A genome sequencing system for universal newborn screening, diagnosis, and precision medicine for severe genetic diseases.

Newborn screening (NBS) dramatically improves outcomes in severe childhood disorders by treatment before symptom onset. In many genetic diseases, however, outcomes remain poor because NBS has lagged behind drug development. Rapid whole-genome sequencing (rWGS) is attractive for comprehensive NBS because it concomitantly examines almost all genetic diseases and is gaining acceptance for genetic disease diagnosis in ill newborns. We describe prototypic methods for scalable, parentally consented, feedback-informed NBS and diagnosis of genetic diseases by rWGS and virtual, acute management guidance (NBS-rWGS). Using established criteria and the Delphi method, we reviewed 457 genetic diseases for NBS-rWGS, retaining 388 (85%) with effective treatments. Simulated NBS-rWGS in 454,707 UK Biobank subjects with 29,865 pathogenic or likely pathogenic variants associated with 388 disorders had a true negative rate (specificity) of 99.7% following root cause analysis. In 2,208 critically ill children with suspected genetic disorders and 2,168 of their parents, simulated NBS-rWGS for 388 disorders identified 104 (87%) of 119 diagnoses previously made by rWGS and 15 findings not previously reported (NBS-rWGS negative predictive value 99.6%, true positive rate [sensitivity] 88.8%). Retrospective NBS-rWGS diagnosed 15 children with disorders that had been undetected by conventional NBS. In 43 of the 104 children, had NBS-rWGS-based interventions been started on day of life 5, the Delphi consensus was that symptoms could have been avoided completely in seven critically ill children, mostly in 21, and partially in 13. We invite groups worldwide to refine these NBS-rWGS conditions and join us to prospectively examine clinical utility and cost effectiveness.

Muscle Oxygenation, Neural, and Cardiovascular Responses to Isometric and Workload-matched Dynamic Resistance Exercise.

Differences in blood flow patterns and energy cost between isometric and dynamic resistance exercise may result to variant cardiovascular, neural, and muscle metabolic responses. We aimed to compare the cardiovascular, baroreceptor sensitivity, and muscle oxygenation responses between workload-matched, large muscle-mass isometric and dynamic resistance exercises. Twenty-four young men performed an isometric and a dynamic double leg-press protocol (4 sets×2 min) with similar tension time index (workload). Beat-by-beat hemodynamics, baroreceptor sensitivity, muscle oxygenation, and blood lactate were assessed. The increase in blood pressure was greater (p<0.05) in the 1st set during dynamic than isometric exercise (by ~4.5 mmHg), not different in the 2nd and 3rd sets, and greater in the 4th set during isometric exercise (by ~5 mmHg). Dynamic resistance exercise evoked a greater increase in heart rate, stroke volume, cardiac output, and contractility index (p<0.05), and a greater decline in peripheral resistance, baroreceptor sensitivity, and cardiac function indices than isometric exercise (p<0.05). Participants exhibited a greater reduction in muscle oxyhemoglobin and a greater increase in muscle deoxyhemoglobin in dynamic versus isometric exercise (p<0.001-0.05), with no differences in total hemoglobin and blood lactate. In conclusion, large muscle-mass, multiple-set isometric exercise elicits a relatively similar blood pressure but blunted cardiovascular and baroreceptor sensitivity responses compared to workload-matched dynamic resistance exercise. Differences in blood pressure responses between protocols appear small (~5 mmHg) and are affected by the number of sets. The muscle oxidative stimulus is greater during dynamic resistance exercise than workload-matched isometric exercise.

Brain oxygenation during multiple sets of isometric and dynamic resistance exercise of equivalent workloads: Association with systemic haemodynamics.

Brain function relies on sufficient blood flow and oxygen supply. Changes in cerebral oxygenation during exercise have been linked to brain activity and central command. Isometric- and dynamic-resistance exercise-(RE) may elicit differential responses in systemic circulation, neural function and metabolism; all important regulators of cerebral circulation. We examined whether (i) cerebral oxygenation differs between isometric- and dynamic-RE of similar exercise characteristics and (ii) cerebral oxygenation changes relate to cardiovascular adjustments occurring during RE. Fourteen men performed, randomly, an isometric-RE and a dynamic-RE of similar characteristics (bilateral-leg-press, 2-min×4-sets, 30% of maximal-voluntary-contraction, equivalent tension-time-index/workload). Cerebral-oxygenation (oxyhaemoglobin-O2Hb; total haemoglobin-tHb/blood-volume-index; deoxyhemoglobin-HHb) was assessed by NIRS and beat-by-beat haemodynamics via photoplethysmography. Cerebral-O2Hb and tHb progressively increased from the 1st to 4th set in both RE-protocols (p < 0.05); HHb slightly decreased (p < 0.05). Changes in NIRS-parameters were similar between RE-protocols within each exercise-set (p = 0.91-1.00) and during the entire protocol (including resting-phases) (p = 0.48-0.63). O2Hb and tHb changes were not correlated with changes in systemic haemodynamics. In conclusion, cerebral oxygenation/blood-volume steadily increased during multiple-set RE-protocols. Isometric- and dynamic-RE of matched exercise characteristics resulted in similar prefrontal oxygenation/blood volume changes, suggesting similar cerebral haemodynamic and possibly neuronal responses to maintain a predetermined force.

Exertional Desaturation in Idiopathic Pulmonary Fibrosis: The Role of Oxygen Supplementation in Modifying Cerebral-Skeletal Muscle Oxygenation and Systemic Hemodynamics.

BACKGROUND: In patients with idiopathic pulmonary fibrosis (IPF) with isolated exertional desaturation, there are limited data regarding the effectiveness of oxygen supplementation during exercise training; the underlying mechanisms that contribute to these responses are unknown. OBJECTIVES: To examine in these IPF patients the effects of oxygen supplementation during submaximal exercise (vs. medical air) on cerebral/skeletal muscle oxygenation and systemic hemodynamics. METHODS: In this randomized, cross-over, placebo-controlled trial, IPF patients (n = 13; 63.4 ± 9.6 years) without resting hypoxemia but a significant desaturation during maximal cardiopulmonary exercise testing underwent 2 steady-state exercise trials (65% peak-work-load), breathing either oxygen-enriched or medical air. Cerebral/skeletal muscle oxygenation (near-infrared spectroscopy) and beat-by-beat hemodynamics (photoplethysmography) were monitored. RESULTS: In the air protocol, from the initial minutes of submaximal exercise, patients exhibited a marked decline in cerebral oxygenated hemoglobin (O2Hb) and an abrupt rise in deoxygenated hemoglobin (HHb). Oxygen supplementation alleviated desaturation, lessened dyspnea, and prolonged exercise duration (p < 0.01). Oxygen supplementation during exercise (i) attenuated cerebral deoxygenation (cerebral-HHb: 0.7 ± 1.9 vs. 2.5 ± 1.5 µmol/L, O2 and air protocol; p = 0.009) and prevented cerebral-Hbdifference decline (2.1 ± 2.7 vs. -1.7 ± 2.0 µmol/L; p = 0.001), (ii) lessened the decline in muscle O2-saturation index, and (iii) at isotime exercise, it resulted in lower muscle-HHb (p = 0.05) and less leg fatigue (p < 0.05). No differences between protocols were observed in exercise cardiac output and vascular resistance. CONCLUSIONS: IPF patients with isolated exertional hypoxemia exhibit an inability to increase/maintain cerebral oxygenation during submaximal exercise. Correcting desaturation with O2 supplementation prevented the decline in brain oxygenation, improved muscle oxygenation, and lessened dyspnea, suggesting an efficacy of acute oxygen supplementation during exercise training in protecting brain hypoxia in these IPF patients.

Meniscofibular ligament: how much do we know about this structure of the posterolateral corner of the knee: anatomical study and review of literature.

PURPOSE: The present study is a systematic review of a relatively unknown structure of the posterolateral corner of the knee, the meniscofibular ligament (MFL), aiming at summarizing and broadening current scientific knowledge regarding this ligament anatomy, function, imaging and injury. MATERIALS AND METHODS: A systematic review was performed according to the PRISMA guidelines. Medline (PubMed) and Cochrane Library databases were reviewed for every kind of study reporting on the MFL through December 2019. Due to between-study differences in (anatomy, function, imaging, injury) examining the ligament, the findings were summarized from each study, but the results were not pooled. RESULTS: The MFL is a ligament extending between the inferolateral portion of lateral meniscus, just anterior to the popliteus tendon, and the fibular head. It provides stability to the posterolateral corner of the knee joint, it can be demonstrated in magnetic resonance imaging and magnetic resonance arthrography and has a potential role in lateral meniscus injuries. Further research is required to clearly understand the prognosis and management of MFL injury. CONCLUSION: The current systematic review, focusing only on the MFL of the knee, summarizes the existing knowledge on anatomy, gross morphology, histology, function, biomechanics and imaging and contributes to the further understanding of the MFL.

Dietary nitrate improves muscle microvascular reactivity and lowers blood pressure at rest and during isometric exercise in untreated hypertensives.

OBJECTIVE: This double-blind, cross-over study examined in drug-naïve hypertensives the effects of a single dose of dietary nitrate (beetroot juice, BRJ) on (a) office/ambulatory BP and arterial stiffness, (b) muscle microvascular function, and (c) hemodynamic responses and cardiovagal baroreceptor sensitivity (cBRS) at rest and during isometric exercise. METHODS: Eighteen untreated hypertensives (44.0 ± 2.6 years) consumed randomly, a nitrate-rich (8.1 mmol-BRJnitrate ) and a nitrate-depleted (BRJplacebo ) BRJ. Office BP and pulse wave velocity were assessed before/after BRJ. An occlusion-reperfusion maneuver with continuous monitoring of muscle oxygenated hemoglobin (O2 Hb) and total hemoglobin (tHb), via NIRS, followed. Participants performed submaximal isometric handgrip with beat-by-beat monitoring of hemodynamics and cBRS. Ambulatory BP assessment followed. RESULTS: During reperfusion, following arterial occlusion, the magnitude and rate of muscle microvascular reoxygenation (O2 Hb) and red blood cell content (tHb) were higher in BRJnitrate vs BRJplacebo (P < 0.05), suggesting improved microvascular reactivity. Office/ambulatory BP were lower following BRJnitrate vs BRJplacebo (P < 0.05); pulse-wave-velocity was not altered. During isometric handgrip, BP and peripheral resistance rise were smaller in BRJnitrate vs BRJplacebo (P < 0.01-0.05), with no differences in cBRS. CONCLUSIONS: In drug-naïve hypertensives, a single dose of BRJ induces (a) short-term reductions in resting/ambulatory BP, (b) acute improvements in muscle microvascular function, and (c) attenuation in BP and peripheral resistance responses during isometric exercise.

Ulnar trochlear notch articular surface has three morphological patterns: a neglected major anatomical feature.

PURPOSE: The typical anatomical illustration of the trochlear notch articular surface includes a transverse rough non-articular ridge which separates the olecranon and coronoid part of the joint. This transverse ridge, the "bare area", is not covered by cartilage and represents the optimal entry point for olecranon osteotomies. Aim of the present study was to encounter the anatomical variations in the morphology of the trochlear notch articular surface. METHODS: Two-hundred seventy-three dried ulnae were inspected and a qualitative classification of the variations of the trochlear notch articular surface was done. Correlation to gender and side was examined. RESULTS: Three distinct morphological patterns were observed. Separate olecranon and coronoid facets (Type I) were the most common pattern (165/273, 60.4%). Partial fusion of olecranon and coronoid facets (Type II) was observed in 75 out of 273 bones (27.5%), while a single olecranon and coronoid facet (Type III) was present in 33 out of 273 bones (12.1%). The occurrence of Type II and III was significantly more common in females (p < 0.001). CONCLUSIONS: The most common morphological pattern of the proximal ulna articular surface was the olecranon and coronoid facets separated by the transverse ridge, which is considered as the typical anatomical pattern. The partial fusion of olecranon and coronoid facets was the second most common pattern (27.5%) and the single olecranon and coronoid facet with no transverse ridge present was the rarest one (12.1%). These variations affect the area covered by cartilage. They are noticeable in an elbow MRI and they may have implications on olecranon osteotomy. Absence of the transverse ridge may confuse the surgeon during elbow arthroscopy.

Beetroot Increases Muscle Performance and Oxygenation During Sustained Isometric Exercise, but Does Not Alter Muscle Oxidative Efficiency and Microvascular Reactivity at Rest.

OBJECTIVE: To examine the effects of beetroot juice (BRJ) on (i) in vivo skeletal muscle O2 consumption (mVO2) and microvascular reactivity at rest and (ii) muscle performance, muscle oxygenation, and mVO2 during sustained isometric handgrip exercise (IHG). METHODS: Sixteen young males consumed, randomly, a nitrate-rich (8.1 mmol BRJnitrate) or nitrate-depleted (BRJplacebo) BRJ. After 2.5 hours, they performed an occlusion-reperfusion maneuver at rest, a 3-minute sustained IHG, and a sustained IHG to exhaustion with arterial occlusion. Changes in muscle oxygenated hemoglobin (O2Hb), deoxygenated hemoglobin (HHb), microvascular red blood cell content (tHb), and mVO2 were measured using near-infrared spectroscopy. Force output was recorded. RESULTS: During occlusion, the O2Hb decline did not differ between BRJnitrate and BRJplacebo (magnitude: -30.3 ± 1.6 vs. -31.1 ± 1.5 ΔµΜ; slope: -0.107 ± 0.007 vs. -0.111 ± 0.007 µΜ second-1). During reperfusion, all microvascular reactivity indices were not altered after BRJnitrate (e.g., O2Hbslope: 1.584 ± 0.093 vs. 1.556 ± 0.072 µΜ second-1). During the second and third minute of IHG, O2Hb and tHb were higher in BRJnitrate versus BRJplacebo (p < 0.05), and force output was higher during the third minute (10.8 ± 0.7 vs. 9.5 ± 1.2 kg; p < 0.05); HHb did not differ between trials. In IHG with arterial occlusion, BRJnitrate prolonged the time to fatigue (94.1 ± 5.8 vs. 80.1 ± 3.3 seconds; p < 0.01), with no effects on O2Hb decline (O2Hbslope: -0.226 ± 0.015 vs. -0.230 ± 0.026 µΜ s-1) and mVO2 (14.1 ± 1.0 vs. 14.3 ± 1.6 µmol l-1 minute-1). CONCLUSION: Acute BRJ ingestion in moderately trained individuals (i) did not alter in vivo skeletal muscle microvascular reactivity (index of microvascular function at rest) and basal oxidative efficiency, (ii) increased muscle oxygenation during IHG (possibly via enhanced O2 delivery), and (iii) provided ergogenic benefits during sustained IHG with no effects on muscle oxidative efficiency. The ergogenic effects of BRJ appeared independent of its tissue perfusion benefits.

Chronic Lymphocytic Leukemia Patient Clustering Based on Somatic Hypermutation (SHM) Analysis.

Somatic Hypermutation (SHM) load in the immunoglobulin heavy variable (IGHV) gene of the clonotypic B cell receptor immunoglobulin (BcR IG) is one of the most important prognostic markers in CLL, segregating patients into two distinct categories, with contrariwise disease course. Over the last years, immunogenetic studies have identified that ∼30% of CLL patients carry (quasi)identical BcR IG and thus can be assigned to different subsets with distinct clinicobiological profiles. This characterization was achieved by applying rules mainly concerning the diversity of the VH complementarity determining region 3 (CDR3). Following, studies have also identified subset-specific somatic hypermutation further highlighting antigen selection in disease ontogeny and evolution. In this study, an innovative attempt to explore possible associations amongst SHMs in different CLL patients is implemented and also the potential correlations with VH CDR3 stereotypy is examined, leading to a new classification algorithm implicating both SHM and CDR3 patterns. All results are classified to a ground level analysis, focusing on the most frequent SHMs, their paired associated amino acid changes and the formation of subgroups sharing the same VH CDR3 pattern, the latter being used as a similarity metric. In addition, all results are compared to established VH CDR3 patterns of the well-known CLL subsets in order to confirm the validity of our findings.

An entity evolving into a community: defining the common ancestor and evolutionary trajectory of chronic lymphocytic leukemia stereotyped subset #4.

Patients with chronic lymphocytic leukemia (CLL) assigned to stereotyped subset #4 express highly homologous B-cell receptor immunoglobulin (BcR IG) sequences with intense intraclonal diversification (ID) in the context of ongoing somatic hypermutation (SHM). Their remarkable biological and clinical similarities strongly support derivation from a common ancestor. We here revisited ID in subset #4 CLL to reconstruct their evolutionary history as a community of related clones. To this end, using specialized bioinformatics tools we assessed both IGHV-IGHD-IGHJ rearrangements (n = 511) and IGKV-IGKJ rearrangements (n = 397) derived from eight subset #4 cases. Due to high sequence relatedness, a number of subclonal clusters from different cases lay very close to one another, forming a core from which clusters exhibiting greater variation stemmed. Minor subclones from individual cases were mutated to such an extent that they now resembled the sequences of another patient. Viewing the entire subset #4 data set as a single entity branching through diversification enabled inference of a common sequence representing the putative ancestral BcR IG expressed by their still elusive common progenitor. These results have implications for improved understanding of the ontogeny of CLL subset #4, as well as the design of studies concerning the antigenic specificity of the clonotypic BcR IGs.

Determinants of muscle metaboreflex and involvement of baroreflex in boys and young men.

This study aimed to assess the arterial pressure (AP) determinants during the muscle metaboreflex in boys and men and to investigate the contribution of baroreflex and sympathovagal function to the metaboreflex-induced responses. Fourteen pre-adolescent boys and 13 men performed a protocol involving: baseline, isometric handgrip exercise, circulatory occlusion, and recovery. The same protocol was repeated without occlusion. During baseline, boys had lower beat-to-beat AP, higher heart rate (HR), and lower low/high frequency HR variability. During exercise, a parasympathetic withdrawal was evident in both groups. In adults, HR was the key contributor to the pressure response, with no changes in stroke volume, whereas in boys, the lower HR increase was counterbalanced by an increase in stroke volume, resulting in similar relative increases in AP in both groups. In recovery, boys exhibited a faster rate of HR-decay, rapid vagal reactivation, and greater decrease in TPR than men. An overshoot in baroreceptor sensitivity was observed in men. The isolated metaboreflex resulted in a similar AP elevation in both age groups (by ~15 mmHg), and attenuated spontaneous baroreceptor sensitivity. However, during the metaboreflex, pre-adolescent males exhibited a lower increase in peripheral resistance and a greater bradycardic response than adults, and a fast restoration of vagal activity to non-occlusion levels. During metaboreflex, boys were capable of eliciting a pressure response similar to the one elicited by men; however, the interplay of the mechanisms underlying the rise in AP differed between the two groups with the vagal contribution being greater in the younger participants.

Exercise as a model to study redox homeostasis in blood: the effect of protocol and sampling point.

Twenty males ran either on a level treadmill (nonmuscle-damaging condition) or on a downhill treadmill (muscle-damaging condition). Blood and urine samples were collected before and after exercise (immediately after, 1h, 4h, 24h, 48h, and 96h). The following assays were performed: F(2)-isoprostanes in urine, protein carbonyls in plasma, glutathione, superoxide dismutase, glutathione peroxidase, and catalase in erythrocytes. The main finding was that monophasic redox responses were detected after nonmuscle-damaging exercise compared to the biphasic responses detected after muscle-damaging exercise. Based on these findings, muscle-damaging exercise may be a more appropriate experimental model to induce physiological oxidative stress.

Effects of oxygen supplementation in autonomic nervous system function during exercise in patients with idiopathic pulmonary fibrosis and exertional desaturation.

INTRODUCTION: Patients with idiopathic pulmonary fibrosis (IPF) have reduced exercise capacity and often present exertional dyspnea and desaturation. The role of autonomic nervous system (ANS) as a pathogenetic contributor to this dysfunction has not been evaluated. OBJECTIVE: To evaluate whether improvement of arterial oxygen saturation (SpO2 ) via oxygen supplementation results to ANS function improvement, during steady state submaximal exercise. METHODS: This is a secondary analysis of a single-blind, randomized, placebo-controlled, cross-over trial, including 12 IPF patients, with isolated exertional desaturation. Following a maximal cardiopulmonary test, participants underwent two submaximal steady state tests during which they received either supplementary oxygen or medical air. Continuous beat-to-beat blood pressure measurements were recorded (Finapres Medical Systems, Amsterdam, The Netherlands). Autonomic function was assessed non-invasively by heart rate variability (HRV); root mean square of successive differences (RMSSD) and standard-deviation-Poincare-plot (SD1) were used as indices of parasympathetic output. Entropy and detrended fluctuation analysis (DFA) were also used. RESULTS: During rest, oxygen supplementation did not significantly alter RMSSD and SD1. During exercise, subjects presented no significant alterations compared with baseline, in most HRV indices examined. There was no improvement of this behavior with O2 -supplementation. Approximate-entropy increased during exercise, with no differences between protocols. CONCLUSIONS: IPF patients presented an inadequate adaptive response of their ANS to exercise and recovery. Although oxygen supplementation significantly prolonged exercise duration and prevented the substantial exertional desaturation, the blunted vagal response to steady-state exercise in these patients was not improved, suggesting that acute oxygen supplementation does not sufficiently improve ANS dysfunction in these patients.

A randomized placebo-control trial of the acute effects of oxygen supplementation on exercise hemodynamics, autonomic modulation, and brain oxygenation in patients with pulmonary hypertension.

BACKGROUND: The integrative physiological effects of O2 treatment on patients with pulmonary hypertension (PH) during exercise, have not been fully investigated. We simultaneously evaluated, for the first time, the effect of oxygen supplementation on hemodynamic responses, autonomic modulation, tissue oxygenation, and exercise performance in patients with pulmonary arterial hypertension (PAH)/Chronic Thromboembolic PH(CTEPH). MATERIAL-METHODS: In this randomized, cross-over, placebo-controlled trial, stable outpatients with PAH/CTEPH underwent maximal cardiopulmonary exercise testing, followed by two submaximal trials, during which they received supplementary oxygen (O2) or medical-air. Continuous, non-invasive hemodynamics were monitored via photophlythesmography. Cerebral and quadriceps muscle oxygenation were recorded via near-infrared spectroscopy. Autonomic function was assessed by heart rate variability; root mean square of successive differences (RMSSD) and standard-deviation-Poincare-plot (SD1) were used as indices of parasympathetic output. Baroreceptor sensitivity (BRS) was assessed throughout the protocols. RESULTS: Nine patients (51.4 ±â€¯9.4 years) were included. With O2-supplementation patients exercised for longer (p = 0.01), maintained higher cerebral oxygenated hemoglobin (O2Hb;p = 0.02) levels, exhibited an amelioration in cortical deoxygenation (HHb;p = 0.02), and had higher average cardiac output (CO) during exercise (p < 0.05), compared to medical air; with no differences in muscle oxygenation. With O2-supplementation patients exhibited higher BRS and sample-entropy throughout the protocol (p < 0.05) vs. medical air, and improved the blunted RMSSD, SD1 responses during exercise (p = 0.024). CONCLUSION: We show that O2 administration improves BRS and autonomic function during submaximal exercise in PAH/CTEPH, without significantly affecting muscle oxygenation. The improved autonomic function, along with enhancements in cardiovascular function and cerebral oxygenation, probably contributes to increased exercise tolerance with O2-supplementation in PH patients.

Are Blood Pressure and Cardiovascular Stress Greater in Isometric or in Dynamic Resistance Exercise?

Medical and sports medicine associations are reluctant to endorse isometric exercise to the same extent as dynamic resistance exercise (RE). The major concern is the fear of greater increases in blood pressure (BP) that might be associated with isometric exercise. This review comprehensively presents all human studies that directly compared the magnitude of hemodynamic responses between isometric and dynamic RE. We also discuss possible mechanisms controlling BP-response and cardiovascular adjustments during both types of RE. The most prominent finding was that isometric and dynamic RE using small-muscle mass evoke equal increases in BP; however, the circulatory adjustments contributing to this response are different in dynamic and isometric RE. In contrast, studies using large-muscle mass report inconsistent results for the magnitude of BP-response between the two types of RE. Thus, when the same muscles and workloads are used, the increase in BP during isometric and dynamic RE is more comparable to what is commonly believed. However, it should be noted that only a few studies equalized the workload in two types of RE, most used small sample sizes, and all studies employed healthy participants. More studies are needed to compare the cardiovascular risks associated with isometric and dynamic RE, especially in individuals with chronic disease.

Smoking before isometric exercise amplifies myocardial stress and dysregulates baroreceptor sensitivity and cerebral oxygenation.

This crossover study examined whether acute cardiovascular responses, baroreceptor sensitivity (BRS), and brain oxygenation during isometric exercise are altered after cigarette smoking. Twelve young, habitual smokers randomly performed a smoking and a control protocol, during which participants smoked one cigarette (0.9 mg nicotine) or a sham cigarette, before exercise. Testing involved baseline, a 5-minute smoking, a 10-minute post-smoking rest, 3-minute handgrip exercise (30% maximum voluntary contraction), and recovery. Beat-to-beat blood pressure, heart rate (HR), and cerebral oxygenation (near infrared spectroscopy) were continuously monitored. Double-product, stroke volume (SV), cardiac output, systemic vascular resistance and BRS were assessed. During post-smoking rest, systolic or diastolic blood pressure (140.8 ± 12.1/87.0 ± 6.9 vs. 125.9 ± 7.1/77.3 ± 5.5 mm Hg), HR, and double product were higher in the smoking versus the control protocol, whereas BRS was lower (P < .05). During handgrip exercise, smoking resulted in greater HR and double product (17,240 ± 3893 vs. 15,424 ± 3173 mm Hg·bpm) and lower BRS versus the control protocol (P < .05), without significant differences in stroke volume and systemic vascular resistance between protocols. During recovery, smoking elicited a delayed return of brain oxygenation indices, lower BRS, and higher double product. Smoking a cigarette shortly before the exercise session amplifies myocardial stress and dysregulates autonomic function and cerebral oxygenation during exercise and recovery, even in young habitual smokers, perceived as free from long-term cardiovascular effects of smoking.

Impaired Muscle Oxygenation and Elevated Exercise Blood Pressure in Hypertensive Patients: Links With Vascular Stiffness.

This study examined in vivo (1) skeletal muscle oxygenation and microvascular function, at rest and during handgrip exercise, and (2) their association with macrovascular function and exercise blood pressure (BP), in newly diagnosed, never-treated patients with hypertension and normotensive individuals. Ninety-one individuals (51 hypertensives and 40 normotensives) underwent office and 24-hour ambulatory BP, arterial stiffness, and central aortic BP assessment, followed by a 5-minute arterial occlusion and a 3-minute submaximal handgrip exercise. Changes in muscle oxygenated and deoxygenated hemoglobin and tissue oxygen saturation were continuously monitored by near-infrared spectroscopy and beat-by-beat BP by Finapres. Hypertensives had higher (P<0.001) central aortic BP and pulse wave velocity versus normotensives and exhibited (1) a blunted tissue oxygen saturation response during occlusion, with slower (P=0.006) deoxygenation rate, suggesting reduced muscle oxidative capacity, and (2) a slower reoxygenation rate and blunted hyperemic response (P<0.05), showing reduced microvascular reactivity. Muscle oxygenation responses were correlated with aortic systolic and pulse pressure and augmentation index (P<0.05; age and body mass index (BMI) adjusted). When exercising at the same submaximal intensity, hypertensives required a significantly greater (P<0.001) increase in BP for achieving similar muscle oxygenation levels as normotensives. This response was correlated with the magnitude of microvascular hyperemia and aortic BP. In conclusion, nontreated patients with hypertension exhibit prominent reductions in in vivo indices of skeletal muscle oxidative capacity, suggestive of mitochondrial dysfunction, and blunted muscle microvascular reactivity. These dysfunctions were associated with higher aortic systolic BP and arterial stiffness. Dysregulations in muscle oxygen delivery/utilization and microvascular stiffness, in hypertensive patients, partially contribute to their exaggerated BP during exercise.