Citations

Objective: To understand the patient and caregiver experience with the management of neurogenic orthostatic hypotension (nOH) Background: nOH is a sustained reduction in blood pressure (BP) with postural change associated with autonomic dysfunction. Clinical symptoms may include falls, leading to activity limits and a diminished sense of well-being. Methods: A US-based survey designed by the authors was conducted by Harris Poll. Eligible participants had Parkinson disease (PD), multiple system atrophy, or pure autonomic failure and ≥1 of the following: orthostatic hypotension (OH), nOH, low BP, OH/nOH symptoms, or were caregivers of eligible patients. Descriptive statistics are reported. Results: PD was the most frequent underlying diagnosis (Table 1) . Healthcare provider (HCP) communication with patients was rated as satisfactory by ≥75% of respondents, yet when nOH symptoms were first discussed with the HCP, only 35% of patients and 31% of caregivers reported the patient received guidance on management. The most frequently recommended interventions are listed in Table 1 ; 25% of patients reported that no interventions were recommended. Medication prescribed to treat nOH was reported by 34% of patients and 45% of caregivers. Among patients treated, 79% of patients and 71% of caregivers said that the patient’s symptoms were somewhat to very well managed. Conclusions: Survey findings suggest the need for increased awareness of nOH and engagement with patients and caregivers regarding symptom management. A variety of interventions were recommended; no single treatment approach was noted. Respondents felt nOH symptoms were at least somewhat well managed with treatment.

Objective: To understand the burden and impact of symptoms of neurogenic orthostatic hypotension (nOH) on patients Background: nOH and its symptoms such as dizziness/lightheadedness are common in patients with Parkinson disease (PD) and other forms of autonomic dysfunction. Methods: An author-designed, US-based survey was conducted by Harris Poll. Eligible participants were aged ≥18 years with PD, multiple system atrophy (MSA), or pure autonomic failure and ≥1 of the following: orthostatic hypotension, nOH, low BP, OH/nOH symptoms, or were caregivers of eligible patients. Results: Most patients (90%) had a diagnosis of PD, and most caregivers (88%) cared for a patient with PD (Table 1) . Patients (34%) and caregivers (49%) reported experiencing nOH symptoms before PD or MSA motor symptoms and >40% indicated that nOH symptoms were more troublesome than motor manifestations of PD or MSA. Less than a quarter (22%) of respondents suggested symptoms were most severe in the morning; more (30%) reported a consistent severity throughout the day. Patients (40%) and caregivers (63%) reported trouble managing symptoms during the day. In the past 12 months, a fall due to nOH symptoms was reported by 57% of patients and 80% of caregivers. Conclusions: These findings suggest that nOH symptoms may predate the onset of motor symptoms in neurodegenerative conditions linked to alpha-synuclein pathology. Many respondents report nOH symptoms are the same severity through the day. Patients with nOH may have trouble managing symptoms and note an increased risk for falls.

Objective: To understand the challenges to diagnosis in patients with neurogenic orthostatic hypotension (nOH) Background: nOH is a sustained reduction in blood pressure (BP) with postural change associated with autonomic dysfunction. Despite symptoms of nOH, many patients struggle to find an accurate diagnosis. Methods: An online, US-based survey designed by the authors was conducted by Harris Poll. Eligible participants were ≥18 years of age with Parkinson disease, multiple system atrophy, or pure autonomic failure and ≥1 of the following: orthostatic hypotension (OH), nOH, low BP, OH/nOH symptoms, or were caregivers of eligible participants. Results: The survey included 363 patients and 128 caregivers. Groups were separate, where caregivers were not the caregivers to patient responders. Respondents indicated that patients experienced nOH symptoms long term (Table 1) . Most patients (69%) and caregivers (59%) reported discussing nOH symptoms with a healthcare provider (HCP) within the first year of symptom onset, but only 36% of patients and 16% of caregivers reported a formal diagnosis of OH or nOH. Of those with a formal diagnosis, the majority of patients (50%) were frustrated by the path to diagnosis and more than 40% of patients and caregivers reported that the patient saw ≥3 HCPs before diagnosis. After diagnosis, most patients (70%) and caregivers (60%) reported improved symptom management. Conclusions: This survey reveals that patients and caregivers may find the path to nOH diagnosis challenging and suggests increased awareness among HCPs is needed. Once a diagnosis is made nOH symptoms are better managed.

Background: Between 1990-2006, there was a tremendous increase in utilization of single photon emission computed tomography myocardial perfusion imaging (SPECT). Characteristics of the observed increase of SPECT utilization have never been studied. Methods: Using the Mayo Clinic nuclear cardiology database, we examined all SPECT tests performed between 1/1/1991-12/31/2007 in patients without prior coronary artery disease (CAD). Patients with history of CAD, left bundle branch block, paced rhythm, bicycle/ rest-only tests, cardiomyopathy, valvular heart disease, and technically unsatisfactory studies were excluded. The study cohort was divided into 4 time periods: 1991-5, 1996-2000, 2001-5, and 2006-7. Results: There were 29255 eligible SPECT tests (mean age 62.4 ± 12y, 54% men). Annual utilization of SPECT studies increased from 682 in 1992 to a peak of 2738 in 2002, and then decreased to 2134 in 2007, Fig 1. There were very modest changes in CAD risk factors over time. Testing of asymptomatic patients nearly doubled (21.9% in 1991-5 to 42.7% in 2006-7). Tests on patients with typical angina decreased dramatically (18.3% in 1991-5 to 5.3% in 2006-7), Fig 2. Summed stress score, summed difference score, and high risk SPECT tests decreased over time, Fig 3. Normal SPECT studies and negative study ECG increased for both pharmacologic and exercise tests. Conclusions: In Mayo Clinic Rochester, annual SPECT utilization in patients without prior CAD increased between 1992 and 2002, but then decreased in advance of national trends. Normal tests increased, while summed stress score, summed difference score, and high risk tests all decreased. These data suggest that SPECT was increasingly utilized in patients with a lower prevalence of CAD.

Background: Over the past 20 years, there has been an increasing decline in the prevalence of abnormal stress single-photon emission computed tomography myocardial perfusion imaging (SPECT) studies among patients with no history of coronary artery disease (CAD). The trend of SPECT studies among patients with known CAD has not been evaluated before. Methods: Using the Mayo Clinic nuclear cardiology database, we examined all stress SPECT tests performed between 1/1991-12/2012 in patients with prior history of CAD defined as having prior myocardial infarction, percutaneous coronary intervention, and/or coronary artery bypass grafting. Patients with left bundle branch block, paced rhythm, bicycle or rest-only tests, cardiomyopathy, valvular heart disease, and technically unsatisfactory studies were excluded. The study cohort was divided into 5 time periods: 1991-5, 1996-2000, 2001-5, 2006-10, and 2011-12. Results: There were 19373 eligible SPECT tests (mean age 66.2 ± 10.9y, 75.4% men). Annual utilization of SPECT studies in patients with history of CAD increased from an average of 495 tests per year between 1991-1995 to a peak of 1425 in 2003; and then decreased to 552 tests in 2012. Asymptomatic patients comprised 33% in 1991-1995, peaked at 48% in 2006, and then decreased back to 31% in 2012. Over time, patients with typical angina decreased while patients with dyspnea increased, P <0.001 (Fig 1). The percentage of high risk SPECT tests significantly decreased, and the percentage of low-risk SPECT tests significantly increased despite the overall decline of SPECT utilization between 2003 and 2012. Almost 80% of all tests performed in 2012 had a low risk summed stress score compared to 29% in 1991, P <0.001 (Fig 2). Conclusions: In Mayo Clinic Rochester, annual SPECT utilization in patients with prior CAD increased between 1992 and 2003, but then decreased significantly after 2003. Fewer patients had typical angina while patients with dyspnea increased over time. High risk SPECT tests declined while low risk tests increased dramatically. These data suggest that stress SPECT was being increasingly utilized in CAD patients without typical angina who are at low risk.

Background : Unrecognized myocardial infarction (UMI), as diagnosed by surveillance electrocardiography (ECG), has the same poor prognosis as recognized (RMI), independent of ejection fraction or ischemia. The value of post UMI risk stratification by infarct size is unknown. Methods : The study group consisted of 5430 patients who underwent 2 day stress (exercise n = 191, pharmacologic n = 155) and rest Tc-99m sestamibi SPECT studies. UMI was diagnosed if ECG showed Q wave MI in the absence of history of MI. SPECT infarct size was quantitated based on a 60% of peak counts threshold method and was expressed as a percentage of the left ventricle (% LV). The association between infarct size and mortality was adjusted for clinical and exercise test prognostic scoring systems. Results : The population consisted of 346 UMI, 628 RMI, and 4456 patients without MI (No MI). Compared to No MI, mortality risk was increased in UMI (RR 1.7, 95% CI 1.6–1.9; p < 0.001) and RMI (RR 1.6, 95% CI 1.4–1.9; p < 0.001) patients. In the UMI group, infarct size was significantly associated with mortality ( p < 0.001), which persisted after adjustment for Mayo prognostic score alone (available in all patients) ( p < 0.001) and for Mayo prognostic score, Framingham risk score, and Duke treadmill score (data available in 137 patients) ( p < 0.001). For every 10% LV increase in infarct size, mortality risk increased 30% (RR = 1.3, 95% CI 1.2–1.5) (see figure ). Conclusions: In patients with UMI, larger quantitated SPECT infarct size predicts increased mortality independent of clinical and exercise test prognostic scoring systems. This finding supports the use of infarct size imaging for risk stratification of UMI patients.

Background— The Bypass Angioplasty Revascularization Investigation trial demonstrated that symptomatic diabetics with multivessel coronary artery disease had a survival advantage with initial coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI). No published study has examined different treatments and outcome in asymptomatic diabetics. Methods and Results— This study group consisted of 826 asymptomatic diabetics (age 62±12 years; 76% men) without known coronary artery disease who had abnormal myocardial perfusion during stress single photon emission computed tomography (SPECT). SPECT images were classified as low-, intermediate-, and high-risk. Early revascularization (CABG or PCI ≤4 months after SPECT) was performed in 76 patients. Survival (follow-up, 5.3±3.3 years) was compared in patients treated with CABG, PCI, or medical therapy. Revascularization (CABG or PCI) was performed in 54 of 261 patients with high-risk scans and was independently associated with improved survival (χ 2 =4.55; P =0.03 after multivariate adjustment). Subset analysis demonstrated that the survival advantage was confined to patients treated with CABG (n =39), with a 5-year survival CABG at 85%, PCI at 72%, and medical therapy at 67% ( P =0.02 for 3 groups). Although CABG was associated with better survival, mortality remained high (3% per year). There was no survival advantage by treatment for patients with less-severe SPECT abnormalities. Conclusions— These nonrandomized data suggest that CABG improves survival in asymptomatic diabetic patients with high-risk SPECT, although revascularization was performed infrequently in these patients. These results parallel those of the Bypass Angioplasty Revascularization Investigation trial in symptomatic diabetic patients.

NBCe1 is an electrogenic Na + bicarbonate cotransporter expressed as three isoforms. NBCe1A is mainly found in the kidney (100% activity), NBCe1B is a general isoform (~25% activity), and NBCe1C is found in the nervous system (20% activity). This project was to characterize mice with loss of NBCe1 in the kidney and urogenital tract and to test isoform activity ± IRBIT. Previous work has shown that NBCe1‐B is activated when IRBIT is present and interacts with the N‐terminus (Nt). Even though NBCe1C shares this Nt, the effects of IRBIT on human NBCe1C are unknown. Interstitial Cells of Cajal (ICC)pacemaker cells in the gastrointestinal tract ( c‐kit + ) have NBCe1C, IRBIT and require bicarbonate for normal gut activity. Developmentally similar ICC cells are found in the urogenital tract; however, NBCe1C locations within the kidney and urogenital tract are unknown. Using c‐kit ‐copGFP and NBCe1A‐knockout mice, kidneys, ureters, prostate, bladder, and urethra were dissected and analyzed via direct imaging, sectioning, and immunofluorescence. Oocytes injected with NBCe1C ± IRBIT were voltage clamped to determine the cotransporter's activity. “Strings” of c‐kit + ‐cells were found in the copGFP & nbce1A kidneys. In nbce1 (+/−) ‐(Het) mice (Figure), prostate ducts appeared enlarged, and in nbce1A − / − kidney, c‐kit protein was broadly expressed, showing cluster colocalization with NBCe1C. NBCe1C is not obviously expressed in WT or copGFP mice. Electrophysiology data showed that IRBIT activates NBCe1C by ~10‐fold. As c‐kit is also a marker of stem cells, NBCe1C/c‐kit association and c‐kit increase in nbce1A − / − mice, could suggest that NBCe1A loss elicits kidney repair itself (proliferation) and causes expression of other NBCe1‐isoforms. Support or Funding Information R25‐DK101405, R01‐DK057061, U54‐DK100227 (Mayo) and U54‐DK104310 (UW‐Madison) This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Electrical slow wave activity, generated by interstitial cells of Cajal (ICC), is essential for efficient gastrointestinal (GI) transit. Electrophysiology of slow waves has been extensively studied; inclusion of bicarbonate (HCO 3 − ) in extracellular solutions is required for recording normal slow wave activity. HCO 3 − transport contributes to regulation of intracellular pH, which has multiple consequences for normal cellular function. Previous transcriptional profiling found that the Na + / HCO 3 − cotransporter (NBCe1/Slc4a4) is enriched in pacemaker myenteric ICC (ICC‐MY) compared to non pacemaker ICC in the deep muscular plexus (ICC‐DMP) of the small intestine. Our aim was to determine the distribution and identity of Slc4a4/NBCe1 variants in ICC in the GI tract. NBCe1 immunoreactivity (IR) was detected by fluorescence labeling of parafomaldehyde‐fixed cross sections and whole mounts of adult mouse small intestine, colon and stomach using primary antibodies directed against a 329 amino acid sequence in the N terminus of the NBCe1 protein. Labeling of Kit receptor tyrosine kinase with a goat anti‐Kit polyclonal antibody was used to detect ICC. Slc4a4 knockout (KO) mice were bred from heterozygous founders. Slc4a4 fl/fl mice were bred with ETV1 CreERT2/− mice to allow targeted, conditional KO of Slc4a4 in ICC in response to tamoxifen treatment (130 mg/Kg). mRNA transcripts for Slc4a4 in Kit expressing cells were isolated from Kit‐ribotag mice, which were generated by breeding Kit creERT2 with Rpl22 tm1.1Psam mice. The abundance of specific Slc4a4 transcripts was measured by quantitative real time PCR (qRT‐PCR). Green fluorescent protein (GFP)‐labeled ICC were dissociated from the small intestine of neonatal Kit copGFP mice and RNA expression levels were determined using the Single Cell‐to‐CT™ qRT‐PCR Kit from Ambion. NBCe1‐IR was absent in all cells in Slc4a4‐KO tissues but co‐localized with Kit in ICC‐MY, but not in ICC‐DMP, in small intestine of wild type mice. In the proximal and distal colon, pacemaker submucosal ICC (ICC‐SMP) but not intramuscular ICC (ICC‐IM) or ICC‐MY showed NBCe1‐IR. In the corpus and antrum of the stomach NBCe1‐IR was detected in ICC‐MY but not in ICC‐IM. NBCe1‐IR did not co‐localize with Kit in the gastric fundus. mRNA for variant C, but not variants A or B of Slc4a4, was detected in small intestinal ICC‐MY. Reduced NBCe1‐IR was restricted to small intestinal ICC‐MY of Slc4a4 conditional KO mice. NBCe1 is enriched in subtypes of ICC responsible for pacemaker activity in all regions of the GI tract indicating a role for this transporter in slow wave generation. The presence of the C variant of Slc4a4 in ICC‐MY suggests dynamic regulation of NBCe1 activity in ICC by the I P 3 R b inding protein released with i nositol 1, 4, 5‐ t risphosphate (IRBIT). Support or Funding Information Supported by NIH R01 DK57061. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Ano1 is a Ca 2+ activated Cl − channel expressed in several proliferating cell types including various epithelia, gastrointestinal stromal tumors, interstitial cells of Cajal (ICC) and CFPAC‐1 cells. The aim of this study was to determine if Ano1 regulates proliferation. ICC from Ano1 (−/−) and Ano1 (+/+) mice were cultured with Cl − channel inhibitors or in low Cl − media. CFPAC‐1 cells grown in low Cl − media were pulsed with EdU for 1 h. Incorporation was measured by flow cytometry. For immunoblots on mouse jejunum, antibodies to pRb, phospho(Ser773)‐pRb and GAPDH were used. Fewer proliferating ICC were detected in Ano1 (−/−) cultures (15 ± 3.5% Ki67 + ICC vs 25 ± 4% in Ano1 (+/+) , mean ± SEM, n = 4, p < 0.05). Cl − channel inhibitors DIDS (10 μM), niflumate (10 μM) and tamoxifen (1 μM) decreased ICC proliferation by 53, 53 and 59%, respectively ( p < 0.05). This effect was reduced in cultures from Ano1 (−/−) mice (29% and 19 % decrease, 22% increase, p > 0.05). Fewer proliferating ICC and CFPAC‐1 cells were detected in low Cl − media (% EdU + ICC: 120 mM; 19.8 ± 5.3, 12 mM; 8.5 ± 3.2, n = 4, and % EdU + CFPAC‐1: 120 mM; 29.5, 12 mM; 14.3 p < 0.05). Proportionally less Ser773‐phosphorylated pRb was detected in jejunum from Ano1 (−/−) mice (Ano1 (+/+) ; 5.98 ± 0.78, Ano1 (−/−) ; 3.60 ± 0.49, mean ± SEM, n = 7, p < 0.05). In conclusion, Ano1 regulates proliferation possibly by promoting the G 1 /S transition of the cell cycle. Support: DK57061 and DK68055.