Background: Frailty is considered highly prevalent in old age and to confer high risk for falls, disability, hospitalization, and mortality. Frailty has been considered synonymous with disability, comorbidity, and other characteristics, but it is recognized that it may have a biologic basis and be a distinct clinical syndrome. A standardized definition has not yet been established. 

Methods: To develop and operationalize a phenotype of frailty in older adults and assess concurrent and predictive validity, the study used data from the Cardiovascular Health Study. Participants were 5,317 men and women 65 years and older (4,735 from an original cohort recruited in 1989-90 and 582 from an African American cohort recruited in 1992-93). Both cohorts received almost identical baseline evaluations and 7 and 4 years of follow-up, respectively, with annual examinations and surveillance for outcomes including incident disease, hospitalization, falls, disability, and mortality. 

Results: Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. The overall prevalence of frailty in this community-dwelling population was 6.9%; it increased with age and was greater in women than men. Four-year incidence was 7.2%. Frailty was associated with being African American, having lower education and income, poorer health, and having higher rates of comorbid chronic diseases and disability. There was overlap, but not concordance, in the cooccurrence of frailty, comorbidity, and disability. This frailty phenotype was independently predictive (over 3 years) of incident falls, worsening mobility or ADL disability, hospitalization, and death, with hazard ratios ranging from 1.82 to 4.46, unadjusted, and 1.29-2.24, adjusted for a number of health, disease, and social characteristics predictive of 5-year mortality. Intermediate frailty status, as indicated by the presence of one or two criteria, showed intermediate risk of these outcomes as well as increased risk of becoming frail over 3-4 years of follow-up (odds ratios for incident frailty = 4.51 unadjusted and 2.63 adjusted for covariates, compared to those with no frailty criteria at baseline). 

Conclusions: This study provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition. It also finds that there is an intermediate stage identifying those at high risk of frailty. Finally, it provides evidence that frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty. This provides a potential basis for clinical assessment for those who are frail or at risk, and for future research to develop interventions for frailty based on a standardized ascertainment of frailty.

https://www.sharp.com/services/hospice/upload/phenotype5-13.pdf

Frailty in Older Adults Evidence for a Phenotype

ABCD
: Appropriate Blood pressure Control in Diabetes
ABI
: ankle–brachial index
ABPM
: ambulatory blood pressure monitoring
ACCESS
: Acute Candesartan Cilexetil Therapy in Stroke Survival
ACCOMPLISH
: Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension
ACCORD
: Action to Control Cardiovascular Risk in Diabetes
ACE
: angiotensin-converting enzyme
ACTIVE I
: Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events
ADVANCE
: Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation
AHEAD
: Action for HEAlth in Diabetes
ALLHAT
: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart ATtack
ALTITUDE
: ALiskiren Trial In Type 2 Diabetes Using Cardio-renal Endpoints
ANTIPAF
: ANgioTensin II Antagonist In Paroxysmal Atrial Fibrillation
APOLLO
: A Randomized Controlled Trial of Aliskiren in the Prevention of Major Cardiovascular Events in Elderly People
ARB
: angiotensin receptor blocker
ARIC
: Atherosclerosis Risk In Communities
ARR
: aldosterone renin ratio
ASCOT
: Anglo-Scandinavian Cardiac Outcomes Trial
ASCOT-LLA
: Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm
ASTRAL
: Angioplasty and STenting for Renal Artery Lesions
A-V
: atrioventricular
BB
: beta-blocker
BMI
: body mass index
BP
: blood pressure
BSA
: body surface area
CA
: calcium antagonist
CABG
: coronary artery bypass graft
CAPPP
: CAPtopril Prevention Project
CAPRAF
: CAndesartan in the Prevention of Relapsing Atrial Fibrillation
CHD
: coronary heart disease
CHHIPS
: Controlling Hypertension and Hypertension Immediately Post-Stroke
CKD
: chronic kidney disease
CKD-EPI
: Chronic Kidney Disease—EPIdemiology collaboration
CONVINCE
: Controlled ONset Verapamil INvestigation of CV Endpoints
CT
: computed tomography
CV
: cardiovascular
CVD
: cardiovascular disease
D
: diuretic
DASH
: Dietary Approaches to Stop Hypertension
DBP
: diastolic blood pressure
DCCT
: Diabetes Control and Complications Study
DIRECT
: DIabetic REtinopathy Candesartan Trials
DM
: diabetes mellitus
DPP-4
: dipeptidyl peptidase 4
EAS
: European Atherosclerosis Society
EASD
: European Association for the Study of Diabetes
ECG
: electrocardiogram
EF
: ejection fraction
eGFR
: estimated glomerular filtration rate
ELSA
: European Lacidipine Study on Atherosclerosis
ESC
: European Society of Cardiology
ESH
: European Society of Hypertension
ESRD
: end-stage renal disease
EXPLOR
: Amlodipine–Valsartan Combination Decreases Central Systolic Blood Pressure more Effectively than the Amlodipine–Atenolol Combination
FDA
: U.S. Food and Drug Administration
FEVER
: Felodipine EVent Reduction study
GISSI-AF
: Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-Atrial Fibrillation
HbA1c
: glycated haemoglobin
HBPM
: home blood pressure monitoring
HOPE
: Heart Outcomes Prevention Evaluation
HOT
: Hypertension Optimal Treatment
HRT
: hormone replacement therapy
HT
: hypertension
HYVET
: HYpertension in the Very Elderly Trial
IMT
: intima-media thickness
I-PRESERVE
: Irbesartan in Heart Failure with Preserved Systolic Function
INTERHEART
: Effect of Potentially Modifiable Risk Factors associated with Myocardial Infarction in 52 Countries
INVEST
: INternational VErapamil SR/T Trandolapril
ISH
: Isolated systolic hypertension
JNC
: Joint National Committee
JUPITER
: Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin
LAVi
: left atrial volume index
LIFE
: Losartan Intervention For Endpoint Reduction in Hypertensives
LV
: left ventricle/left ventricular
LVH
: left ventricular hypertrophy
LVM
: left ventricular mass
MDRD
: Modification of Diet in Renal Disease
MRFIT
: Multiple Risk Factor Intervention Trial
MRI
: magnetic resonance imaging
NORDIL
: The Nordic Diltiazem Intervention study
OC
: oral contraceptive
OD
: organ damage
ONTARGET
: ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial
PAD
: peripheral artery disease
PATHS
: Prevention And Treatment of Hypertension Study
PCI
: percutaneous coronary intervention
PPAR
: peroxisome proliferator-activated receptor
PREVEND
: Prevention of REnal and Vascular ENdstage Disease
PROFESS
: Prevention Regimen for Effectively Avoiding Secondary Strokes
PROGRESS
: Perindopril Protection Against Recurrent Stroke Study
PWV
: pulse wave velocity
QALY
: Quality adjusted life years
RAA
: renin-angiotensin-aldosterone
RAS
: renin-angiotensin system
RCT
: randomized controlled trials
RF
: risk factor
ROADMAP
: Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention
SBP
: systolic blood pressure
SCAST
: Angiotensin-Receptor Blocker Candesartan for Treatment of Acute STroke
SCOPE
: Study on COgnition and Prognosis in the Elderly
SCORE
: Systematic COronary Risk Evaluation
SHEP
: Systolic Hypertension in the Elderly Program
STOP
: Swedish Trials in Old Patients with Hypertension
STOP-2
: The second Swedish Trial in Old Patients with Hypertension
SYSTCHINA
: SYSTolic Hypertension in the Elderly: Chinese trial
SYSTEUR
: SYSTolic Hypertension in Europe
TIA
: transient ischaemic attack
TOHP
: Trials Of Hypertension Prevention
TRANSCEND
: Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease
UKPDS
: United Kingdom Prospective Diabetes Study
VADT
: Veterans' Affairs Diabetes Trial
VALUE
: Valsartan Antihypertensive Long-term Use Evaluation
WHO
: World Health Organization

### 1.1 Principles

The 2013 guidelines on hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology …

/pdf/2013-esh-esc-guidelines-for-the-management-of-arterial-4ydvs5ifsx.pdf

2013 ESH/ESC Guidelines for the management of arterial hypertension: The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

Cardiovascular Health Study Collaborative Research Group : Frailty in older adults : evidence for a phenotype

http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

2007 Guidelines for the Management of Arterial Hypertension : The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).

Abstract 1537: Basal Phosphorylation Of Ca2+ Cycling Proteins By Both PKA And CAMKII is Required For Robust Generation Of Local Subsarcolemmal Ca2+ Releases To Drive Sinoatrial Node Cell Automaticity

Time for primary review 14 days. 

Despite major advances in the understanding of cardiovascular physiology and pathophysiology and the development of new therapies in the 20th century, cardiovascular disease is projected to become the leading overall cause of mortality worldwide within the next couple of decades [1]. In the western world, an increasing proportion of older people in the population accounts for the lack of reduction in the absolute number of cardiovascular deaths, whereas in developing countries, part of the reason is the adoption of “western” lifestyles and their accompanying coronary risk factors as socioeconomic status gradually improves and mortality from infectious and other diseases of early life decrease. There remain significant gaps in our understanding of many aspects of cardiovascular diseases and the contribution of risk factors such as smoking, hypercholesterolaemia, hypertension and diabetes. In addition, increasing numbers of patients who survive ischaemic cardiac disorders develop heart failure.

Traditionally, the focus of research into cardiovascular disease was the heart and myocardium, but in the last several decades, the importance of the vasculature and of other body systems has been better appreciated. The field of vascular biology has blossomed. Traditionally, investigators focused on mechanical function. However, in the last several decades, investigative approaches have broadened dramatically, ranging from molecular and cellular biology and physiology, to in vitro and in vivo studies in animal models of disease, to studies of individual human subjects, to population genetics and epidemiology. The methodologies available and their precision have altered out of all recognition compared to the approaches of 40–50 years ago.

Within this context, the questions that are considered in this article are: How should myocardial performance best be assessed? What are the advantages and disadvantages of currently used methodologies? How far can and should reductionism be pursued? What is the relevance of … 

* Corresponding author. Tel.: +44 1222 742338; Fax: +44 1222 743500; E-mail: shaham2@cf.ac.uk

Physio-pharmacological evaluation of myocardial performance: an integrative approach

The current functional paradigm of sinoatrial node (SAN), the hearts natural pacemaker, postulates the entrainment of full-scale action potentials (APs) at one common frequency and does not involve any subcellular events or subthreshold signals. SAN cells studied in isolation, however, generate subcellular, spontaneous, rhythmic, local Ca2+ releases (LCRs) and, while each LCR is a small, subthreshold signal, the emergent LCR ensemble signal critically contributes to generation of spontaneous APs and accounts for the heterogeneity of AP firing rates of these cells. We hypothesized that cells embedded in SAN tissue also generate heterogeneous subthreshold LCR signals of different rates and amplitudes and that self-organization of the LCRs within and among cells critically contributes to the ignition of APs that emerge from the SAN to excite the heart. To this end we combined immunolabeling with a novel technique to image microscopic Ca2+ dynamics, including both LCRs and AP-induced Ca2+ transients (APCTs) within and among individual pacemaker cells across the entire mouse SAN. Immunolabeling identified a meshwork of HCN4(+)/CX43(-) non-striated cells of different morphologies that extended along the crista terminalis from the superior vena cava to the inferior vena cava, becoming intertwined with a network of striated cells, rich in F-actin and CX43, but devoid of HCN4 immunolabeling. The earliest APCTs within a given pacemaker cycle occurred within a small area of HCN4 meshwork below the superior vena cava, just medial to the crista terminalis. Although subsequent APCT appearance throughout the SAN at low magnification resembled a continuous propagation pattern, higher magnification imaging revealed that APCT appearance at different sites within the SAN was patchy and discontinuous. Both LCR dynamics and APCTs were markedly heterogeneous in amplitudes and frequencies among SAN cells: in some cells, APCT occurrence was preceded by diastolic LCRs occurring in the same cell; other cells did not generate spontaneous APCTs, but had subthreshold LCRs only, which preceded APCT generation by adjacent cells; APCTs of various frequencies were generated steadily or in bursts. In summary, we discovered a novel, microscopic Ca2+ signalling paradigm of SAN operation that could not be detected with low-resolution, macroscopic tissue methods employed in prior studies: synchronized macroscopic signals within the SA node, including full-scale APs, emerge from heterogeneous microscopic subthreshold Ca2+ signals. This multiscale, complex process of impulse generation within the SAN resembles the emergence of organized signals from heterogeneous local signals generated within clusters of neurons within neuronal networks.

https://biorxiv.org/content/10.1101/2020.04.14.039461v1.full.pdf

Synchronized cardiac impulses emerge from multi-scale, heterogeneous local calcium signals within and among cells of heart pacemaker tissue

The world population in both industrialized and developing countries is aging. For example, in the United States, 35 million people are over the age of 65 years, and the number of older Americans is expected to double by the year 2030. The clinical and economic implications of this demographic shift are staggering because age is the most powerful risk factor for cardiovascular diseases (CVDs). The incidence and prevalence of hypertension, coronary artery disease (CAD), congestive heart failure, and stroke, the quintessential diseases of Western society, increase exponentially with age. Although epidemiological studies have discovered that some aspects of lifestyle and genetics are risk factors for these diseases, age, per se, confers the major risk. Thus, it is reasonable to hypothesize that specific pathophysiological mechanisms that underlie these diseases become superimposed on cardiac and vascular substrates that have been modified by an “aging process,” and that the latter modulates disease occurrence and severity. In other words, age-associated changes in cardiovascular structure and function become “partners” with pathophysiological disease mechanisms, lifestyle, and genetics in determining the threshold, severity, and prognosis of CVD occurrence in older persons (Fig. 1).

Aging of the Heart and Arteries

https://www.heartrhythmjournal.com/article/S1547-5271(09)01256-9/pdf

Edward G. Lakatta

Papers

Abstract 1537: Basal Phosphorylation Of Ca2+ Cycling Proteins By Both PKA And CAMKII is Required For Robust Generation Of Local Subsarcolemmal Ca2+ Releases To Drive Sinoatrial Node Cell Automaticity

Physio-pharmacological evaluation of myocardial performance: an integrative approach

Synchronized cardiac impulses emerge from multi-scale, heterogeneous local calcium signals within and among cells of heart pacemaker tissue

Aging of the Heart and Arteries

Yin and yang of the cardiac pacemaker clock system in health and disease