measures of ventricular volume coupled with sphygmomanometer-measured pressure and Doppler estimates of filling pressure. The end-systolic and end-diastolic PV relations and the area between them as a function of end-diastolic pressure, the isovolumic PV area (PVA(iso)), were calculated. Clinical, demographic, and PV indices were compared between V122I and ATTRwt subjects and between survivors and nonsurvivors at baseline and over time. Cox proportional hazards model identified correlates for mortality. Stroke volume decline was associated with alterations in ventricular-vascular coupling and a decrease in ventricular capacitance with significant decrement in ejection fraction (56±12% to 48±14%, P=0.0001) over 18 months. PVA(iso) was lower in V122I subjects compared with wild-type at baseline and declined over time. Twelve (41%) subjects died or underwent a cardiac transplant after a mean follow-up of 478 days (range, 31 to 807). Multivariable survival analysis demonstrated that initial ejection fraction (a measure of ventricular-vascular coupling) <50% was associated with increased mortality (hazard ratio, 6.6; 95% confidence interval, 1.1 to 40.3). CONCLUSIONS: In ATTR cardiac amyloidosis secondary to a V122I mutation and wild-type transthyretin, PV analysis reveals alterations that are associated with reductions in the ability of the ventricle to perform work and, ultimately, with reduced survival in these subjects.

Circadian trafficking of calbindin-ir in fibers of SCN neurons.

Calbindin-D28K (CalB)-containing cells form a distinct cluster within the core of the hamster suprachiasmatic nucleus (SCN). These cells are directly retinorecipient but lack detectable rhythms in clock gene expression or electrical activity. In studies exploring SCN connectivity using double-label immunochemistry, we previously reported an absence of contacts among CalB fibers and vasopressin (VP) cells in animals sacrificed during the day. Here, we explored circadian variations in CalB-immunoreactivity (-ir) and re-examined the connections between CalB and other SCN cell types at zeitgeber times (ZT) 4 and 14. The results reveal a circadian rhythm of CalB-ir in fibers of SCN cells with high expression during the night and subjective night and low expression during the day and subjective day. This circadian difference is not seen in the other brain regions studied. Significantly more appositions were detected between CalB fibers and VP cells during the night than during the day, while circadian variation in numbers of contacts was not seen between CalB fibers and vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), or gastrin-releasing peptide (GRP) cells. There was no detectable variation in appositions from any peptidergic fiber type onto CalB cells. The present findings suggest that CalB cells relay photic information to VP oscillator cells of the SCN shell in a temporally gated manner.