- oxigenare Hb - filtru (particule, bacterii) - eliminarea CO2 – echilibru acido-bazic

CIRCULATIA CIRCULATIA PULMONARA BRONSICA

Sange venos sange arteriala. pulmonara a. bronsiceCapilare Capilare

Vene pulmonare Vene sistemice

CIRCULATIA

PULMONARA NORMALA

PLAMANUL

Sunt fiziologic dr-stg

(pana la 30% din DC)

- bronsiectazii

- fibroza chistica

- boli congenitale

cardio-vasculare

CIRCULATIA BRONSICA

NORMALA SISTEMICE – media 20-25% din diam. vasuluiA. PULMONARE - media < 10- 5% din diam. vasuluiArteriolele pulmonare nu au tunica medie si nu contribuie

la rezistenta vasculara

VD – fluxul coronarian cel mai mare in sistola- depinde de gradientul pres. pulm. – aorta

Pres. VD creste – gradientul scade – fluxul coronar drept scade – ischemie VD

HIPERTENSIUNEA PULMONARA (HTP)

NORMALPRES. A. PULMONARA - sist. 18-25 mm Hg

- diast. 6-10 mm Hg- medie 12-16 mm Hg

PRES V. PULMONARE – 2-10 mm HgREZIST. VASC. PULM. = 1/10 din REZIST. SISTEMICA

HIPERTENSIUNEA PULMONARA (HTP)PRES. A. PULMONARA - sist. > 30-35 mm Hg

- medie > 20-25 mm Hg- diast. > 15 mm Hg

Reducerea calibrului vaselor pulmonare Cresterea fluxului

HIPERTENSIUNEA PULMONARA (HTP)

HIPOXIA VASOCONSTRICTIE PULMONARA

-histamina – receptori H1 vasculari

- endoteliu - echilibru NO – endoteline

- patrunderea Ca 2+ in celula musculara neteda

HIPOXIA CRONICA

1. Extensia musculaturii netede in peretele arterelor din periferia plamanilor

2. Ingrosarea peretilor arterelor musculare

3. Reducerea nr. arterelor – cresterea raportului alveole/artere

REACTIVITATEA VASCULARA PULMONARA

VASOCONSTRICTIEHipoxiaAcidozaProstaglandine F2α si A2

HISTAMINA – H1

SEROTONINA ?ANGIOTENSINA A2

ALTITUDINE

VASODILATATIEAlcalozaPROSTAGLANDINE I2 si EBLOCANTI αSTIMULARE β(ISOPROTERENOL)ACETILCOLINA (prin EDRF)HISTAMINA (prin H2 ?)

INDOMETACIN – creste rezistenta

pulmonara

La 10 000 m altitudine

TA pulmonara medie = 25 mm Hg in repaus

> 50 mm Hg in efort

1. HTP arteriala1.1. Idiopatica1.2. Ereditara1.3. Indusa de droguri si toxine1.4. Asociata cu:

Boli de colagenHIVHipertensiune portalaBoli cardiace congenitaleSchistosomiazaAnemie hemolitica cronica

1.5. HTP persistenta la nou nascut1’ Boala venoocluziva pulmonara si/sau hemangiomatoza capilara pulmonara

CLASIFICAREA HTPDana Point, 2008

2. HTP prin suferinta ventriculului stang

2.1. Disfunctie sistolica

2.2. Disfunctie diastolica

2.3. Boli valvulare

CLASIFICAREA HTPDana Point, 2008

3. HTP prin boli pulmonare sau hipoxie

3.1. BPOC

3.2. Boli interstitiale

3.3. Alte boli cu restrictie si obstructie

3.4. Apneea de somn

3.5. Boli cu hipoventilatie alveolara

3.6. Expunerea cronica la mare altitudine

3.7. Anomalii de dezvoltare fizica

CLASIFICAREA HTPDana Point, 2008

4. HTP prin tromboembolism

5. HTP prin factori multipli neclari

5.1. Boli hematologice: mieloproliferare, hipersplenism

5.2. Boli sistemice: sarcoidoza, histiocitoza pulmonaracu celule Langerhans

5.3. Boli metabolice: B. Gaucher, glicogenoze, disfunctiitiroidiene

5.4. Altele: obstructii tumorale, mediastinita fibrozanta,, IRC sau dializa

CLASIFICAREA HTPDana Point, 2008

In suferinta inimii stangi

PRESIUNE ATRIU STG = 7 mm Hg

scade rezistenta pulmonara (recrutare de vase)

>7 mmHg – creste presiunea in a. pulmonara (fluxul ramane constant; gradientul ramane constant)

> 25 mmHg – crestere disproportionata de presiune in a. pulmonara (gradientul creste; fluxul constant sau scade)

CATEVA MECANISME FIZIOPATOLOGICE

Variabilitatea reactivitatii vasculare pulmonare: creste presiunea venoasa – distrugere sau inchidere de cai

aeriene – hipoxie – creste presiunea in a. pulmonara creste presiunea venoasa – edem interstitial – rigidizarea

vaselor – HTP drenajul limfatic creste starea VD

normal hipertrofic insuficient miopatic (+ VS) hipoperfuzat (infarct)

Volumul sanguin pulmonar (depinde de debitul celor 2 ventriculi si de distensibilitatea vaselor pulmonare)

CATEVA MECANISME FIZIOPATOLOGICE

- Celule endoteliale capilare umflate

- Membrane bazale capilare ingrosate

- Edem interstitial

- Rupturi de membrane bazale – transudare de eritrocite –hemosideroza

- Alveole fibroase

- Destindere de limfatice

MODIFICARI ANATOMICE

Test Notable Findings

Chest x-ray Enlargement of central pulmonary arteries reflects level of PA pressure and duration.

Electrocardiography Right axis deviation and precordial T wave abnormalities are early signs.

Pulmonary function tests Elevated pulmonary artery pressure causes restrictive physiology.

Perfusion lung scan Nonsegmental perfusion abnormalities can occur from severe pulmonary vascular disease.

Chest computed tomography scan Minor interstitial changes may reflect diffuse disease; mosaic perfusion pattern indicates thromboembolism and/or left heart failure.

Echocardiography Right ventricular enlargement will parallel the severity of the pulmonary hypertension.

Contrast echocardiography Minor right to left shunting rarely produces hypoxemia.

Doppler echocardiography This is too unreliable for following serial measurements to monitor therapy.

Exercise testing This is very helpful to assess the efficacy of therapy. Severe exercise-induced hypoxemia should cause consideration of a right-to-left shunt.

TABLE 73-2 -- Clues for Interpretation of Diagnostic Tests for Pulmonary

Hypertension

Toate sunturile sistemico-pulmonare rezultand din mari defecte care duc la cresteri de presiune in VD sila inversarea suntului (pulmonar-sistemic) sau suntbidirectional cu: cianoza, eritrocitoza si multiple suferinte de organ

SINDROM EISENMENGER

GR. I : hipertrofia mediei artereor mici musculare

GR. II : + proliferarea intimei

GR. III: + fibroza concentrica cu obliterare de vase

GR. IV: “leziuni plexiforme”, dilatatii, trombi

GR. V: complexe plexiforme, leziuni angiomatoase si cavernoase si hialinizaea fibrozei intimale

GR. VI: arterita necrozanta

MODIFICARI ANATOMICE

Histopathology of endothelial cell lesions in

IPAH. A. Pulmonary artery showing medial

hypertrophy and lined by a single layer of

endothelial cells, as outlined by Factor VIII

related antigen immunostaining (arrow).

Plexiform lesion (outlined by the rim of

arrowheads) with the proximal vascular arterial

segment with marked intimal and medial

thickening by smooth muscle cells (arrow). Note

the proliferation of endothelial cells with the

outer edge (3–5 o’clock) occupied by dilated

blood vessel-like structures. C. Cross section of

a plexiform lesion, outlined by arrowheads. Note

perilesional inflammatory infiltrate (arrow). D.

High magnification histology of plexiform lesions

shown slit-like vascular channels lined by

hyperchromatic and cuboidal endothelial cells.

Cells in the core do not display distinct

cytoplamic borders. E. Low magnification

immunohistology with Factor VIII related antigen

immunohistochemistry of different endothelial

cell based vascular lesions. This area has re-

vascularized lesions (possibly an organized

thrombus), with well-formed and distinct small

capillaries/vessels (arrowhead), a plexiform

lesion (arrow), and dilated/angiomatoid lesions

(between arrowheads). F. High magnification

immunohistology of cellular plexiform lesion

stained with Factor VIII related antigen

(arrowheads). G and H. Histological

identification of plexiform and dilation lesions (G)

is markedly improved by Factor VIII related

antigen immunohistochemistry (H)

(arrowheads), while the parent vessel (arrow)

shows mild medial remodeling. I. Highlight of

vascular dilation/angiomatoid lesions with Factor

VIII related antigen immunohistochemistry. J.

Endothelial cells in plexiform lesion is

highlighted by CD34 immunohisochemistry

(arrowheads). Proximal pulmonary artery with

marked intima and medial thickening is

highlighted by the arrow. K and I. Endothelial

cells are highlighted by CD31

immunohistochemistyr (arrowheads). Note that

capillary endothelial cells express CD31 as well

(arrow in I),

A. Fibrotic, relatively paucicellular

intima thickening (outlined by

arrowheads) in a pulmonary artery

with the media highlighted with the

arrow. B. Marked intima remodeling

with almost complete obliteration by

fibrous tissue with a marked

intravascular and perivascular

inflammatory infiltrate (arrows). C.

Smooth muscle cell hypertrophy, with

prominent thickening of medial layer

(arrow). D. Highlight of medial

hypertrophy with smooth muscle α

actin immunohistochemistry. E.

Markedly remodeled pulmonary artery

with endothelial cell layer highlighted

by Factor VIII related antigen

immunohistochemistry. Note that the

intima and medial smooth muscle

cells are negative for Factor VIII

related antigen reactivity. F. Ingrowth

of smooth muscle cells in a plexiform

lesions, highlighted by smooth

muscle cell α actin

immunohistochemistry (arrow).

Veno-occlusive PH. A. Low-power histological view of thickened pulmonary veins running into the lung parenchyma from the

pleural surface (left edge) (arrows). Note marked vein wall thickening and decreased lumen. Adjacent alveoli are filled with blood

and show septal thickening with engorged capillaries (arrowhead). B. Marked vein thickening with intimal projection probably

representing organized thrombus (arrow). Alveolar hemorrhage and septal thickening are highlighted with arrowhead. C and D.

Movat stained pulmonary vein showing arterialization pattern with internal and external elastic layers (arrow). The vein shows

marked intima thickening with organized thrombus (arrowheads).

Normal Flux crescut in lobii inferiori

Gravitatie

Presiuni diferite intra –alveolare

Raport A/B = 1,2 : 1

CRESTEREA FLUXULUI PULMONARFLUX - Φ VASE x 8 (rezerva) +

Φ vase - flux + presiune

- presiune

Creste Φ venos

Rx – 1/3 ext. vascularizata

- Circ. Inf = circ. sup.

N – Φ a. pulm. desc. dr. = 10-15 mm la barbati si 9-14 mm la femei

Rx în HTP

HTP arteriala

- vasoconstrictie periferica

- vasospasm

- ingrosarea peretelui vascular

Rx- scade circulatia (creste transparenta) in 1/3 ext.

- vasele centrale elastice se largesc

- calcificari ale vaselor centrale

Rx în HTP

HTP de origine venoasa

P venoasa > 8 – 12 mm Hg

fluxul pulmonar este redistribuit spre lobii superiori

Rx – inversare a aspectului normal (cefalizarea fluxului arterial si venos)

P venoasa > 25 mm Hg Edem pulmonar

Rx în HTP

Mecanisme Sechestrarea de lichid interstitial in lobii inferiori

↓ Presiunea interstitiala ↑

↓ Complianta pulmonara ↓

↓ Fluxul spre lobii inferiori ↓

+ Spasm arterial

Fluxul este redistribuit spre lobii superiori

Rx în HTP

ETIOLOGIE Embolism pulmonar recurent, asimptomatic

Embolism amniotic

Tromboza in situ, tulburari de coagulare si fibrinoliza , contraceptive

Vasoconstrictie cronica → necroza fibrinoida → leziuni plexiforme

Vasculita generala cu fenomen Raynaud

Hipersensibilitate la droguri

Ingestia de fumarat de aminorex (anorexigen)

Hormoni feminini

HTP IDIOPATICA

MODIFICARI HISTOLOGICE Ingrosarea intimala a a. mici si arteriole cu fibroza in

“foi de ceapa”

Ingrosarea mediei a. musculare si muscularizarea arteriolelor

Arterita necrozanta cu necroza fibrinoida

Leziuni plexiforme → arteriopatie pulmonara plexogenica → umbre vasculare → reducerea patului vascular

HTP IDIOPATICA

HIPOXIE → raspuns anormal → disfunctie endoteliala

Modificarea raportului EDRF - endoteline

Distrugeri de endoteliu

Tromboza

Vasoconstrictie → necroza fibrinoida

Leziuni plexiforme

HTP IDIOPATICA

ASPECTE CLINICE

Femei tinere4 simptome principale

Dispnee de efort Accentuarea zgomotului II Modificari Rx – cardiomegalie

- a. pulmonara proeminenta Modificari ECG : - HVD

- deviatie axiala dr.- HAD

Mai rar:- Ameteli si sincope de efort- Dureri toracice de efort- Edeme

- Fenomene Raynaud- Ciroza hepatica- Istoric de tromboflebita superficiala

HTP IDIOPATICA

PROGNOSTIC

Prost (supravietuire peste 5 ani – 21%) Anticoagulantele imbunatatesc prognosticul

MOARTEA Insuficienta cardiaca congestiva Pneumonie Moarte subita Moarte la cateterism Disectie de a pulmonara

HEMOPTIZIA IN STADII TARDIVE Ruptura de leziuni plexiforme Tromboze in situ Embolism pulmonar

DUREREA TORACICA Ischemia subendocardului VD Distensia a pulmonare

HTP IDIOPATICA

SEMNE CLINICE Zgomot II intarit la pulmonara Suflu sistolic la pulmonara Semne de insuficienta cardiaca dreapta Semne de regurgitare triscuspidiana Cianoza - tardiv prin deschidere de foramen ovale Paralizie de recurent (rara)

HTP IDIOPATICA

LABORATOR - Uneori defecte de coagulare si fibrinoliza

ECG: HVD, HAD

Rx: largirea a pulmonare; marirea atriului si ventriculului dr

CT – Φ a pulmonare

TESTE FUNCTIONALE - Disfunctie restrictiva

ECHOCARDIOGRAFIAMarirea atriului si ventriculului dreptCavitati stangi normaleIngrosarea septuluiRegurgitare tricuspidiana si prolaps de valva mitrala secundare dilatatiei

de VD

HTP IDIOPATICA

SCINTIGRAFIA PULMONARA - normala

In stadii avansate poate fi daunatoare – trasorul legat de albumina –procoagulant

CATETERISMUL CARDIAC SI ANGIOGRAFIA RISCANTE

Presiunea in VD egala sau chiar mai mare decit presiunea sistemica

Rezistenta vasculara pulmonara depaseste uneori pe cea sistemica

Uneori foramen ovale este patent

Presiunile stg. sunt normale sau mici, dar uneori greu de determinat

BIOPSIA PULMONARA

HTP IDIOPATICA

HTP IDIOPATICA

DIAGNOSTIC DIFERENTIALHTP secundara (mai benigna si mai tratabila)

In sala de cateterism cardiac

PAPm dupa administrarea de NO inhalator (sau adenozina iv, epoprostenol iv sau inhalator)

Test + = reducerea cu 20% a PAPm sau a rezistentei vasculare pulmonare – bolnavul va primi vasodilatator indelungat

TESTUL VASODILATATOR

Supravietuirea medie in HTP netratata = 2,8 aniFactori de prognostic:Varsta < 14 ani sau 65 ani – prognostic prostClasa NYHA: I – II: supravietuire 6 ani in medie

III: supravietuire 2,5 ani in medieIV: supravietuire 0,5 ani in medie

Scaderea capacitatii de efortSincopaHemoptizieSemne de insuficienta ventriculara dreaptaO2 in a pulmonara > 63 – 55% supravietuire la 5 ani

< 63 – 17% supravietuire la 5 aniIndexul cardiac < 2,1 l/min/m2 supravietuire medie 17 luniPresiunea in AD < 10 mmHg - supravietuire 4 ani in medie

> 20 mmHg - supravietuire medie o lunaTest de vasodilatatie negativ

PROGNOSTICUL

1. Anticoagulantele

Warfarina dubleaza supravietuirea in HPP

Indicatiile anticoagularii permanente: toti pacientii cu HTPI

Tromboembolismul pulmonar (INR = 2-3)

HTP secundare, daca nu exista contraindicatii

2. OxigenoterapiaSe recomanda monitorizarea Sat O2 nocturna, Sat O2 < 90% in aerul atmosferic corectabila la administrarea de O2, indica oxigenoterapia nocturna

3. Tratamentul insuficientei ventriculare drepte:- Diuretice

- Digoxinul creste DC in administrarea acuta in HTPI, efectul sau in administrarea cronica este discutabil

TRATAMENTUL MEDICAL

4. Tratamentul vasodilatatorAntagonistii de Ca (diltiazem sau nifedipina):

HTP de tip arterial cu test vasodilatator pozitiv

CI in : HTP venoasa (precipita EPA)

HTP hipoxica din bolile cronice pulmonare cu Sat O2 in sangele venos < 63% (agraveaza hipoxemia)

PAD > 10 mm Hg

Index cardiac < 2,1 l/min/m2

TRATAMENTUL MEDICAL

Responders: Ca.-blockers

(if bradicardic)

Nifedipine :120 -240 mg

(if tahicardic)

Diltiazem 240-720 mg

Begin low dosage , increase weekly

Less than ½ of pts tolerate maximum dosage

5. Prostaglandinele – efectele pozitive ale tratamentului indelungat (min 3 luni)Reducerea rezistentei vasculare pulmonare

Cresterea indexului cardiac

Dublarea supravietuirii la 5 ani

Reducerea riscului si ameliorarea evolutiei dupa transplantul pulmonar

TRATAMENTUL MEDICAL (PG)

Indicatii

Bolnavii cu ICC cl III – IV, index cardiac < 2,1 l/min/m2 si/sau Sat O2 in artera pulmonara < 63% si/sau PAD > 10 mmHg, indiferent de testul vasodilatator

Toti bolnavii care nu raspund la tratamentul medical conventional, in asteptarea transplantului pulmonar

TRATAMENTUL MEDICAL

Efecte adverse:

Diaree, dureri abdominale, cefalee, flush, artralgii, dureri musculare

Ascita, edem pumonar (prin cresterea permeabilitatii vasculare)

Toleranta ce necesita cresterea dozelor

Rebound al HTP la intreruperea brusca a tratamentului

Infectii de cateter

TRATAMENTUL MEDICAL (PG)

Preparate folosite:

Epoprostenol = PGI2 iv. Se incepe cu 2 ng/kc/min in pev continua si se creste doza dupa o saptamana pana la doza maxima tolerata de pacient

Iloprost = analog al epoprostenolului, mai puternic iv (pev continua) sau in aerosoli, 6-9 inhalatii/zi (50 -200 μg/zi)

Trepostenil (UT – 15) este analog de PGI2. Doza initiala este de 1,25 ng/kc/min si se creste cu 1,25 ng/kc/min la 7 zile pana la 9,3 ng/kc/min

TRATAMENTUL MEDICAL (PG)

Beraprost: derivat stabil de PGI2, poate fi adminisrat p.o. 1 tb = 20μg. Se incepe cu 1 tb/zi si dupa 6 saptamani de titrare, se ajunge la 6 tb/zi (studiul ALPHABET). Rezultate bune in HTPI, neconcludente in HTP sec. Se pare ca nu este eficient in stadiile avansate de boala.

TRATAMENTUL MEDICAL (PG)

Prostanoid analogues

CTD= boala de tesut conjunctiv

Epoprostenolshort HL, temp.-dependent , i- v (infusion pump ) , local facilities

2-4ng/kg/min ..20-40 ( tolerance , rebound , adverse reactions: common)

>100.000 $ /year

Rubin LJ Ann. Intern.Med. 1990;112:485-92

Barst RJ N.Engl. J Med 1996;334:296-304

Badesch DB Ann. Intern.Med. 2000;132:425-34

3 month results: indic. surv/altern

Conversion to oral agents ??

Treprostenilsufficient chemical stability to be

administered at ambient temperature

allow iv / subcutaneous /oral ( bid )

and inhalatory adm.(6-9 d )

Beraprost

Orally :40-80microg qid/zi

efficacy does not appear to be sustained

with extended duration of therapy

Iloprost

Inhalations 6-12 times/d

(20-40 microg/d.)

Advant: selective to pulm.circ.

J Am CollCardiol. 2003 Jun 18;41(12): 2119–25

6. Antagonistii receptorilor de endotelinaBosentan (ET1RA) po. Doze: 62,5 mg de 2 ori/zi, pana la 125 mg de 2 ori/zi, timp de 16 saptamani.

TRATAMENTUL MEDICAL (ARE)

Endothelin receptor antagonists

Type A receptor :

vasoconstriction, proliferation, fibrosis.

Type B receptor (endotelial):

increases the synthesis of nitric oxide

( vasodilation )

Type B receptor (SMC):

activates aldosterone,

thromboxane, norepinephrine.

( vasoconstriction )

Bosentan ( Tracleer ) available in Romaniadual ETA and ETB-receptor antagonist

125 mg bid BREATHE-1BREATHE-3 (children )

10% liver enzimes > BREATHE -5 EARLY

Sitaxsentan6500 times greater affinity for the ETA STRIDE I and II

Chest , 2008; 134(4): 775 - 782.100-300 mg od 2004 : Level of evidence : BIncl .HTP in congenitals/CTD aproved in EuropeWarfarine interference

Ambrisentan ARIES-2 . Am J Respir Cirt Care Med. 2006;173: lower incidence of liver enzyme abnormality Ann. Pharmacother, 2008; 42(11): 1653 absence of significant drug interactions -

2004 : Level of evidence : C

7. Inhibitori de fosfodiesteraza (Sildenafil)

TRATAMENTUL MEDICAL (IFD)

Phosphodiesterase inhibitors

Sildenafil ( REVATIO )

25 mg t.i.d.

Available in Romania

Humbert M N Engl J Med 2004;351: 1425–36.

Type 5 Phosphodiesterase inhibitors

Vardenafil HCL ( Levitra ) Br J Pharmacol., 154(4):787-96. 2008 Apr 21

Tadalafil ( Cialis )longer half-life (17.50 hours )marketing approval began in late 2008

J Am Coll Cardiol, 2004; 44:1488-1496 Circulation. 2004;110:3149-3155

The three PDE5 inhibitors differ markedly in :

kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil) selectivity for the pulmonary circulation (sildenafil and tadalafil, but

not vardenafil),

impact on arterial oxygenation (improvement with sildenafil only).

Septostomie atriala. Procedeu paleativ ce scade presiunea

in inima dreapta.

Indicatii: HTP severa, care nu raspunde la prostaglandine

Se exclud pacientii cu Insuf Ventr dr severa, disfunctie de VS sau in stare critica

Trombendarterectomie

Transplant pulmonar

TRATAMENTE CHIRURGICALE

Indicatii transplant

HTPI simptomatica, progresiva in ciuda tratamentului medical optim, cu test de mers de 6 min < 400 m, cu index cardiac < 2,1 l/min/m2 si/sau Sat O2 in artera pulmonara < 63% si/sau PAD > 10 mm Hg sau PAP m > 55 mmHg

TRATAMENTE CHIRURGICALE

Test vasodilatator acut

Raspuns +

Sv O2>63%, IC > 2,1

Raspuns -

NYHA I/II, Sv O2>63%,

IC > 2,1

NYHA III/IV, Sv O2<63%,

IC < 2,1

Blocanti de CaNu raspund la tratament

Prostaglandine

+/- transplant

Warfarina + diuretic + digoxin

Frequently asked questions

At which level of pulm .pressure should we begin pharmacological treatment in sec. PHT ?Adapted to etiology ! Unknown borderline !

Is it harmful to use CCB in nonresponders ?Yes , at least for high doses

ACCP Gd.: Level of evidence: expert opinion; benefit: substantial;

grade of recommendation: E/A.

Would it be better to use the more active drugsfor responders also ?

Probably yes , but economically unwise

Frequently asked questions

How useful is multiple drug therapy

Which order of introduction /doses ?

BREATHE -2

Is atrial septostomy an option ?

Rarely (bridge to… ) ; 5-15% mortality

CONCLUSIONS

PPHT pts to be treated in dedicated centers

New therapies available ; debate on results

Combination therapy in developpement

Rapid change of recomandations /guidelines

Cost –effectiveness analysis vital

Hard end points-including mortality may be influenced