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Background: Peripheral venous distension evokes a pressor reflex (venous distension reflex). Afferent group III and IV nerves innervating veins are suggested as the afferent arm of the venous distension reflex. Prostaglandins stimulate/sensitize group III/IV nerves. We hypothesized that inhibition of prostaglandin synthesis by local cyclooxygenase blockade would attenuate the muscle sympathetic nerve activity (MSNA) and blood pressure responses to venous distension. Methods: Nineteen healthy volunteers (age, 27±5 years) participated in the study with 2 visits. To induce venous distension, a volume of solution (saline alone or 9 mg ketorolac tromethamine in saline) was infused into the vein in the antecubital fossa of an arterially occluded forearm. During the procedure, beat-by-beat heart rate, blood pressure and MSNA were recorded simultaneously. The vein size was measured with ultrasound. Results: In both visits, the venous distension procedure significantly increased blood pressure, heart rate, and MSNA (all, P P Conclusions: The presented data show that cyclooxygenase blockade attenuates the responses in MSNA and blood pressure to peripheral venous distension reflex. The results suggest that cyclooxygenase products play a key role in evoking afferent activation responsible for the venous distension reflex.

The venous distension reflex (VDR) is a pressor response evoked by peripheral venous distension and accompanied by increased muscle sympathetic nerve activity (MSNA). The effects of venous distension on the baroreflex, an important modulator of blood pressure (BP), have not been examined. The purpose of this study was to examine the effect of the VDR on baroreflex sensitivity (BRS). We hypothesized that the VDR will increase the sympathetic BRS (SBRS). Beat-by-beat heart rate (HR), BP, and MSNA were recorded in 16 female and 19 male young healthy subjects. To induce venous distension, normal saline equivalent to 5% of the forearm volume was infused into the veins of the occluded forearm. SBRS was assessed from the relationship between diastolic BP and MSNA during spontaneous BP variations. Cardiovagal BRS (CBRS) was assessed with the sequence technique. Venous distension evoked significant increases in BP and MSNA. Compared with baseline, during the maximal VDR response period, SBRS was significantly increased (−3.1 ± 1.5 to −4.5 ± 1.6 bursts·100 heartbeats−1·mmHg−1, P < 0.01) and CBRS was significantly decreased (16.6 ± 5.4 to 13.8 ± 6.1 ms·mmHg−1, P < 0.01). No sex differences were observed in the effect of the VDR on SBRS or CBRS. These results indicate that in addition to its pressor effect, the VDR altered both SBRS and CBRS. We speculate that these changes in baroreflex function contribute to the modulation of MSNA and BP during limb venous distension.

Acute whole body heat stress evokes sympathetic activation. However, the chronic effects of repeated moderate heat exposure (RMHE) on muscle sympathetic nerve activity (MSNA) in healthy individuals remain unclear. We performed RMHE with 4 wk (5 days/wk) of warm baths (∼40°C, for 30 min) in nine healthy older (59 ± 2 yr) volunteers. Hemodynamic variables and MSNA were examined before, 1 day after, and 1 wk following 4 wk of RMHE in a laboratory at ∼23°C. Cold pressor test (CPT) and handgrip (HG) exercise were performed during the tests. Under normothermic condition, the resting MSNA burst rate (prior, post, post 1-wk: 31.6 ± 2.0, 25.2 ± 2.0, and 27.7 ± 1.7 bursts/min; P < 0.001) and burst incidence (P < 0.001) significantly decreased after RMHE. Moreover, the resting heart rate significantly decreased after RMHE (62 ± 2, 60 ± 2, and 58 ± 2 beats/min, P = 0.031). The sensitivity of baroreflex control of MSNA and heart rate were not altered by RMHE, although the operating points were reset. The MSNA and hemodynamic responses (i.e., changes) to handgrip exercise or cold pressor test were not significantly altered. These data suggest that the RMHE evoked by warm baths decreases resting sympathetic activity and heart rate, which can be considered beneficial effects. The mechanism(s) should be examined in future studies. NEW & NOTEWORTHY To our knowledge, this is the first study to observe the effects of repeated warm baths on sympathetic nerve activity during rest and stress in healthy middle age and older individuals. The data suggest that the repeated warm baths decreased resting sympathetic activity and heart rate, which can be considered beneficial effects. This study also provides the first evidence that the repeated warm baths did not alter the baroreflex sensitivity and the sympathetic responses to stress.

The effects of nitroglycerin (glyceryl trinitrate, GTN) on baroreflex sensitivity (BRS) are incompletely understood. Moreover, there are no reports evaluating the acute responses in both the sympathetic BRS (SBRS) and the cardiovagal BRS (CBRS) to the administration of sublingual GTN. We hypothesized that sublingual GTN modulates both CBRS and SBRS. In 10 healthy subjects, beat-to-beat heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were recorded before and for 10 min after sublingual administration of GTN 0.4 mg. SBRS was evaluated from the relationship between spontaneous variations in diastolic BP and MSNA. CBRS was assessed with the sequence technique. These variables were assessed during baseline, during 3rd–6th min ( post A), and 7th–10th min ( post B) after GTN administration. Two min after GTN administration, MSNA increased significantly and remained significantly elevated during recording. Compared with baseline, CBRS decreased significantly ( post A: 12.9 ± 1.6 to 7.1 ± 1.0 ms/mmHg, P < 0.05), whereas SBRS increased significantly ( post A: 0.8 ± 0.2 to 1.5 ± 0.2 units·beat−1·mmHg−1, P < 0.05) with an upward shift of the operating point. There were no differences in these variables between posts A and B. A clinical dose of GTN increased MSNA rapidly through effects on both CBRS and SBRS. These effects should be kept in mind when nitrates are used to clinically treat chest pain and acute coronary syndromes and used as vasodilators in experimental settings.

Although it is known that peripheral arterial disease (PAD) is associated with chronic myopathies, the acute muscular responses to exercise in this population are less clear. This study used diffusion tensor imaging (DTI) to compare acute exercise-related muscle damage between PAD patients and healthy controls. Eight PAD patients and seven healthy controls performed graded plantar flexion in the bore of a 3T MRI scanner. Exercise began at 2 kg and increased by 2 kg every 2 min until failure, or completion of 10 min of exercise. DTI images were acquired from the lower leg pre- and post-exercise, and were analyzed for mean diffusivity, fractional anisotropy (FA), and eigenvalues 1–3 (λ1–3) of the medial gastrocnemius (MG) and tibialis anterior (TA). Results indicated a significant leg by time interaction for mean diffusivity, explained by a significantly greater increase in diffusivity of the MG in the most affected legs of PAD patients (11.1 × 10–4 ± 0.5 × 10–4 mm2/s vs. 12.7 × 10–4 ± 1.2 × 10–4 mm2/s at pre and post, respectively, P = 0.02) compared to healthy control subjects (10.8 × 10–4 ± 0.3 × 10–4 mm2/s vs. 11.2 × 10–4 ± 0.5 × 10–4 mm2/s at pre and post, respectively, P = 1.0). No significant differences were observed for the TA, or λ1–3 (all P ≥ 0.06). Moreover, no reciprocal changes were observed for FA in either group (all P ≥ 0.29). These data suggest that calf muscle diffusivity increases more in PAD patients compared to controls after exercise. These findings are consistent with the notion that acute exercise results in increased muscle damage in PAD.

Autonomic blood pressure control is fundamentally altered during a single bout of exercise, as evidenced by the downward resetting of the baroreflex following exercise (postexercise hypotension). However, it is unclear if an acute bout of exercise is also associated with a change in the sensitivity of the exercise pressor response to a controlled stimulus, such as a static contraction. This study tested the hypothesis that the blood pressure response to a controlled static contraction would be attenuated after unilateral cycling of the contralateral (opposite) leg, but preserved after cycling of the ipsilateral (same) leg. To test this, the blood pressure response to 90 s of isometric plantar flexion [50% maximal voluntary contraction (MVC)] was compared before and after 20 min of contralateral and ipsilateral single-leg cycling at 20% peak oxygen consumption and rest (control) in 10 healthy subjects (three males and seven females). The mean arterial pressure response was significantly attenuated after contralateral single-leg cycling (+9.8 ± 7.5% ∆mmHg vs. +6.7 ± 6.6% ∆mmHg pre and postexercise, respectively, P = 0.04) and rest (+9.0 ± 7.5% ∆mmHg vs. +6.6 ± 5.2% ∆mmHg pre and postexercise, respectively, P = 0.03). In contrast, the pressor response nonsignificantly increased following ipsilateral single-leg cycling (+5.5 ± 5.2% ∆mmHg vs. +8.9 ± 7.2% ∆mmHg pre and postexercise, respectively, P = 0.08). The heart rate, leg blood flow, and leg conductance responses to plantar flexion were not affected by any condition ( P ≥ 0.12). These results are consistent with the notion that peripheral, but not central mechanisms promote exercise pressor reflex sensitivity after exercise.

As the overlap between heart disease and cancer patients increases as cancer-specific mortality is decreasing and the surviving population is aging, it is necessary to identify cancer patients who are at an increased risk of death from heart disease. The purpose of this study is to identify cancer patients at highest risk of fatal heart disease compared to the general population and other cancer patients at risk of death during the study time period. Here we report that 394,849 of the 7,529,481 cancer patients studied died of heart disease. The heart disease-specific mortality rate is 10.61/10,000-person years, and the standardized mortality ratio (SMR) of fatal heart disease is 2.24 (95% CI: 2.23–2.25). Compared to other cancer patients, patients who are older, male, African American, and unmarried are at a greatest risk of fatal heart disease. For almost all cancer survivors, the risk of fatal heart disease increases with time., As the overlap between heart disease and cancer patients increases as cancer-specific mortality is decreasing, identifying cancer patients who are at an increased risk of death from heart disease is important. Here the authors report on risk of death from heart diseases among more than 7.5 million cancer patients.

Patients with peripheral artery disease (PAD) have an accentuated exercise pressor reflex (EPR) during exercise of the affected limb. The underlying hemodynamic changes responsible for this, and its effect on blood flow to the exercising extremity, are unclear. We tested the hypothesis that the exaggerated EPR in PAD is mediated by an increase in total peripheral resistance (TPR), which augments redistribution of blood flow to the exercising limb. Twelve patients with PAD and 12 age- and sex-matched subjects without PAD performed dynamic plantar flexion (PF) using the most symptomatic leg at progressive workloads of 2–12 kg (increased by 1 kg/min until onset of fatigue). We measured heart rate, beat-by-beat blood pressure, femoral blood flow velocity (FBV), and muscle oxygen saturation ([Formula: see text]) continuously during the exercise. Femoral blood flow (FBF) was calculated from FBV and baseline femoral artery diameter. Stroke volume (SV), cardiac output (CO), and TPR were derived from the blood pressure tracings. Mean arterial blood pressure and TPR were significantly augmented in PAD compared with control during PF. FBF increased during exercise to an equal extent in both groups. However, [Formula: see text] of the exercising limb remained significantly lower in PAD compared with control. We conclude that the exaggerated pressor response in PAD is mediated by an abnormal TPR response, which augments redistribution of blood flow to the exercising extremity, leading to an equal rise in FBF compared with controls. However, this increase in FBF is not sufficient to normalize the SmO2 response during exercise in patients with PAD. NEW & NOTEWORTHY In this study, peripheral artery disease (PAD) patients and healthy control subjects performed graded, dynamic plantar flexion exercise. Data from this study suggest that previously reported exaggerated exercise pressor reflex in patients with PAD is driven by greater vasoconstriction in nonexercising vascular territories which also results in a redistribution of blood flow to the exercising extremity. However, this rise in femoral blood flow does not fully correct the oxygen deficit due to changes in other mechanisms that require further investigation.

Venous saline infusions in an arterially occluded forearm evoke reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) in humans (venous distension reflex). It is unclear if the inputs from metabolically sensitive skeletal muscle afferents (i.e., muscle metaboreflex) would modify the venous distension reflex. We hypothesized that muscle metaboreceptor stimulation might augment the venous distension reflex. BP (Finapres), heart rate (ECG), and MSNA (microneurography) were assessed in 18 young healthy subjects. In trial A, saline (5% forearm volume) was infused into the veins of an arterially occluded arm (nonhandgrip trial). In trial B, subjects performed 2-min static handgrip followed by postexercise circulatory occlusion (PECO) of the arm. During PECO, saline was infused into the veins of the arm (handgrip trial). In trial A, the infusion increased MSNA and BP as expected (both P < 0.001). In trial B, handgrip significantly raised MSNA, BP, and venous lactic acid concentrations. Venous saline infusion during PECO further raised MSNA and BP (both P < 0.001). The changes in MSNA (Δ8.6 ± 1.5 to Δ10.6 ± 1.8 bursts/min, P = 0.258) and mean arterial pressure ( P = 0.844) evoked by the infusion during PECO were not significantly different from those in the nonhandgrip trial. These observations indicate that venous distension reflex responses are preserved during sympathetic activation mediated by the muscle metaboreflex.

Smoking is a risk factor for cardiovascular diseases. Prior reports showed a transient increase in blood pressure (BP) following a spontaneous burst of muscle sympathetic nerve activity (MSNA). We hypothesized that this pressor response would be accentuated in smokers. Using signal-averaging techniques, we examined the BP (Finometer) response to MSNA in 18 otherwise healthy smokers and 42 healthy nonsmokers during resting conditions. The sensitivities of baroreflex control of MSNA and heart rate were also assessed. The mean resting MSNA, heart rate, and mean arterial pressure (MAP) were higher in smokers than nonsmokers. The MAP increase following a burst of MSNA was significantly greater in smokers than nonsmokers (Δ3.4 ± 0.3 vs. Δ1.6 ± 0.1 mmHg, P < 0.001). The baroreflex sensitivity (BRS) of burst incidence, burst area, or total activity was not different between the two groups. However, cardiac BRS was lower in smokers than nonsmokers (14.6 ± 1.7 vs. 24.6 ± 1.5 ms/mmHg, P < 0.001). Moreover, the MAP increase following a burst was negatively correlated with the cardiac BRS. These observations suggest that habitual smoking in otherwise healthy individuals raises the MAP increase following spontaneous MSNA and that the attenuated cardiac BRS in the smokers was a contributing factor. We speculate that the accentuated pressor increase in response to spontaneous MSNA may contribute to the elevated resting BP in the smokers.

Prior reports show that whole body heat stress attenuates the pressor response to exercise in young healthy subjects. The effects of moderate whole body heating (WBH; e.g., increase in internal temperature Tcore of ∼0.4°C–0.5°C) or limb heating on sympathetic and cardiovascular responses to exercise in older healthy humans remain unclear. We examined the muscle sympathetic nerve activity (MSNA), mean arterial blood pressure (MAP), and heart rate (HR) in 14 older (62 ± 2 yr) healthy subjects during fatiguing isometric handgrip exercise and postexercise circulatory occlusion (PECO). The protocol was performed under normothermic, moderate WBH, and local limb (i.e., forearm) heating conditions during three visits. During the mild WBH stage (increase in Tcore of core of ∼0.4°C), BP decreased, HR increased, and MSNA was unchanged from baseline. Compared with the normothermic trial, the absolute MAP during fatiguing exercise and PECO was lower during the WBH trial. Moreover, MSNA and MAP responses (i.e., changes) to fatiguing exercise were also less than those seen during the normothermic trial. Limb heating induced a similar increase in forearm muscle temperature to that seen in the WBH trial (∼0.7°C–1.5°C). Limb heating did not alter resting MAP, HR, or MSNA. The MSNA and hemodynamic responses to exercise in the limb heating trial were not different from those in the normothermic trial. These data suggest that moderate WBH attenuates MSNA and BP responses to exercise in older healthy humans.

One in three Americans suffer from kidney diseases such as chronic kidney disease, and one of the etiologies is suggested to be long-term renal hypoxia. Interestingly, sympathetic nervous system activation evokes a renal vasoconstrictor effect that may limit oxygen delivery to the kidney. In this report, we sought to determine if sympathetic activation evoked by lower body negative pressure (LBNP) would decrease cortical and medullary oxygenation in humans. LBNP was activated in a graded fashion (LBNP; −10, −20, and −30 mmHg), as renal oxygenation was measured (T2*, blood oxygen level dependent, BOLD MRI; n = 8). At a separate time, renal blood flow velocity (RBV) to the kidney was measured (n = 13) as LBNP was instituted. LBNP significantly reduced RBV (P = 0.041) at −30 mmHg of LBNP (Δ−8.17 ± 3.75 cm/s). Moreover, both renal medullary and cortical T2* were reduced with the graded LBNP application (main effect for the level of LBNP P = 0.0008). During recovery, RBV rapidly returned to baseline, whereas medullary T2* remained depressed into the first minute of recovery. In conclusion, sympathetic activation reduces renal blood flow and leads to a significant decrease in oxygenation in the renal cortex and medulla. NEW & NOTEWORTHY In healthy young adults, increased sympathetic activation induced by lower body negative pressure, led to a decrease in renal cortical and medullary oxygenation measured by T2*, a noninvasive magnetic resonance derived index of deoxyhemoglobin levels. In this study, we observed a significant decrease in renal cortical and medullary oxygenation with LBNP as well as an increase in renal vasoconstriction. We speculate that sympathetic renal vasoconstriction led to a significant reduction in tissue oxygenation by limiting oxygen delivery to the renal medulla.

Background and objectiveIncreasing mortality and decreasing life expectancy in the USA are largely attributable to accidental overdose, alcohol-related disease and suicide. These ‘deaths of despair’ often follow years of morbidity, yet little is known about trends in the clinical recognition of ‘diseases of despair’. The objective of this study is to characterise rates of clinically documented diseases of despair over the last decade and identify sociodemographic risk factors.DesignRetrospective study using a healthcare claims database with 10 years of follow-up.SettingParticipants resided nationwide but were concentrated in US states disproportionately affected by deaths of despair, including Pennsylvania, West Virginia and Delaware.ParticipantsCohort included 12 144 252 participants, with no restriction by age or gender.Outcome measuresDiseases of despair were defined as diagnoses related to alcohol misuse, substance misuse and suicide ideation/behaviours. A lookback period was used to identify incident diagnoses. Annual and all-time incidence/prevalence estimates were computed, along with risk for current diagnosis and patterns of comorbidity.Results515 830 participants received a disease of despair diagnosis (58.5% male, median 36 years). From 2009 to 2018, the prevalence of alcohol-related, substance-related and suicide-related diagnoses respectively increased by 37%, 94%, and 170%. Ages 55–74 had the largest increase in alcohol/substance-related diagnoses (59% and 172%). Ages ConclusionsIncreasing clinical rates of disease of despair diagnoses largely mirror broader societal trends in mortality. While the opioid crisis remains a top public health priority, parallel rises in alcohol-related diagnoses and suicidality must be concurrently addressed. Findings suggest opportunities for healthcare systems and providers to deploy targeted prevention to mitigate the progression of morbidities towards mortality.

Peripheral arterial diseases (PAD) is an atherosclerotic occlusive disease in the periphery affecting 8-12 million U.S.adults. It has been reported that the PAD patients have attenuated coronary blood flow response to stress, however how the diseases influence aortic arterial pulse wave properties during exercise, and its relationship with coronary perfusion in this patient population is unknown. Accordingly, the primary aim of this study was to examine myocardial supply and demand relationship by investigating aortic pulse wave properties and their relationship with coronary perfusion during exercise in PAD. Methods: 13 PADpatients and 13 healthy (age, sex, BMI-matched) control subjects performed rhythmic plantar flexion for 14 minutes or until fatigue (30 contractions per minute). The workload started at 2 kg and increased by 1 kg every minute up to12 kg. Brachial (oscillometric cuff) and aortic (SphygmoCor, utilizing transfer function and brachial blood pressures) blood pressures were measured during supine rest and plantar flexion exercise as well as aortic pulse wave properties from derived-aortic pulse waveforms. On a separate visit, coronary blood flow velocity was measured non-invasively during rest and exercise. Results: Due to earlier arrival of reflected wave (140.9± 2.3 vs. 150.5± 3.4 ms; P =0.0289), baseline augmented pressure (15.9± 2.4 vs. 9.3± 1.7 mmHg; AP, P =0.0380), augmentation index (27.2± 2.7 vs. 19.1± 2.2 %; AI, P =0.0263), and cardiac wasted energy (4625± 590 vs. 2875± 491 s· dyne· cm 2 ; E w , P =0.0321) were greater compared to healthy control. During exercise, changes in aortic mean arterial pressure(21.90± 5.04 vs. 9.36± 2.20 mmHg; ΔaMAP, P =0.0041), end-systolic pressure (133.38± 4.85 vs. 111.46± 4.97 mmHg; ΔESP, P =0.0043), and the tension time index (1027± 216 vs. 504± 117 mmHg· S -1 · min -1 ; ΔTTI, P =0.0035) were significantly greater in PAD while ΔAI was not different. Intriguingly, despite the augmented TTI, the first and second peaks of CBV during exercise were not different between the groups leading to significantly attenuated subendocardial viability ratio responses to exercise (-34.66± 4.19 vs. -23.03± 3.37 %; ΔSEVR, P =0.0164). Conclusions: At this peak workload for PAD patients, the patients had a greater myocardial demand compared to healthy control. However, despite the increase in the myocardial demand and the accompanying increase in initial coronary perfusion pressure (ESP), CBV of PAD patients was not different from that seen in healthy control indicating limited myocardial supply during exercise in PAD. Consequently, PAD exhibited a greater mismatch of myocardial demand and supply at the peak workload. This suggests that, in PAD patients, there are mechanisms aside from changes in coronary perfusion pressure that limit myocardial supply during exercise (i.e. a greater coronary vascular tone and diastolic dysfunction).

Earlier reports suggest that limb venous distension evokes reflex increases in muscle sympathetic nerve activity (MSNA) and blood pressure (BP) (i.e., venous distension reflex). Our recent report also shows that suction of arterially occluded limb evokes venous distension reflex. We postulate that the venous distension reflex contributes to autonomic responses to orthostatic stress. In this study, we hypothesized that orthostatic tolerance would be linked to the MSNA response seen with lower limb suction. Fifteen healthy subjects were tested in the supine position. Negative pressure (−100 mmHg) was applied on an arterially occluded lower limb for 2 min. MSNA from the peroneal nerve in the limb not exposed to suction, ECG, and BP (Finometer) was recorded throughout the study. Limb occlusion without suction was used as a control trial. In a separate visit, the individual’s orthostatic tolerance was assessed using a graded lower body negative pressure (LBNP) tolerance test. Mean arterial BP and MSNA (18.6 ± 1.9 to 23.6 ± 2.0 bursts/min) significantly (both P < 0.05) increased during limb suction. Orthostatic tolerance index positively correlated ( R = 0.636, P = 0.011) with the MSNA response seen with suction during occlusion. Since the venous distension reflex strength correlates with the level of orthostatic tolerance, we speculate that lower-limb venous distension reflex engagement increases the sympathetic responses during orthostatic challenge and serves to maintain BP with postural stress.

The purpose of this study was to investigate blood pressure (BP) and leg skeletal muscle oxygen saturation (Smo2) during treadmill walking in patients with peripheral artery disease (PAD) and healthy subjects. Eight PAD patients (66 ± 8 yr, 1 woman) and eight healthy subjects (65 ± 7 yr, 1 woman) walked on a treadmill at 2 mph (0.89 m/s). The incline increased by 2% every 2 min, from 0 to 15% or until maximal discomfort. BP was measured every 2 min with an auscultatory cuff. Heart rate (HR) was recorded continuously with an ECG. Smo2 in the gastrocnemius muscle was measured on each leg using near-infrared spectroscopy. The change in systolic BP from seated to peak walking time (PWT) was greater in PAD (healthy: 23 ± 9 vs. PAD: 44 ± 19 mmHg, P = 0.007). HR was greater in PAD patients compared with controls at PWT ( P = 0.011). The reduction in Smo2 (PWT − seated) was greater in PAD (healthy: 15 ± 12 vs. PAD: 49 ± 5%, P < 0.001) in the most affected leg and in the least affected leg (healthy: 12 ± 11 vs. PAD: 32 ± 18%, P = 0.003). PAD patients have an exaggerated decline in leg Smo2 during walking compared with healthy subjects, which may elicit the exaggerated rise in BP and HR during walking in PAD. NEW & NOTEWORTHY This is the first study to simultaneously measure skeletal muscle oxygen saturation and blood pressure (BP) during treadmill exercise in patients with peripheral arterial disease. We found that BP and leg deoxygenation responses to slow-paced, graded treadmill walking are greater in patients with peripheral arterial disease compared with healthy subjects. These data may help explain the high cardiovascular risk in patients with peripheral arterial disease.

Importance Diseases of despair (ie, mortality or morbidity from suicidality, drug abuse, and alcoholism) were first characterized as increasing in rural White working-class populations in midlife with low educational attainment and associated with long-term economic decline. Excess mortality now appears to be associated with working-class citizens across demographic and geographic boundaries, but no known qualitative studies have engaged residents of rural and urban locales with high prevalence of diseases of despair to learn their perspectives. Objective To explore perceptions about despair-related illness and potential intervention strategies among diverse community members residing in discrete rural and urban hotspots. Design, Setting, and Participants In this qualitative study, high-prevalence hotspots for diseases of despair were identified from health insurance claims data in Central Pennsylvania. Four focus groups were conducted with 60 community members in organizations and coalitions from 3 census block group hotspot clusters in the health system between September 2019 and January 2020. Focus groups explored awareness and beliefs about causation and potential intervention strategies. Main Outcomes and Measures A descriptive phenomenological approach was applied to thematic analysis, and a preliminary conceptual model was constructed to describe how various factors may be associated with perpetuating despair and with public health. Results In total, 60 adult community members participated in 4 focus groups (44 women, 16 men; 40 White non-Hispanic, 17 Black, and 3 Hispanic/Latino members). Three focus groups with 43 members were held in rural areas with high prevalence of diseases of despair, and 1 focus group with 17 members in a high-prevalence urban area. Four themes emerged with respect to awareness and believed causation of despair-related illness, and participants identified common associated factors, including financial distress, lack of critical infrastructure and social services, deteriorating sense of community, and family fragmentation. Intervention strategies focused around 2 themes: (1) building resilience to despair through better community and organizational coordination and peer support at the local level and (2) encouraging broader state investments in social services and infrastructure to mitigate despair-related illness. Conclusions and Relevance In this qualitative study, rural and urban community members identified common factors associated with diseases of despair, highlighting the association between long-term political and economic decline and public health and a need for both community- and state-level solutions to address despair. Health care systems participating in addressing community health needs may improve processes to screen for despair (eg, social history taking) and codesign primary, secondary, and tertiary interventions aimed at addressing factors associated with distress. Such actions have taken on greater urgency with the COVID-19 pandemic.

OBJECTIVES: Gardeners may have better health outcomes, and consume more fruits and vegetables (F&V), than non-gardeners. However, this evidence is mainly based on small, non-representative samples. The purpose of this study was to understand differences in dietary and health outcomes between gardeners and non-gardeners using physical activity data from the 2019 Behavioral Risk Factor Surveillance System (BRFSS). METHODS: Adults (age 18+) with complete self-reported physical activity (PA) data were included. Participants were grouped as those who: (1) did not engage in any PA (non-exercisers), (2) reported gardening as their first or second PA (gardeners), or (3) reported any PA other than gardening (exercisers). Logistic and linear regression models identified associations between cardiovascular disease risk factors (self-reported, yes/no for body mass index (BMI)≥ 25 kg/m(2), high cholesterol, or hypertension) or F&V intake (times/day, continuous) and group after controlling for age, race, sex, and education level. RESULTS: The sample (n = 396,261) was 55% women, majority white (81%), with more than a high school education (66%), and a mean age of 51 years. It was 7.6% gardeners, 65.2% other exercisers, and 27.2% non-exercisers. Gardeners were significantly more likely than exercisers or non-exercisers to be women (60.7% v. 49.3% and 53.4%, P

Peripheral artery disease (PAD) is an atherosclerotic vascular disease that affects 200 million people worldwide. Although PAD primarily affects large arteries, it is also associated with microvascular dysfunction, an exaggerated blood pressure (BP) response to exercise, and high cardiovascular mortality. We hypothesized that fatiguing plantar flexion exercise that evokes claudication elicits a greater reduction in skeletal muscle oxygenation (SmO2) and a higher rise in BP in PAD compared with age-matched healthy subjects, but low-intensity steady-state plantar flexion elicits similar responses between groups. In the first experiment, eight patients with PAD and eight healthy controls performed fatiguing plantar flexion exercise (from 0.5 to 7 kg for up to 14 min). In the second experiment, seven patients with PAD and seven healthy controls performed low-intensity plantar flexion exercise (2.0 kg for 14 min). BP, heart rate (HR), and SmO2 were measured continuously using near-infrared spectroscopy (NIRS). SmO2 is the ratio of oxygenated hemoglobin to total hemoglobin, expressed as a percent. At fatigue, patients with PAD had a greater increase in mean arterial BP (18 ± 2 vs. vs. 10 ± 2 mmHg, P = 0.029) and HR (14 ± 2 vs. 6 ± 2 beats/min, P = 0.033) and a greater reduction in SmO2 (−54 ± 10 vs. −12 ± 4%, P = 0.001). However, both groups had similar physiological responses to low-intensity, nonpainful plantar flexion exercise. These data suggest that patients with PAD have altered oxygen uptake and/or utilization during fatiguing exercise coincident with an augmented BP response. NEW & NOTEWORTHY In this laboratory study, patients with peripheral artery disease performed plantar flexion exercise in the supine posture until symptoms of claudication occurred. Relative to age- and sex-matched healthy subjects we found that patients had a higher blood pressure response, a higher heart rate response, and a greater reduction in skeletal muscle oxygenation as determined by near-infrared spectroscopy. Our data suggest that muscle ischemia contributes to the augmented exercise pressor reflex in peripheral artery disease.

Heat stress evokes significant increases in muscle sympathetic nerve activity (MSNA) in healthy individuals. The MSNA response to heat stress in chronic heart failure (CHF) is unknown. We hypothesized that the MSNA response to heat stress is attenuated in CHF. Passive whole body heating was applied with water-perfused suits in 13 patients (61 ± 2 yr) with stable class II-III CHF, 12 age-matched (62 ± 2 yr) healthy subjects, and 14 young (24 ± 1 yr) healthy subjects. Mild heating (i.e., increases in skin temperature ΔTsk ~2–4°C, internal temperature ΔTcore

Background Peripheral arterial disease (PAD) is an atherosclerotic vascular disease that affects over 200 million people worldwide. The hallmark of PAD is ischemic leg pain and this condition is also associated with an augmented blood pressure response to exercise, impaired vascular function, and high risk of myocardial infarction and cardiovascular mortality. In this study, we tested the hypothesis that coronary exercise hyperemia is impaired in PAD. Methods Twelve patients with PAD and no overt coronary disease (65 ± 2 years, 7 men) and 15 healthy control subjects (64 ± 2 years, 9 men) performed supine plantar flexion exercise (30 contractions/min, increasing workload). A subset of subjects ( n = 7 PAD, n = 8 healthy) also performed isometric handgrip exercise (40% of maximum voluntary contraction to fatigue). Coronary blood velocity in the left anterior descending artery was measured by transthoracic Doppler echocardiography; blood pressure and heart rate were monitored continuously. Results Coronary blood velocity responses to 4 min of plantar flexion exercise (PAD: Δ2.4 ± 1.2, healthy: Δ6.0 ± 1.6 cm/sec, P = 0.039) and isometric handgrip exercise (PAD: Δ8.3 ± 4.2, healthy: Δ16.9 ± 3.6, P = 0.033) were attenuated in PAD patients. Conclusion These data indicate that coronary exercise hyperemia is impaired in PAD, which may predispose these patients to myocardial ischemia.

The effects of whole body heat stress on sympathetic and cardiovascular responses to stimulation of muscle metaboreceptors and mechanoreceptors remains unclear. We examined the muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate in 14 young healthy subjects during fatiguing isometric handgrip exercise, postexercise circulatory occlusion (PECO), and passive muscle stretch during PECO. The protocol was performed under normothermic and whole body heat stress (increase internal temperature ~0.6°C via a heating suit) conditions. Heat stress increased the resting MSNA and heart rate. Heat stress did not alter the mean blood pressure (MAP), heart rate, and MSNA responses (i.e., changes) to fatiguing exercise. During PECO, whole body heat stress accentuated the heart rate response [change (Δ) of 5.8 ± 1.5 to Δ10.0 ± 2.1 beats/min, P = 0.03], did not alter the MSNA response (Δ16.4 ± 2.8 to Δ17.3 ± 3.8 bursts/min, P = 0.74), and lowered the MAP response (Δ20 ± 2 to Δ12 ± 1 mmHg, P < 0.001). Under normothermic conditions, passive stretch during PECO evoked significant increases in MAP and MSNA (both P < 0.001). Of note, heat stress prevented the MAP and MSNA responses to stretch during PECO (both P > 0.05). These data suggest that whole body heat stress attenuates the pressor response due to metaboreceptor stimulation, and the sympathetic nerve response due to mechanoreceptor stimulation.

It is unclear if the exaggerated exercise pressor reflex observed in peripheral arterial disease (PAD) patients facilitates Oxygen (O2) transport during presymptomatic exercise. Accordingly, this study compared O2 transport between PAD patients and healthy controls during graded presymptomatic work. Seven PAD patients and seven healthy controls performed dynamic plantar flexion in the bore of a 3T MRI scanner. Perfusion, T2* (an index of relative tissue oxygenation), and SvO2 (a measure of venous oxygen saturation) were collected from the medial gastrocnemius (MG) during the final 10 seconds of each stage. Blood pressure was also collected during the final minute of each stage. As expected, the pressor response to presymptomatic work (4 kg) was exaggerated in PAD patients compared to controls (+14 mmHg ± 4 and +7 mmHg ± 2, P ≤ 0.034). When normalized to changes in free water content (S0), T2* was lower at 2 kg in PAD patients compared to controls (−0.91 Δms/ΔAU ± 0.3 and 0.57 Δms/ΔAU ± 0.3, P ≤ 0.008); followed by a greater increase in perfusion at 4 kg in the PAD group (+18.8 mL/min/100g ± 6.2 vs. −0.21 mL/min/100g ± 3.2 in PAD and controls, P ≤ 0.026). Lastly, SvO2 decreased at 4 kg in both groups (−13% ± 4 and −2% ± 4 in PAD and controls, P ≤ 0.049), suggesting an increase in O2 extraction in the PAD group. Based on these findings, O2 transport appears to be augmented during graded presymptomatic work in PAD patients, and this may be partially mediated by an exaggerated pressor response.

Radiofrequency catheter ablation (RFCA) is a frequently performed procedure in patients with atrial fibrillation. Prior studies have shown that the RFCA may directly stimulate vagal afferents during the procedure, whereas the vagal tone assessed by heart rate variability (HRV) is lowered weeks after the RFCA procedure. The effects of RFCA performed in the left atrium on sympathetic nerve activity have not been assessed. In the present study, we hypothesized that RFCA would lower muscle sympathetic nerve activity (MSNA) during ablation and would raise MSNA 1 day postablation. A total of 18 patients were studied. In protocol 1 ( n = 10), electrocardiogram, blood pressure, and MSNA in the peroneal nerve were recorded through the RFCA procedure performed in the electrophysiology laboratory. In protocol 2, eight patients were studied before the procedure and 1 day postablation. RFCA led to a decrease in MSNA immediately after the procedure (25.4 ± 3.2 to 17.2 ± 3.8 bursts/min, P < 0.05). Cardiac parasympathetic activity was determined using indexes of HRV and increased during the procedure. One day postablation, MSNA was above baseline values (21.3 ± 3.7 to 35.7 ± 2.6 bursts/min, P < 0.05). HRV indexes of cardiac parasympathetic activity fell, and the HRV index of sympathovagal balance was not significantly altered. The results show that RFCA raised cardiac parasympathetic activity and decreased MSNA during the procedure. One day postablation, MSNA rose and cardiac parasympathetic activity fell. In addition, RFCA evokes differentiated sympathetic responses directed to the heart and skeletal muscles. NEW & NOTEWORTHY The effects of radiofrequency catheter ablation performed in the left atrium on muscle sympathetic nerve activity (MSNA) have not been assessed. The results of this study show that radiofrequency catheter ablation raised cardiac parasympathetic activity and decreased MSNA during the procedure. One day postablation, MSNA rose and cardiac parasympathetic activity fell. We speculate that the partial autonomic afferent denervation induces these effects on autonomic activity.