Patient case: 55-year-old male with Melanoma. Genetic variant: NRAS (Q61K). Other conditions: Hypertension.

Clinical trial: Cardiovascular Responses to Cold in Hypertension

Summary: Wintertime is associated with increased morbidity and mortality and a majority is related to cardiovascular causes, such as myocardial infarctions, heart failures, and strokes. It is also known, that both acute and long-term cold exposure increase blood pressure and cardiac workload, and this may contribute to the observed excess morbidity and mortality during the cold season.
  Although the effects of cold on blood pressure are known among healthy people, these responses among risk groups, such as hypertensive people, are not established. In addition, changes in cardiac electrical activity or autonomic regulation are largely unknown. The cardiovascular responses in the cold could be different among hypertensive people because of disturbances in the circulatory regulation or function, such as aortic stiffening and increased vasomotor tone of peripheral arteries due to endothelial dysfunction associated with the disease. To assess this, a controlled experiment employing a cold exposure similar to everyday winter circumstances in a subarctic climate was performed.

Detailed description: Introduction.
  Wintertime is associated with increased morbidity and mortality and a majority is related to cardiovascular causes, such as myocardial infarctions, heart failures, and strokes. It is also known, that both acute and long-term cold exposure increase blood pressure and cardiac workload, and this may contribute to the observed excess morbidity and mortality during cold season.
  Although the effects of cold on blood pressure are established among healthy people, the effects among risk groups, such as hypertensive people, are not known. In addition to blood pressure, information on cardiac electrical activity or autonomic regulation are needed. Cardiovascular responses in the cold could be different among hypertensive people because of disturbances in autonomic nervous system and the circulatory regulation or function, such as aortic stiffening and increased vasomotor tone of peripheral arteries due to endothelial dysfunction associated with the disease. To assess this, a controlled experiment employing a cold exposure similar to everyday winter circumstances in a subarctic climate was performed in a climatic chamber.
  Aims of the research.
  The objective of the research was to assess how short-term cold exposure affects cardiovascular function of middle-aged untreated hypertensive and normotensive men. The hypotheses of the study were: a) cold exposure induces adverse changes in cardiovascular function, such as higher blood pressure and cardiac workload and b) hypertensive men demonstrate an aggravated response to cold exposure and the recovery of the cardiovascular system to baseline is delayed compared to normotensive subjects.
  Material and Methods.
  Study participants.
  The study participants were chosen through a population-based recruitment and where a random sample of 1000 men (55-65 years old) living in Oulu, Finland was drawn from the Finnish Population Register. The subjects were screened by telephone interviews for eligibility for the study. Eligible attendees measured their blood pressure at home for a week according to the recommendations of the European Society of Hypertension. Based on these measurements they were classified either to hypertensive (systolic blood pressure ≥135 and/or diastolic blood pressure ≥85 mmHg) or normotensive (blood pressure <135/85mmHg).(16) The exclusion criteria was the presence of coronary heart or respiratory diseases, use of antihypertensive drugs for any indication, an average home BP ≥175/105 mm Hg, and failed home BP measurements. We aimed at recruiting a 2:1 ratio of hypertensive and normotensive subjects. The final study group consisted of 56 hypertensive and 35 normotensive middle-aged men.
  Measurement protocol.
  Before the measurements the participants filled a questionnaire with health and cold habituation related questions. The laboratory experiments began with a short familiarization to the measurement protocol and climatic chambers. Height, body composition, and physical fitness of the subjects were measured.
  The participants were exposed for 15 min to temperature of -10°C and wind of 3m/s while protected from the cold with proper winter clothing, i.e. conditions similar to common habitual winter time cold exposure in subarctic countries. Participants were followed 15 min before (control measurements) and 20 min after (recovery) the exposure in a climatic chamber where the temperature was adjusted to +18°C and wind was set to <0.2m/s). The participants were standing with their arms supported during the measurements.Cardiovascular function was assessed by measuring brachial, central aortic, and continuous "beat to beat" blood pressure, as well as ECG measurements. The intensity of cold exposure was evaluated with skin temperature measurements (middle finger, back of the hand, shoulder blade, and cheek) and by assessing thermal perception for the whole body and face using subjective judgement scales.
  The collected data was analyzed to assess the cold related changes in blood pressure (brachial and central aortic) and heart rate. ECG morphology and vector cardiographic parameters were computed from derived 12-lead ECG recordings at the Institute of Clinical Medicine at University of Oulu. Arrhythmias were detected automatically and confirmed with visual inspection by trained health care professional. To assess the regulation of circulation, continuous blood pressure signal and simultaneously recorded three lead ECG are applied to compute baroreflex sensitivity and heart rate variability at the Verve research center. In the data analyses responses to cold exposure will be evaluated and compared between hypertensive and normotensive subjects. In addition to the above mentioned topics combined risk factors for adverse changes in cardiovascular function during cold exposure will be evaluated, such as high arterial stiffness, altered ECG, and low heart rate variability. Based on this, a profile of a high risk patient will be defined and shared with physicians treating hypertensive patients to reduce adverse cold-related cardiac events.
  Site of research and availability of equipment and services required for the research.
  The laboratory measurements were implemented in the climatic chambers of Kastelli Research Center, Oulu, Finland. The data analyses and reporting are performed in facilities of Center for Environmental and Respiratory Health Research (University of Oulu). In addition, data analyses are performed in the Oulu University Hospital and at Verve department of Exercise and Cardiac rehabilitation.
  Co-operation.
  The Center for Environmental and Respiratory Health Research - Adjunct professor Tiina M Ikäheimo, Professor Jouni JK Jaakkola, Professor J Hassi, PhD A Rantala, MHSc H Hyrkäs; Department of Exercise and Medical Physiology, Verve, Oulu - Adjunct professor M Tulppo, Adjunct professor A Kiviniemi, Adjunct professor Arto Hautala; Institute of Occupational Health, Oulu - Professor H Rintamäki; Institute of Clinical Medicine, University of Oulu - Professor H Huikuri, PhD T Kenttä; Institute of Biomedicine, Department of Physiology and Biocenter of Oulu, University of Oulu - Professor KH Herzig; Institute of Health Sciences, University of Oulu - Professor S Keinänen-Kiukaanniemi, Professor R Antikainen, Professor M Mäntysaari; Department of Biology - Professor E Hohtola; Oulu University of Applied Sciences - Principal lecturer of Medical Engineering J Jauhiainen.
  Ethical issues.
  The study was approved by the ethics committee of Northern Ostrobothnia Hospital District (statement number 240/2010) and all participants were informed of the study and were requested for informed consent. They had also the possibility to terminate the study at any point. The data collected during the study is maintained unavailable from other than project personnel and protected with passwords. Data-analyses are performed without any personal identification (name, address etc.). The research applied a short cold exposure with well protected subjects and did not, therefore, cause any pain or harm to the participants.
  Implications.
  WHO has defined high blood pressure as the leading global risk for mortality in the world. Approximately half of the middle-aged men and one third of women have hypertension in Finland. On the other hand, with proper blood pressure control the risk of adverse cardiovascular events among hypertensive patients can be considerably reduced.
  Wintertime and cold weather remarkably increase the risk of cardiovascular morbidity and mortality. There is an excess of ca. 2000-3000 deaths occurring in Finland during the winter and even half of them are for cardiovascular reasons. Both acute and and repeated exposures to cold increase blood pressure and may contribute to the higher wintertime cardiovascular morbidity and mortality. It has been suggested, that cold-related cardiovascular deaths could be prevented by proper protection from cold temperature.
  The study will produce novel information of cardiovascular responses to short-term cold exposure among untreated hypertensive men. This knowledge will help health care personnel to advice hypertensive patients to protect themselves during habitual cold exposure, which could reduce the adverse cardiac events related to the cold weather. This knowledge is useful for medical doctors when considering medication for their patients. In addition, hypertensive people may need advice for their proper protection to reduce cold-related changes in cardiovascular function, such as blood pressure increases, and the related adverse cardiovascular events in cold climates.

Eligibility: Inclusion Criteria:
  -  Measured BP (home measurements of one week) above 135/85 mmHg were selected to the group of hypertensive subjects.
  -  Those with BP below 135/85 mmHg were selected as controls.
  Exclusion Criteria:
  -  Presence of coronary heart disease, respiratory diseases, and the use of antihypertensive drug treatment.
  -  an average home BP ≥175/105 mmHg, initiating antihypertensive drug treatment, failed home BP measurements, and having a respiratory infection within a week prior to the controlled measurements

Relevance to patient case: not relevant