Mullan, Brian P.

BACKGROUND: Blood volume (BV) profiles vary markedly in patients with heart failure (HF), but how HF phenotypes and patient sex impact volume profiles remain to be explored. The aim of the study was to differentiate BV, plasma volume, and red blood cell mass profiles by phenotypes of preserved and reduced left ventricular ejection fractions and assess the impact of patient sex on profile heterogeneity. METHODS: Retrospective analysis of clinical and BV data was undertaken in patients with chronic New York Heart Association II–III heart failure. BV was quantitated using the nuclear medicine indicator-dilution methodology. RESULTS: A total of 530 BV analyses (360 HF with reduced ejection fraction and 170 HF with preserved ejection fraction) were identified in 395 unique patients. Absolute BV was greater in HF with reduced ejection fraction (6.7±1.8 versus 5.9±1.6 liters: P <0.001); however, large variability in frequency distribution of volume profiles was observed in both phenotypes (−22% deficit to +109% excess relative to normal volumes). HF with reduced ejection fraction was characterized by a higher prevalence of BV expansion ≥+25% of normal (39% versus 26%; P =0.003), and HF with preserved ejection fraction was characterized a by more frequent normal BV (42% versus 24%; P <0.001). Male sex in both phenotypes was associated with a larger absolute BV (7.0±1.6 versus 5.1±1.3 liters; P <0.001) and higher frequency of large BV and plasma volume expansions above normal (both P <0.001), while females in both phenotypes demonstrated a higher prevalence of normal BV and plasma volume (both P <0.001). CONCLUSIONS: Findings support significant differences in BV, plasma volume, and red blood cell mass profile distributions between heart failure phenotypes, driven in large part by sex-specific factors. This underscores the importance of identifying and distinguishing individual patient volume profiles to help guide volume management strategies.

Abstract Aims To identify different red blood cell mass (RBCM) profiles, separate from haemoglobin concentrations, and their impact on blood volume expansion and clinical outcomes in chronic heart failure. Methods and results RBCM was measured at hospital discharge using standardized nuclear medicine indicator-dilution methodology in patients following diuretic treatment for clinical congestion. Individual RBCM phenotypes were prospectively identified and analysed for heart failure-related mortality or first rehospitalization over 1 year. Of 132 patients, 42 (32%) demonstrated normal RBCM, 36 (27%) RBCM deficit (true anaemia), and 54 (41%) RBCM excess (erythrocythemia). Dilutional ‘anaemia’ defined by haemoglobin &lt;12 g/dL with normal or an excess in RBCM with plasma volume expansion was identified in 37 (28%) patients. There were 61 composite outcome events, which included 38 deaths (29% of cohort) occurring over the 1 year follow-up period [14/36 (39%) in RBCM deficit, 12/42 (29%) in normal RBCM, and 12/54 (22%) in RBCM excess subgroups]. By Kaplan–Meier and multivariate analyses, RBCM excess was independently associated with the best event-free survival while RBCM deficit (true anaemia) the poorest outcomes; both compared with normal RBCM (P &lt; 0.001). Dilutional ‘anaemia’ demonstrated a lower risk compared with true anaemia (P = 0.03). Conclusions Markedly different RBCM profiles are identifiable among comparably compensated heart failure patients, and this variability carries significant implications for post-hospital outcomes. Novel to this analysis and in contrast to RBCM deficit is the independent association of RBCM excess with better event-free survival compared with normal RBCM. The distinction of RBCM profiles to guide risk stratification and individualized patient management strategies warrants further study.

AbstractIntravascular volume is largely regulated by the kidneys but how differences in intravascular volume profiles interact with chronic kidney disease (CKD) to influence outcomes in chronic heart failure (HF) has not been explored. Our hypothesis was that a greater degree of volume expansion (VE) would moderate the impact of CKD on HF‐related clinical outcomes. Quantitative blood volume (BV) data were available in 137 patients at the time of hospital discharge using a nuclear medicine radiolabeled albumin indicator‐dilution technique. The study patients were stratified by the cohort median glomerular filtration rate (GFR, 44 ml/min/1.73 m2). An a priori cut‐point of ≥+25% above normal BV was then used to further stratify the two GFR subgroups and prospectively analyzed for 1‐year HF‐related mortality or 1st re‐hospitalization. Persistent BV expansions ≥+25% were present in 51% of the cohort. In the subgroup with GFR above the median (N = 68) greater or lesser BV expansion from +25% did not differentiate outcomes. However, in the subgroup with GFR below the median (N = 69), BV expansion‐stratified risk (log‐rank p = 0.022) with <+25% VE associated with poorer outcomes, while VE ≥ + 25% was associated with lower risk and comparable to GFR above the median. In patients with chronic HF, significant intravascular VE and CKD are common co‐existing conditions. The presence of larger VE, however, appears to be a factor mitigating the impact of declining renal function on clinical outcomes, and as an element of volume pathophysiology warrants further study.

The novel findings of this study demonstrate that intravascular volume profiles among the patients with chronic heart failure (HF) vary substantially even with similar clinical compensation. Importantly, a profile of blood volume (BV) expansion (compared with a normal BV) is associated with lower HF mortality/morbidity. Furthermore, RBC polycythemia is common and independently associated with improved outcomes. These observations support BV expansion with RBC polycythemia as a compensatory mechanism in chronic HF.

Background: The role of coronary microvascular disease and its impact on functional and energetic reserve in heart failure with preserved ejection fraction (HFpEF) remains unclear. We hypothesized that in response to submaximal pharmacologic stress (dobutamine), patients with HFpEF have impairment in left ventricular (LV) myocardial mechanical (external work [EW]), energetic (myocardial O 2 consumption [MVO 2 ]), and myocardial blood flow (MBF) reserve. We further assessed whether coupling of MBF to EW is impaired in HFpEF and associated with compensatory increases or pathological decreases in myocardial O 2 extraction. Lastly, we assessed whether coupling of MVO 2 to EW (mechanical efficiency) was impaired in HFpEF. Methods and Results: In prospectively enrolled patients with HFpEF (n=19) and age/sex-matched healthy controls (n=19), we performed 11 C-acetate positron emission tomography assessing MVO 2 and MBF at rest and during dobutamine infusion. EW was calculated as stroke volume (echo)×end-systolic pressure×heart rate. At rest, compared with controls, patients with HFpEF had higher LV EW, MVO 2 , and MBF. With dobutamine, LV EW, MVO 2 , and MBF increased in both HFpEF and controls; however, the magnitude of increases was significantly smaller in HFpEF. In both groups, MBF increased in relation to EW, but in HFpEF, the slope of the relationship was significantly smaller than in controls. Myocardial O 2 extraction was increased in HFpEF. Mechanical efficiency was similar in HFpEF and controls. In a post hoc analysis, HFpEF patients with LV hypertrophy (n=10) had significant reductions in LV mechanical efficiency relative to controls. Conclusions: In HFpEF during submaximal dobutamine stress, there is myocardial mechanical-, energetic- and flow-reserve dysfunction with impaired coupling of blood flow to demand and slight increases in myocardial O 2 extraction. These findings provide evidence that coronary microvascular dysfunction is present in HFpEF, limits O 2 supply relative to demand, and is associated with reserve dysfunction.

ABSTRACT BACKGROUND AND PURPOSE SISCOM and STATISCOM were clinically proved to be effective for ictal/inter‐ictal single‐photon emission computed tomography (SPECT) analysis coregistered with magnetic resonance imaging (MRI) for seizure localization. Recently, a software package also became available for this analysis. This study aimed to investigate and compare the performance of these analysis methods for seizure localization. METHODS A total of 378 patients who underwent 99m Tc‐ethyl cysteinate dimer (ECD) SPECT scans were retrospectively reviewed and 28 remained after applying exclusion criteria. Their SPECT and MRI images were analyzed with SISCOM (with z ‐score of 1.5 and 2), STATISCOM, and MIMneuro, resulting in a total of 112 image data sets. Two experienced radiologists participated in the blind review process using a custom tool and they can mark up to two hyper‐ and/or hypoperfusion regions. Their review results were analyzed using the Jackknife Free Response Receiver‐Operating Characteristics (JAFROC) test and the JAFROC figure‐of‐merit (FoM) was reported for each method. The interobserver agreement was also assessed using Cohen's kappa test. RESULTS Based on the readers’ two choices, averaged FoM was 85.7%, 83.9%, 66.1%, and 51.8% for STATISCOM, MIMneuro, SISCOM ( z ‐score = 2), and SISCOM ( z ‐score = 1.5), respectively. The average confidence rating was 2.5, 2.3, 1.6, and 1.1 for STATISCOM, MIMneuro, SISCOM ( z ‐score = 2), and SISCOM ( z ‐score = 1.5), respectively. For interobserver agreement, kappa was .742 for STATISCOM, .816 for MIMneuro, .517 for SISCOM ( z ‐score = 2), and .441 for SISCOM ( z ‐score = 1.5; all P < .001). CONCLUSION Our study demonstrated that STATISCOM showed the best performance for seizure localization, which was closely followed by MIMneuro. In addition, MIMneuro was not inferior to SISCOM with either z ‐score.

Postprandial symptoms of bloating, distension, early satiety, and nausea are associated with impaired postprandial gastric accommodation, which is detectable by means of an intragastric, barostatically controlled balloon in the proximal stomach and by ultrasound in the distal stomach. Our aim was to develop a noninvasive method to measure the entire gastric accommodation reflex. In 10 healthy volunteers, we used single photon emission computed tomography (SPECT) to measure fasting and postprandial gastric volumes. This method involved intravenous injection of99mTc pertechnetate and gastric reconstruction of tomographic images with Analyze software. SPECT-Analyze imaging detects the postprandial gastric accommodation reflex in vivo. Mean fasting gastric volume was 182 ± 11 (SE) ml and mean postprandial volume was 690 ± 32 ml ( P < 0.001). Both proximal and distal segments of stomach showed a two- to almost fourfold difference in volumes postprandially. Intraobserver coefficients of variation in estimated fasting and postprandial volumes were 9 and 8%; interobserver variations were 13 and 12%, respectively. SPECT-Analyze noninvasively measures postprandial gastric (total, proximal, and distal) accommodation in humans. This method appears promising to compare the accommodation response in health and disease and to perform mechanistic studies of the accommodation response.

Central processing of visceral information in humans is incompletely understood. We aimed to demonstrate the feasibility of single photon emission computed tomography (SPECT) and to quantitate the changes in regional cerebral blood flow during rectal distension. Ten healthy volunteers underwent randomized sham and active rectal distensions on separate days, during which cerebral blood flow was assessed by intravenous technetium-99m ethyl cysteinate dimer (99mTc-ECD) SPECT. Three-dimensional coregistration of brain images was used to quantitate activation in four preselected cerebral foci and two control regions. Paired analysis compared blood flow during sham and active distensions. There was increased right anterior cingulate gyrus activity (6.5 ± 2.9%, P = 0.03) with active rectal distension. A 5.4 ± 2.4% reduction in blood flow in the superior parieto-occipital control region ( P = 0.04) suggested blood “redistribution” during stimulation. Marked variability in activation of the frontal cortex, thalamus/basal ganglia complex, and mesiotemporal lobe was noted. Thus rectal distension increases activity in the right anterior cingulate gyrus on average; other foci of cerebral activation are quite variable, suggesting a lack of specific cerebral projections during rectal stimulation.