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Doctor of Philosophy / Department of Kinesiology / David C. Poole / The onset of skeletal muscle contractions induces rapid and robust increases in metabolic rate (V̇O₂) and blood flow (Q̇) in order to supply the energetic demands of the muscle. In young healthy populations, these variables increase proportionally to maintain oxygen flux into the myocyte for both sexes. However, while the resultant changes in V̇O₂ and Q̇ conflate to establish adequate driving pressures of oxygen (PO₂), it appears that the underlying control processes express distinct sexual dimorphism. Estrogen is crucial for cardiovascular control for young women through its relationship with nitric oxide (NO) and results in lower blood pressure and risk of cardiovascular disease for women. However, in post-menopausal women and some disease states, such as heart failure (HF), these protections are lost due to reductions in estrogen and NO bioavailability which causes women to catch and surpass men in rates of hypertension and cardiovascular disease. The purpose of this dissertation is to explore the mechanisms responsible for establishing the oxygen delivery-to-utilization matching (Q̇O₂/V̇O₂) necessary for skeletal muscle contractions in health and disease. In the first investigation (Chapter 1), we explored the effect of altered NO bioavailability on spinotrapezius muscle interstitial space PO₂ (PO₂is; determined by Q̇O₂/V̇O₂) of healthy male and female rats. We show that both sexes regulate PO₂is to similar levels at rest and during skeletal muscle contractions. However, modulating NO bioavailability exposes sex differences in this regulation with females having greater reliance on basal NO bioavailability and males having greater responsiveness to exogenous NO. In the second investigation (Chapter 2), we sought to determine whether measures of central and peripheral function in HF rats predicted exercise tolerance (as critical speed (CS)). We showed for the first time, that CS can be resolved in HF animals and that decrements in central cardiac (echocardiography) and peripheral skeletal muscle function (PO₂is) predicted CS. Building upon these findings, the third investigation (Chapter 3) aimed to determine if the sex differences in the control of PO₂is seen in healthy rats translated to greater deficits in HF for females. Furthermore, this investigation sought to determine if five days of dietary nitrate supplementation (an exogenous NO source) would raise PO₂is in HF rats, with a greater effect seen in females. We revealed that HF reduces PO₂is at rest and during skeletal muscle contractions and this negative effect is exacerbated for females. However, elevating NO bioavailability with dietary nitrate increases resting PO₂is and alters the dynamic response during contractions with females potentially being more responsive than males. The results herein reveal the importance of NO in the control of Q̇O₂/V̇O₂ in health. The onset of HF results in deleterious declines in exercise tolerance, which are mediated through reductions in central and peripheral function, due, in part, to attenuated NO bioavailability. This creates intensified Q̇O₂/V̇O₂ dysfunction in females with HF; however, this can potentially be countered with dietary supplementation of inorganic nitrate. Altogether, the present dissertation suggests that targeting NO bioavailability, particularly in female HF patients, could be a beneficial non-pharmaceutical therapeutic strategy.

Background: Patients older than 75 years with heart failure (HF) are at increased risk for mortality and hospital admissions. Echocardiography and brain natriuretic peptides (BNP, NTproBNP) are important diagnostic tools but sparsely evaluated in elderly PHC patients. Aims: Validate the clinical diagnosis of HF, investigate the types of HF and underlying cardiovascular disorders with focus on sex and age differences. Explore the sensitivity, specificity, negative and positive predictive values (NPV, PPV) of BNP and NT-proBNP in patients with systolic HF. Study the associations of HF or NTproBNP on all-cause and cardiovascular mortality. Study the prognostic value of different biomarkers and HF, on all-cause and cardiovascular hospitalizations. Methods: Patients with suspected HF were recruited from one selected PHC and registered on a prespecified record and referred for an echocardiographic examination and a final cardiologist consultation. Blood samples for natriuretic peptides were stored frozen at – 70° C. Death certificates were used to register all-cause mortality and cardiovascular mortality. To register hospitalisations, medical records were used and classification was defined according to ICD-10. Results The GPs identified 121 women and 49 men with suspected HF of whom 39% (51 women and 16 men) were above 80 years. Myocardial infarction (OR:4,3 CL: 1,8-10,6) hypertension (OR:3,4 CI:1,6-6,9) atrial fibrillation (OR:2,8 CL:1,0-7,9) predicted a confirmed diagnosis of HF. Confirmed HF was verified in 45% of the patients and was significantly more common in men than women (p=0,02). The best NPV was 88 % for NT-proBNP (200 ng/L) and 87 % for BNP (20 pg/ml). Age and male gender were independently associated with higher levels of NT-proBNP. During the 10-year follow up, 71 out of 144 patients died. In univariate Cox regression analysis, significant associations were found for overall HF (hazard ratio [HR]: 1.86; 95% confidence interval [CI]:1.15- 3.01), isolated systolic HF (HR:1.95; 95% CI:1.06-3.61), and combined (systolic and diastolic) HF (HR:3.28; 95% CI:1.74-6.14) with all-cause mortality, but not for isolated diastolic HF. In multivariable analysis, age (HR: 1.11; 95% CI: 1.06-1.17), kidney dysfunction (HR:1.91; 95% CI:1.11- 3.29), smoking (HR:3.70; 95% CI:2.02-6.77), and NTproBNP (HR:1.01; 95% CI:1.00-1.02), but not any type of HF, significantly predicted all-cause mortality. During ten years, 136 (80%) patients were hospitalised with 660 and 207 for all-cause and cardiovascular hospitalisations, respectively. Age (OR:1.1; 95% CI:1.01-1.15) and underlying heart disease (OR:3.5; 95% CI:1.00-11.89), significantly predicted all-cause hospitalisation. Overall HF (HR:1.8; 95% CI:1.06-2.94) significantly predicted time to first all-cause hospitalisations. For cardiovascular hospitalisations age (OR:1.1;95%CI:1.01-1.12), underlying heart disease (OR:3.4;95%CI:1.04-11.40) and NTproBNP ≥800 ng/L (OR:4,3;95%CI:1.5-12.50) were significant predictors. Conclusion: A confirmed diagnosis of HF was present in 45% of the patients. NPV was high, but not as high as in younger patients with HF. Patients with systolic HF had a higher mortality than patients with diastolic HF compared to patients with no HF. Patients with combined HF were at even higher risk for all-cause mortality and cardiovascular mortality. Age, kidney dysfunction, NTproBNP and smoking predicted mortality. Age and underlying heart diseases were predictors for all-cause hospitalisations and together with NTproBNP they also predicted cardiovascular hospitalisations.

Bakgrund: Kronisk hjärtsvikt är ett globalt växande tillstånd i hela världen. Sjuksköterskan har en betydande roll i att ge kunskap och att informera kring hur det är att leva med kronisk hjärtsvikt. Syfte: Att beskriva dagligt liv för patienter med kronisk hjärtsvikt, utifrån ett patientperspektiv.    Metod: En litteraturöversikt där 13 kvalitativa artiklar har inkluderats. Studien baseras på induktiv ansats. Resultat: Personer med hjärtsvikt upplever en förändrad livssituation efter att de har fått diagnosen kronisk hjärtsvikt. Resultatet redovisas i kategorierna: Begränsningar i vardagen, Påverkan av omgivningen och Mötet med vården. Slutsats: Resultatet visar att personer som lever med hjärtsvikt genomgår fysiologiska förändringar, men även känslomässiga, sociala och andliga förändringar. För att möta dessa personer behöver sjuksköterskan ha kunskap i att identifiera individens behov och därefter utforma omvårdnaden utefter den unika individen. / Background: Chronic heart failure is an common disease worldwide. The nurse has a significant role in providing knowledge and information about how to live with chronic heart failure. Aim: To describe daily life for patients with chronic heart failure, from a patient perspective.   Method: A literature review where thirteen qualitative articles were included. The study is based on inductive approach. Results: People with heart failure experience a changed life situation after they have been diagnosed with chronic heart failure. The results are reported in categories: Limitations in everyday life, Influence of the environment and Health Care services. Conclusion: The result shows that people living with heart failure undergo physiological changes, but also emotional, social and spiritual. In order to meet these people, the nurse needs knowledge in identifying the needs of the individual in order to design nursing according to the unique individual.

Die Herzinsuffizienz ist eine der häufigsten chronischen Erkrankungen mit progressivem Krankheitsverlauf. Dieser ist verschiedenen Kompensationsmechanismen geschuldet, die zunächst zur Verbesserung, über einen längeren Zeitraum hinweg jedoch zur Verschärfung der Symptomatik führen. Durch erhöhte Konzentrationen inflammatorischer Zytokine im Rahmen dieser Krankheit kommt es unter anderem zu pathologischen Veränderungen in Muskel- als auch Fettgewebe. Das kürzlich in der Literatur als PGC-1α reguliert beschriebene Molekül FNDC5 (Spaltprodukt Irisin) wird als Myokin bezeichnet, welches zwischen Muskel- und Fettgewebe vermittelt. Bis dato ist jedoch ungeklärt, ob und inwiefern es einen Zusammenhang zwischen einer Herzinsuffizienz, erhöhten Konzentrationen proinflammatorischer Zytokine und dem Molekül FNDC5 in der Skelettmuskulatur gibt. Um diesen Fragestellungen nachzugehen, wurde in der vorliegenden Arbeit zum einen durch LAD-Ligatur in Ratten eine Herzinsuffizienz induziert, um die systemischen Verhältnisse dieser Erkrankung im Tiermodell bestmöglich nachzuempfinden. Zum anderen wurden Mäuse mit TNF-α oder Ang II behandelt und C2C12-Myotuben mit TNF-α, Ang II sowie einer Zytokinkombination inkubiert, um den Einfluss der Zytokine bzw. des Hormons auf die FNDC5-Expression zu untersuchen. Anschließend wurden die Expression von FNDC5 auf mRNA- und Proteinebene sowie die Expression der PGC-1α-mRNA in Skelettmuskelbiopsien bestimmt. Es konnte nachgewiesen werden, dass eine Herzinsuffizienz sowie der Einfluss inflammatorischer Zytokine zur signifikanten Expressionsverminderung von FNDC5 führt. Ang II hingegen bewirkte nicht in allen Versuchen eine deutliche Reduktion der FNDC5-Expression. Außerdem wurde gezeigt, dass die Signaltransduktionswege über p38 und p42/44 MAPK nicht für die Wirkung der Zytokinkombination auf die FNDC5-Expression verantwortlich sind.

Bakgrund: Kronisk hjärtsvikt är en stor folksjukdom och idag en stor bidragande orsak till inläggningar på Sveriges sjukhus. Sjukdomen medför symtom av olika svårighetsgrader där de vanligaste symtomen är energilöshet, andfåddhet och trötthet. Sjuksköterskan har en viktig roll i omvårdnaden kring personer med hjärtsvikt där personcentrerad vård eftersträvas för att bevara integritet och individuella behov. Det är vanligt förekommande att anhöriga har en vårdande roll till personerna med hjärtsvikt. Syfte: Syftet med litteraturstudien var att beskriva personers upplevelse av att leva med kronisk hjärtsvikt i det dagliga livet. Metod: Beskrivande litteraturstudie som innefattade 13 artiklar av kvalitativ ansats framsökta i PubMed och CINAHL, databaser inom omvårdnadsforskning. Huvudresultat: Personer med hjärtsvikt upplevde begränsningar, både fysiskt och psykiskt i det dagliga livet orsakat av hjärtsviktssymtomen. Begränsningarna gjorde att vissa personer var i behov av hjälp dagligen. Många uppskattade det stöd de fick, medan en del upplevde det som en börda. Känslor som rädsla, oro och ångest var något som upplevdes i samband med hjärtsvikt och personernas framtid upplevdes av många som oförutsägbar. Slutsats: Personer med hjärtsvikt upplevde begränsningar i sitt dagliga liv. Begränsningarna medförde att många var i behov av hjälp dagligen och det inverkade på personernas privatliv. Både positiva och negativa känslor upplevdes i samband med sjukdomen. Det är betydelsefullt för sjuksköterskan att ta del av personernas upplevelser i det dagliga livet för deras omvårdnadsarbete av dessa personer. Genom att begripa, hantera och känna meningsfullhet kan det i situationen med hjärtsvikt bidra till större förståelse för sjukdomen och ökad livskvalitet. / Background: Chronic heart failure is a big scourge and are today a contributing factor to inlay at hospitals in Sweden. The disease causes symptoms of different degrees of difficulties, where the most common is lethargy, breathlessness and fatigue. Nurses have an important role with nursing people with heart failure where person-centered care is sought to preserve integrity and see to individual needs. It’s common that family members has a caring-role for persons with heart failure. Purpose: The aim of the literature study was to describe people's experience of living with chronic heart failure in daily life. Method: A descriptive literature study comprising 13 qualitative research articles who was gathered from PubMed and CINAHL, nursing databases. Main result: People with heart failure experienced limitations in daily life, both physical and psychological caused by chronic heart failure symptoms. These limitations meant that some people with heart failure were in need of daily support. Many appreciated the support they received while some experienced it a burden. Fear and anxiety were characterized in contribution to heart failure and people experienced the uncertainty about the future as unpredictable. Conclusion: Person’s with heart failure experienced limitations in their daily life. These limitations resulted in a need of support which affected their personal life. In conjunction with heart failure people experienced both negative and positive feelings towards the progress of the disease. It is of great importance for nurses to take part of how persons with heart failure experiences daily life in contribution to take care and nurse these people. A sense of comprehensibility and meaningfulness for the situation with heart failure could give a greater understanding for the disease and increasing quality of life.